Case Report Dermatology 1992; 185:281-283
Department of Dermatology. Kobe Univer sity School of Medicine, Kobe. Japan
Key Words Acute (cutaneous) graft-versus-host disease Allogeneic bone marrow transplantation
Acute Follicular Graft-versus-Host Disease
Abstract We documented by clinical, histopathologic and immunohistochemical analysis a case of acute follicular graft-versus-host disease (GVHD), in which an erythematous-to-violaceous follicular papular eruption constituted the major clin ical pattern of cutaneous involvement. Although acute follicular GVHD is rare, it is important to recognize it as an early skin manifestation of acute cutaneous GVHD allowing prompt therapy.
Graft-versus-host disease (GVHD) is an often lethal complication of bone marrow transplantation (BMT) [1). The acute form of the disease predominantly affects the skin, liver and gastrointestinal tract. In acute GVHD, the skin biopsy may be an important diagnostic procedure because most patients have skin lesions in conjunction with internal organ involvement and the skin is often the initial site of involvement [2,3], The first recognizable visible skin changes in acute cutaneous GVHD arc maculopapular or scarlatiniform rashes. In severe cases, these rashes develop into toxic-epidermal-necrolysis-like form of acute cuta neous GVHD [4], Recently, Friedman et al. [5] have reported unusual cases of acute cutaneous GVHD follow ing allogeneic BMT in which erythematous-to-violaceous follicular papules constituted a major clinical pattern of cutaneous involvement. We present here another case of acute follicular GVHD documented by clinical, histopath ologic and immunohistochemical analysis.
Case Report A 5-year-old boy suffering from aplastic anemia was treated with an HLA-matched allogncneic BMT following preparation with cyclo phosphamide (50 mg/kg/day on days-5 to -2). antihuman lymphocyte globulin (65 mg/kg/day on days -5 to -3) and total lymph node irradi ation (3.75 Gy/day on days -3 and -2). Cyclosporin A (5.0 mg/kg/day) was administered since day -1. The patient received methotrexate.
Received: April 21. 1992 Accepted: June 24, 1992
15 mg/m' on day 1. and 10 mg/trf on days 3. 6 and 11. On day 32 after the BM P. we saw the patient for the evaluation of a follicular papular eruption on the abdomen and legs, which had begun on day 25. There were multiple, discrete, follicular, violaceous papules with central hyperkeratosis, measuring 1-3 mm in diameter, scattered on the abdo men and extensor surfaces of both legs (fig. 1). The skin on the exten sor surfaces of the legs also showed ichthyosis vulgaris-likc scales. A biopsy specimen of a follicular papule disclosed focal basal cell vacuo lization with a sparse mononuclear cell infiltration and individual necrotic epithelial cells in the basal layer of follicular epithelium as well as the intcrfollicular epidermis (fig.2. 3). These changes were consistent with a grade 2 acute cutaneous graft-versus-host reaction (GVHR). Intranuclear or intracytoplasmic inclusions suggestive of cytomegalovirus (CMV) infection were not identified within histio cytes nor vascular endothelial cells in the dermis. Cytomegalic vasculi tis of small vessels within the dermis was not seen, either. Immuno histochemical studies were performed on unfixed frozen sections from a follicular papule using a peroxidase-antiperoxidase technique. Mono clonal anti-Leu 3a (CD 4). anti-Leu 2a (CD 8). and anti-HLA-DR antibodies were purchased from Becton-Dickinson. Mountain View. Calif.. USA. This showed focal expression of HLA-DR antigen on the surfaces of basal and suprabasal epithelial cells of follicular epithelium and intcrfollicular epidermis. A; the dermoepidermal junction and in the papillary dermis, an infiltrate with large number of suppressor/ cytotoxic T cells (CD 4/CD 8. 2.0) was present. At the same time, liver transaminase (glutamate oxaloacetate transaminase, 58 IU/I. and glu tamate pyruvate transaminase, 49 IU/1). and lactate dehydrogenase (1,141 IU/I) levels became elevated. The patient had had diarrhea with five to seven loose watery stools a day. On day 41 after the BMT. the patient developed cough and dys pnea. A roentgenogram of the chest disclosed severe interstitial pneu monitis. Despite intensive care, he died on day 54.
Masahiro Tani, MI) Department of Dermatology Kobe University School of Medicine 5 Kusunoki-cho. 7 chome C’huo-ku. Kobe 650 (Japan)
© 1992 Karger AG, Basel 1018-8665/92/1854-0281 $2.75/0
Downloaded by: UCL 144.82.238.225 - 2/6/2018 9:18:00 AM
M. Tani A. Adachi
Fig. 2. Histopathology of a follicular papule. There is a dilated hair follicle containing a keratctic plug. At the dcrmoepidermal junc tion and in the papillary dermis, a sparse infiltrate of mononuclear cells is present. HE. x90.
Fig. 1. Scattered violaceous follicular papules on extensor surface of the left leg. Inset: close-up of follicular papules.
Discussion
282
Tani/Adachi
Fig. 3. Basal cell vacuolization and an individual necrotic epithe lial cell (arrow) of a follicular epithelium. HE. x 180.
satellitosis. is not uncommon [2], it is rare that an crythematous-to-violaceous follicular papular eruption develops as a major clinical presentation of acute cutaneous GVHD. We are aware of only 5 similar cases that have been reported previously [5, 7], However, it is important to rec ognize that the follicular papular eruption is a skin manifes tation of acute cutaneous GVHD. The patient received cyclophosphamide, anti-lympho cyte globulin, total lymph node irradiation and cyclosporin A prior to the BMT. and methotrexate and cyclosporin A after the BMT. The histopathologic differentiation between an acute cutaneous GVHD and a toxic drug reac-
Acute Follicular GVHD
Downloaded by: UCL 144.82.238.225 - 2/6/2018 9:18:00 AM
Since acute GVHD is a potentially life-threatening disorder in BMT patients [1], the early diagnosis and prompt therapy for acute GVHD may be necessary to pre vent progression of the condition. The skin is frequently the initial site of involvement in acute GVHD [2. 3], Saurat and Gluckman [6] have shown long before the report of Friedman et al. [5] that, in 2 cases of GVHD. follicular pap ules developed on days 62 and 120 after BMT, respectively. The follicular papules occurred after maculopapular or scarlatiniform rash as a cutaneous sign of acute G VH R had subsided. Therefore, these follicular papules would be bet ter classified as a subacute or early chronic cutaneous GVHR of lichen planopilaris type. On the other hand, the follicular rash in acute follicular GVHD appears prior to the development of the maculopapular or scarlatiniform rash, or both patterns occurred simultaneously [5, 7|. This suggests that the follicular papules in acute follicular GVHD may be an early cutaneous manifestation of acute cutaneous GVHD. Although histopathologic involvement of follicular epithelium by features similar to those found within the epidermis in acute cutaneous GV HR. namely basal cell vacuolization with or without a mild mononuclear cell infiltration, individual necrotic epithelial cells, and
tion is difficult [3]. Pallcr et al. [8] have shown a clear pat tern of transformation of the dermal infiltrate from a pre dominant helper T cell infiltrate with a high CD 4/C'D 8 ratio (>5.0) to an infiltrate with large number of cytotoxic T cells (CD 4/CD 8. 0.8 to 3.0) in all allogeneic patients with acute GVHD who were followed up sequentially. On the other hand, lcsional skin from allogeneic patients with drug reactions showed a high CD 4/CD 8 ratio (7.5 to 42) [8]. The low CD 4/CD 8 ratio (2.0) and HI.A-DR+ keratinocytes in our patient’s cutaneous lesion is therefore com patible with acute cutaneous GVHD. rather than drug eruption. The patient developed interstitial pneumonitis which might be induced by CMV infection. However, it is unlikely that this viral infection played a major role in the development of the follicular papules; viral infection had been implicated in the induction of syngeneic GVHD [9]. Careful examination of the biopsy specimen disclosed no histopathologic findings suggestive of CMV infection. CMV infection with cutaneous manifestations is rare, although a few case reports of cutaneous CMV infection may not accurately reflect the true incidence [ 10]. Clinical features of the reported cases of cutaneous CMV infection are variable. Ulcers, nodules, morbilliform and maculopa-
pular eruptions, verrucous or indurated plaques, vesicles, petechiae, and purpura may all be presenting signs [10]. However, the follicular papular eruption seen in our case has not been reported in cutaneous CMV infection. On the other hand, it is thought that CMV interstitial pneumonitis in allogeneic transplant recipients is an immunopathological condition and that a host immune response is required for the induction of pneumonitis |l l | . Thus, interstitial pneumonitis in allogeneic transplant recipients may be a clinical manifestation of GVHD. Although the 3 patients reported by Friedman et al. [5], 2 by Lycka and Kaye [7] and our patient who had acute follicular GVI ID all died, it is still unknown if acute follicular GVHD may indicate a more severe course than other types of acute cutaneous GVHD [5, 7], Sale et al. 112] and Murphy et al. [13] have demon strated predilection of acute GVHD for the rcte ridges and hair follicles, and suggested that the stem cells at the tip of epidermal rete ridges (14] and in the bulge area of hair fol licles ¡15] may be the targets in cutaneous GVHD. It remains to be understood why erythematous-to-violaceous follicular papules still represent a rare clinical pattern of acute cutaneous GVHD.
References 6 Saurai JH. Gluckman E: l.iehen-planus-like eruption following bone marrow transplanta tion. A manifestation of the graft-versus-host disease. Clin Exp Dermatol 1977:2:335-344. 7 Lyeka BAS. Kaye VN: Acute follicular graftvs-host disease. Arch Dermatol 1988:124: 1442. 8 Pallet AS. Nelson A. Steffen L. Gottschalk I.. Kaizer H: T-lymphocytc subsets in the lcsional skin of allogeneic and autologous bone marrow transplant patients. Arch Dermatol 1988:124: 1795-1801. 9 Gluckman E. Devergie A. Solder.I. Saurai JH: Graft-versus-host disease in recipients of syngeneic bone marrow. Lancet I980:i: 25.3-254. 10 Toomc BK. Bowers KE. Scott G A : Diagnosis of cutaneous cytomegalovirus infection. A review and report of a ease. J Am Acad Der matol 1991:24:857-863. 11 Grundy .IE. Shanley .ID. Griffiths PD: Is cyto megalovirus interstitial pneumonitis in trans plant recipients an immunopathologieal condi tion? Lancet 1987;ii:996-999.
12 Sale GE. Shulman 11M. Gallucei BB. Thomas ED: Young rete ridge kératinocytes are pre ferred targets in cutaneous graft-versus-host disease. Am .1 Pathol 1985;118:278-287. 13 Murphy GF. Lavkcr RM. Whitaker D. Korngold R: Cytotoxic folliculitis in GvIlD. Evi dence of follicular stem cell injury and recov ery. JC u tan Pathol 1991:18:309-314. 14 Lavkcr RM. Sun TT: 1letcrogcneity in epider mal basal kératinocytes. Morphological and functional correlations. Science 1982:215: 1239-1241. 15 Colsarelis G. Sun IT. Lavkcr RM: Labelretaining cells reside in the bulge area of piloscbaccous unit. Implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990:61:1329-1337.
28.3
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1 Glucksbcrg H. Storb R. Fefer A. Buckner CD. Neiman PH. Clil't RA. I.erner KG. Thomas ED: Clinical manifestations of grafl-versushost disease in human recipients of marrow from HI.-A-matched sibling donors. Trans plantation 1974; 18:295-304. 2 Lcrncr KG. Kao GF. Storb R. Buckner CD. Clift RA. Thomas HD: Histopathology of graft-vs.-host reaction (GvFIR) in human recipients of marrow from HL-A-malched sibling donors. Transplant Proc 1974:4: 367- .371. 3 Sale G E. Lcrncr KG. Barker EA. Shulman HM. Thomas ED: The skin biopsy in the diag nosis of acute graft-versus-host disease in man. Am .1 Pathol 1977:89:621-636. 4 Hood AF. Sotcr NA. Rappeport .1. Gigli I: Graft-versus-host reaction. Cutaneous mani festations following bone marrow transplanta tion. Arch Dermatol 1977:113:1087-1091. 5 Friedman KJ. LeBoit PE. Farmer HR: Acute follicular graft-vs-hosl reaction. A distinct clinicopathologic presentation. Arch Dermatol 1988:124:688-691.
Department of Dermatology. Kobe Univer sity School of Medicine, Kobe. Japan
Key Words Acute (cutaneous) graft-versus-host disease Allogeneic bone marrow transplantation
Acute Follicular Graft-versus-Host Disease
Abstract We documented by clinical, histopathologic and immunohistochemical analysis a case of acute follicular graft-versus-host disease (GVHD), in which an erythematous-to-violaceous follicular papular eruption constituted the major clin ical pattern of cutaneous involvement. Although acute follicular GVHD is rare, it is important to recognize it as an early skin manifestation of acute cutaneous GVHD allowing prompt therapy.
Graft-versus-host disease (GVHD) is an often lethal complication of bone marrow transplantation (BMT) [1). The acute form of the disease predominantly affects the skin, liver and gastrointestinal tract. In acute GVHD, the skin biopsy may be an important diagnostic procedure because most patients have skin lesions in conjunction with internal organ involvement and the skin is often the initial site of involvement [2,3], The first recognizable visible skin changes in acute cutaneous GVHD arc maculopapular or scarlatiniform rashes. In severe cases, these rashes develop into toxic-epidermal-necrolysis-like form of acute cuta neous GVHD [4], Recently, Friedman et al. [5] have reported unusual cases of acute cutaneous GVHD follow ing allogeneic BMT in which erythematous-to-violaceous follicular papules constituted a major clinical pattern of cutaneous involvement. We present here another case of acute follicular GVHD documented by clinical, histopath ologic and immunohistochemical analysis.
Case Report A 5-year-old boy suffering from aplastic anemia was treated with an HLA-matched allogncneic BMT following preparation with cyclo phosphamide (50 mg/kg/day on days-5 to -2). antihuman lymphocyte globulin (65 mg/kg/day on days -5 to -3) and total lymph node irradi ation (3.75 Gy/day on days -3 and -2). Cyclosporin A (5.0 mg/kg/day) was administered since day -1. The patient received methotrexate.
Received: April 21. 1992 Accepted: June 24, 1992
15 mg/m' on day 1. and 10 mg/trf on days 3. 6 and 11. On day 32 after the BM P. we saw the patient for the evaluation of a follicular papular eruption on the abdomen and legs, which had begun on day 25. There were multiple, discrete, follicular, violaceous papules with central hyperkeratosis, measuring 1-3 mm in diameter, scattered on the abdo men and extensor surfaces of both legs (fig. 1). The skin on the exten sor surfaces of the legs also showed ichthyosis vulgaris-likc scales. A biopsy specimen of a follicular papule disclosed focal basal cell vacuo lization with a sparse mononuclear cell infiltration and individual necrotic epithelial cells in the basal layer of follicular epithelium as well as the intcrfollicular epidermis (fig.2. 3). These changes were consistent with a grade 2 acute cutaneous graft-versus-host reaction (GVHR). Intranuclear or intracytoplasmic inclusions suggestive of cytomegalovirus (CMV) infection were not identified within histio cytes nor vascular endothelial cells in the dermis. Cytomegalic vasculi tis of small vessels within the dermis was not seen, either. Immuno histochemical studies were performed on unfixed frozen sections from a follicular papule using a peroxidase-antiperoxidase technique. Mono clonal anti-Leu 3a (CD 4). anti-Leu 2a (CD 8). and anti-HLA-DR antibodies were purchased from Becton-Dickinson. Mountain View. Calif.. USA. This showed focal expression of HLA-DR antigen on the surfaces of basal and suprabasal epithelial cells of follicular epithelium and intcrfollicular epidermis. A; the dermoepidermal junction and in the papillary dermis, an infiltrate with large number of suppressor/ cytotoxic T cells (CD 4/CD 8. 2.0) was present. At the same time, liver transaminase (glutamate oxaloacetate transaminase, 58 IU/I. and glu tamate pyruvate transaminase, 49 IU/1). and lactate dehydrogenase (1,141 IU/I) levels became elevated. The patient had had diarrhea with five to seven loose watery stools a day. On day 41 after the BMT. the patient developed cough and dys pnea. A roentgenogram of the chest disclosed severe interstitial pneu monitis. Despite intensive care, he died on day 54.
Masahiro Tani, MI) Department of Dermatology Kobe University School of Medicine 5 Kusunoki-cho. 7 chome C’huo-ku. Kobe 650 (Japan)
© 1992 Karger AG, Basel 1018-8665/92/1854-0281 $2.75/0
Downloaded by: UCL 144.82.238.225 - 2/6/2018 9:18:00 AM
M. Tani A. Adachi
Fig. 2. Histopathology of a follicular papule. There is a dilated hair follicle containing a keratctic plug. At the dcrmoepidermal junc tion and in the papillary dermis, a sparse infiltrate of mononuclear cells is present. HE. x90.
Fig. 1. Scattered violaceous follicular papules on extensor surface of the left leg. Inset: close-up of follicular papules.
Discussion
282
Tani/Adachi
Fig. 3. Basal cell vacuolization and an individual necrotic epithe lial cell (arrow) of a follicular epithelium. HE. x 180.
satellitosis. is not uncommon [2], it is rare that an crythematous-to-violaceous follicular papular eruption develops as a major clinical presentation of acute cutaneous GVHD. We are aware of only 5 similar cases that have been reported previously [5, 7], However, it is important to rec ognize that the follicular papular eruption is a skin manifes tation of acute cutaneous GVHD. The patient received cyclophosphamide, anti-lympho cyte globulin, total lymph node irradiation and cyclosporin A prior to the BMT. and methotrexate and cyclosporin A after the BMT. The histopathologic differentiation between an acute cutaneous GVHD and a toxic drug reac-
Acute Follicular GVHD
Downloaded by: UCL 144.82.238.225 - 2/6/2018 9:18:00 AM
Since acute GVHD is a potentially life-threatening disorder in BMT patients [1], the early diagnosis and prompt therapy for acute GVHD may be necessary to pre vent progression of the condition. The skin is frequently the initial site of involvement in acute GVHD [2. 3], Saurat and Gluckman [6] have shown long before the report of Friedman et al. [5] that, in 2 cases of GVHD. follicular pap ules developed on days 62 and 120 after BMT, respectively. The follicular papules occurred after maculopapular or scarlatiniform rash as a cutaneous sign of acute G VH R had subsided. Therefore, these follicular papules would be bet ter classified as a subacute or early chronic cutaneous GVHR of lichen planopilaris type. On the other hand, the follicular rash in acute follicular GVHD appears prior to the development of the maculopapular or scarlatiniform rash, or both patterns occurred simultaneously [5, 7|. This suggests that the follicular papules in acute follicular GVHD may be an early cutaneous manifestation of acute cutaneous GVHD. Although histopathologic involvement of follicular epithelium by features similar to those found within the epidermis in acute cutaneous GV HR. namely basal cell vacuolization with or without a mild mononuclear cell infiltration, individual necrotic epithelial cells, and
tion is difficult [3]. Pallcr et al. [8] have shown a clear pat tern of transformation of the dermal infiltrate from a pre dominant helper T cell infiltrate with a high CD 4/C'D 8 ratio (>5.0) to an infiltrate with large number of cytotoxic T cells (CD 4/CD 8. 0.8 to 3.0) in all allogeneic patients with acute GVHD who were followed up sequentially. On the other hand, lcsional skin from allogeneic patients with drug reactions showed a high CD 4/CD 8 ratio (7.5 to 42) [8]. The low CD 4/CD 8 ratio (2.0) and HI.A-DR+ keratinocytes in our patient’s cutaneous lesion is therefore com patible with acute cutaneous GVHD. rather than drug eruption. The patient developed interstitial pneumonitis which might be induced by CMV infection. However, it is unlikely that this viral infection played a major role in the development of the follicular papules; viral infection had been implicated in the induction of syngeneic GVHD [9]. Careful examination of the biopsy specimen disclosed no histopathologic findings suggestive of CMV infection. CMV infection with cutaneous manifestations is rare, although a few case reports of cutaneous CMV infection may not accurately reflect the true incidence [ 10]. Clinical features of the reported cases of cutaneous CMV infection are variable. Ulcers, nodules, morbilliform and maculopa-
pular eruptions, verrucous or indurated plaques, vesicles, petechiae, and purpura may all be presenting signs [10]. However, the follicular papular eruption seen in our case has not been reported in cutaneous CMV infection. On the other hand, it is thought that CMV interstitial pneumonitis in allogeneic transplant recipients is an immunopathological condition and that a host immune response is required for the induction of pneumonitis |l l | . Thus, interstitial pneumonitis in allogeneic transplant recipients may be a clinical manifestation of GVHD. Although the 3 patients reported by Friedman et al. [5], 2 by Lycka and Kaye [7] and our patient who had acute follicular GVI ID all died, it is still unknown if acute follicular GVHD may indicate a more severe course than other types of acute cutaneous GVHD [5, 7], Sale et al. 112] and Murphy et al. [13] have demon strated predilection of acute GVHD for the rcte ridges and hair follicles, and suggested that the stem cells at the tip of epidermal rete ridges (14] and in the bulge area of hair fol licles ¡15] may be the targets in cutaneous GVHD. It remains to be understood why erythematous-to-violaceous follicular papules still represent a rare clinical pattern of acute cutaneous GVHD.
References 6 Saurai JH. Gluckman E: l.iehen-planus-like eruption following bone marrow transplanta tion. A manifestation of the graft-versus-host disease. Clin Exp Dermatol 1977:2:335-344. 7 Lyeka BAS. Kaye VN: Acute follicular graftvs-host disease. Arch Dermatol 1988:124: 1442. 8 Pallet AS. Nelson A. Steffen L. Gottschalk I.. Kaizer H: T-lymphocytc subsets in the lcsional skin of allogeneic and autologous bone marrow transplant patients. Arch Dermatol 1988:124: 1795-1801. 9 Gluckman E. Devergie A. Solder.I. Saurai JH: Graft-versus-host disease in recipients of syngeneic bone marrow. Lancet I980:i: 25.3-254. 10 Toomc BK. Bowers KE. Scott G A : Diagnosis of cutaneous cytomegalovirus infection. A review and report of a ease. J Am Acad Der matol 1991:24:857-863. 11 Grundy .IE. Shanley .ID. Griffiths PD: Is cyto megalovirus interstitial pneumonitis in trans plant recipients an immunopathologieal condi tion? Lancet 1987;ii:996-999.
12 Sale GE. Shulman 11M. Gallucei BB. Thomas ED: Young rete ridge kératinocytes are pre ferred targets in cutaneous graft-versus-host disease. Am .1 Pathol 1985;118:278-287. 13 Murphy GF. Lavkcr RM. Whitaker D. Korngold R: Cytotoxic folliculitis in GvIlD. Evi dence of follicular stem cell injury and recov ery. JC u tan Pathol 1991:18:309-314. 14 Lavkcr RM. Sun TT: 1letcrogcneity in epider mal basal kératinocytes. Morphological and functional correlations. Science 1982:215: 1239-1241. 15 Colsarelis G. Sun IT. Lavkcr RM: Labelretaining cells reside in the bulge area of piloscbaccous unit. Implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990:61:1329-1337.
28.3
Downloaded by: UCL 144.82.238.225 - 2/6/2018 9:18:00 AM
1 Glucksbcrg H. Storb R. Fefer A. Buckner CD. Neiman PH. Clil't RA. I.erner KG. Thomas ED: Clinical manifestations of grafl-versushost disease in human recipients of marrow from HI.-A-matched sibling donors. Trans plantation 1974; 18:295-304. 2 Lcrncr KG. Kao GF. Storb R. Buckner CD. Clift RA. Thomas HD: Histopathology of graft-vs.-host reaction (GvFIR) in human recipients of marrow from HL-A-malched sibling donors. Transplant Proc 1974:4: 367- .371. 3 Sale G E. Lcrncr KG. Barker EA. Shulman HM. Thomas ED: The skin biopsy in the diag nosis of acute graft-versus-host disease in man. Am .1 Pathol 1977:89:621-636. 4 Hood AF. Sotcr NA. Rappeport .1. Gigli I: Graft-versus-host reaction. Cutaneous mani festations following bone marrow transplanta tion. Arch Dermatol 1977:113:1087-1091. 5 Friedman KJ. LeBoit PE. Farmer HR: Acute follicular graft-vs-hosl reaction. A distinct clinicopathologic presentation. Arch Dermatol 1988:124:688-691.
