Abstracts
Graft-versus-host disease is observed mainly in recipients of hematopoietic cell transplantation and is expressed by cutaneous or systemic signals and symptoms. Graft-versus-host disease is clinically classified as acute or chronic. Chronic Graft-versus-host disease occurs in up to 70% of hematopoietic cell transplanted patients and its clinical manifestations have important impact on morbidity and quality of life. The authors report an expressive cutaneous, oral and adnexal involvement in a patient with chronic Graft-versus-host disease with multiple lesions of lichenoid and atrophic pattern.
Bone marrow transplantation; Clinical evolution; Graft vs host disease; Lichen sclerosus et atrophicus
Doença enxerto contra hospedeiro é observada principalmente em pacientes transplantados de células de origem hematopoiéticas e se expressa por sinais e sintomas cutâneos ou sistêmicos. Clinicamente, a Doença enxerto contra hospedeiro é classificada em aguda ou crônica. As do tipo crônico ocorrem em até 70% dos pacientes e suas manifestações têm impacto importante na morbidade e na qualidade de vida. Os autores relatam caso com extenso comprometimento cutâneo, oral e de anexos cutâneos em paciente com Doença enxerto contra hospedeiro crônica expressa por inúmeras lesões de padrão liquenóide e de atrofia cutânea.
Doença enxerto-hospedeiro; Evolução clínica; Líquen escleroso e atrófico; Transplante de medula óssea
INTRODUCTION
The graft-versus-host disease (GVHD) is an immune-mediated syndrome expressed by
cutaneous or cutaneous / systemic signals and symptoms, mainly in recipients of
allogeneic stem cells or bone marrow transplantation, but also following blood
transfusion and solid organ transplantation.11. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease.
Lancet. 2009;373:1550-61.
2. Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease. Part I.
Pathogenesis and clinical manifestation of graft-versus-host disease. J Am Acad
Dermatol. 2012;66: 515. e1-18.
-
33. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW,
et al. Comparative analysis of risk factors for acute graft-versus-host disease and
for chronic graft-versus-host disease according to National Institute of Health
consensus criteria. Blood. 2011:117:3214-9. Graft-versushost
disease is induced and maintained by mature donor T cells, which clonally expand in an
antigenspecific manner after the recognition of non-self HLA expressed on the surface of
the host's nucleated cells, thus increasing HLA incompatibility between donor and
recipient.11. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease.
Lancet. 2009;373:1550-61.
2. Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease. Part I.
Pathogenesis and clinical manifestation of graft-versus-host disease. J Am Acad
Dermatol. 2012;66: 515. e1-18.
-
33. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW,
et al. Comparative analysis of risk factors for acute graft-versus-host disease and
for chronic graft-versus-host disease according to National Institute of Health
consensus criteria. Blood. 2011:117:3214-9. Graft-versus-host disease is clinically classified as acute or
chronic. Acute GVHD (aGVHD) is historically defined as the onset of signs and symptoms
within 100 days of transplant, and chronic GVHD (cGVHD) will appear after that
period.11. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease.
Lancet. 2009;373:1550-61. However, recent transplant protocols,
with less aggressive conditioning and new immune modulating strategies have altered the
classification; therefore, the aGVHD category includes the classic aGVHD occurring
within 100 days after transplant and the persistent, recurrent or late aGVHD.44. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SF,
et al. National Institutes of Health consensus development project on criteria for
clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging
working group report. Biol Blood Marrow Transplant. 2005;11:945-55. Chronic GVHD includes the classic cGVHD occurring
any time after transplant and an overlap syndrome in which features of cGVHD and aGVHD
appear together.44. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SF,
et al. National Institutes of Health consensus development project on criteria for
clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging
working group report. Biol Blood Marrow Transplant. 2005;11:945-55. Chronic GVHD occurs in up to
70% of hematopoietic cell transplanted patients.22. Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease. Part I.
Pathogenesis and clinical manifestation of graft-versus-host disease. J Am Acad
Dermatol. 2012;66: 515. e1-18.
,
33. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW,
et al. Comparative analysis of risk factors for acute graft-versus-host disease and
for chronic graft-versus-host disease according to National Institute of Health
consensus criteria. Blood. 2011:117:3214-9. Dermatologists and
stomatologists must play an active role in the management and treatment of patients with
GVHD, as oral and cutaneous lesions have severe impact on morbidity and quality of
life.
We report a clinical case of cGVHD with expressive cutaneous, oral and adnexal involvement occurring despite immunosuppressive therapy, presenting with numerous lichenoid and atrophic lesions.
CASE REPORT
A 52-year-old male patient presented with a history of an allogeneic bone-marrow transplant (matched sibling donor) performed in a reference Hospital, due to acute myeloid leukemia one year before. A conditioning regimen had been followed with oral busulfan and fludarabine phosphate and he was immunosuppressed from day 2 pre-transplant with cyclosporine, initial dose of 3mg/kg and 7mg/kg after the 21th day post-transplant, sustained for 241 days plus tacrolimus and mycophenolate mofetil for seven and 45 days respectively. The patient denied acute GVHD and his clinical follow-up was unremarkable until six months post-transplant, when oral and skin lesions of chronic GVHD appeared. Since then the patient has been treated with prednisone up to 1mg/kg/day with partial remission of the clinical picture. The initial skin lesions were described as erythematous and pruriginous papules, starting on the trunk with progressive spreading and oral lesions similar to lichen planus, with ulcers on the lower lip causing restriction to mouth opening.
Examination showed diffuse spotted hyper and hypopigmented skin, multiple lichenoid and atrophic lesions plus almost complete scarring alopecia, acral edema and erythema plus onychodistrophia of the 20 nails (Figures 1-4). Buccal examination showed shallow ulcers on the buccal mucosa and tongue, periodontal disease, salivary gland hypofunction, depapillated tongue and decreased taste. No pulmonary, gastrointestinal or renal involvement was detected. Histology of skin lesions showed discrete hyperkeratotic and atrophic epidermis with vacuolar interface dermatitis and scattered apoptosis of keratinocytes plus superficial sclerosis, vascular proliferation and mild lymphocytic infiltrate, suggestive of late evolution of lichenoid lesions (Figures 5 and 6).
Graft-versus-host disease: scalp with alopecia and spotted hyper and hypopigmented skin plus lichenoid lesions
Graft-versus-host disease: lichenoid lesions, edema and erythema on the hands with associated onychodistrophia
Graft-versus-host disease: discrete hyperkeratotic and atrophic epidermis plus vascular proliferation and mild lymphocytic infiltrate on the papillary dermis
Graft-versus-host disease: high-power view shows hyperkeratotic and atrophic epidermis, vacuolar changes, apoptotic cell, discrete lymphocytic infiltration and incontinent melanin in the papillary dermis
DISCUSSION
Chronic GVHD is a major complication of allogeneic bone marrow and peripheral blood stem
cell transplantation. The main risk factors include previous aGVHD, advanced recipient
age, female donor to male recipient, transplant in patient with chronic myelogenous
leukemia, previous splenectomy, second allogeneic transplant and a high degree of HLA
mismatching.33. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW,
et al. Comparative analysis of risk factors for acute graft-versus-host disease and
for chronic graft-versus-host disease according to National Institute of Health
consensus criteria. Blood. 2011:117:3214-9. Chronic GVHD has an important
impact on the survival and quality of life of transplanted patients. The skin is the
most commonly involved organ, followed by the oral mucosa, liver, eye and GI tract, but
virtually all organs or systems may be involved.33. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW,
et al. Comparative analysis of risk factors for acute graft-versus-host disease and
for chronic graft-versus-host disease according to National Institute of Health
consensus criteria. Blood. 2011:117:3214-9.
4. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SF,
et al. National Institutes of Health consensus development project on criteria for
clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging
working group report. Biol Blood Marrow Transplant. 2005;11:945-55.
5. Hymes SR, Turner ML, Champlin RE, Couriel. DR . Cutaneous
manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant.
2006;12:1101-13.
-
66. Silva MM, Bouzas LFS, Filgueira AL. Tegumentary manifestations of
graft-versushost disease in bone marrow transplantation recipients. An Bras Dermatol.
2005;80:69-80. Skin lesions in cGVHD
are initially subtle with xerosis, follicular hyperkeratosis or with a pityriasiform,
psoriasiform and eczematous aspect. Later on, more classic lesions of lichenoid or
sclerodermoid pattern appear.11. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease.
Lancet. 2009;373:1550-61.
,
55. Hymes SR, Turner ML, Champlin RE, Couriel. DR . Cutaneous
manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant.
2006;12:1101-13. Sclerotic skin changes are a prominent feature and
a major source of morbidity. Dermal fibrosis may involve all layers of the skin with
loss of subcutaneous tissue and may include the fascia and tendon.55. Hymes SR, Turner ML, Champlin RE, Couriel. DR . Cutaneous
manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant.
2006;12:1101-13. Our patient presents diffuse spotted hyperpigmentation and
hypopigmentation associated with multiple lichenoid and small atrophic, scaly and
hypopigmented plaques with histopathological presentation of atrophic epidermis and
discrete lichenoid pattern.55. Hymes SR, Turner ML, Champlin RE, Couriel. DR . Cutaneous
manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant.
2006;12:1101-13. Buccal lesions
manifest as gingivitis, mucositis, xerostomia and ulcers as observed. Involvement of
oral mucosa is frequent and may be very relevant affecting the health and quality of
life of patients.22. Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease. Part I.
Pathogenesis and clinical manifestation of graft-versus-host disease. J Am Acad
Dermatol. 2012;66: 515. e1-18.
,
66. Silva MM, Bouzas LFS, Filgueira AL. Tegumentary manifestations of
graft-versushost disease in bone marrow transplantation recipients. An Bras Dermatol.
2005;80:69-80. Despite the expressive mucocutaneous and adnexal
involvement, no evidence of systemic disease has been detected in this particular
patient so far, although this possibility cannot be ruled out during the patient's
follow-up .
Systemic steroids are the appropriate first-line treatment for both acute and chronic
GVHD, but if the patient is steroid refractory an alternative is the association of
extracorporeal photopheresis, prednisone and sirolimus, or prednisone, sirolimus plus
calcineurin inhibitors.33. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW,
et al. Comparative analysis of risk factors for acute graft-versus-host disease and
for chronic graft-versus-host disease according to National Institute of Health
consensus criteria. Blood. 2011:117:3214-9.
,
77. Hymes SR, Alousi AM, Cowen. EW. Graft-versus-host disease: part II.
Management of cutaneous graft-versus-host disease. J Am Acad Dermatol.
2012;66:535.e1-16.
8. Gruandmann-Kollmann M, Martin H, Ludwig R, Klein S, Boehncke WH,
Hoelzer D, et al. Narrowband UV-B phototherapy in the treatment of cutaneous graft
versus host disease. Transplantation 2002;74:1631-4.
-
99. Weitzing T, Sticherling M, Simon JC, Hegenbart U, Niederwieser D,
Al-Ali HK. Medium dose long-wavelenght ultraviolet A (UVA-1) photherapy for the
treatment of acute and chronic graft-versus-host disease. Bone Marrow Transplant.
2005;35:515-9. Localized, cutaneous GVHD may respond well to topical steroids or,
alternatively, to tacrolimus and pimecrolimus.77. Hymes SR, Alousi AM, Cowen. EW. Graft-versus-host disease: part II.
Management of cutaneous graft-versus-host disease. J Am Acad Dermatol.
2012;66:535.e1-16.
Although hematopoietic cell transplanted patients are counseled to avoid ultraviolet
radiation due to possible GVHD flare or increased risk of skin cancer, psoralens plus
ultraviolet A light (PUVA) or narrow band-ultraviolet B phototherapy are the choice for
the treatment of sclerotic cGVHD lesions.77. Hymes SR, Alousi AM, Cowen. EW. Graft-versus-host disease: part II.
Management of cutaneous graft-versus-host disease. J Am Acad Dermatol.
2012;66:535.e1-16.
8. Gruandmann-Kollmann M, Martin H, Ludwig R, Klein S, Boehncke WH,
Hoelzer D, et al. Narrowband UV-B phototherapy in the treatment of cutaneous graft
versus host disease. Transplantation 2002;74:1631-4.
-
99. Weitzing T, Sticherling M, Simon JC, Hegenbart U, Niederwieser D,
Al-Ali HK. Medium dose long-wavelenght ultraviolet A (UVA-1) photherapy for the
treatment of acute and chronic graft-versus-host disease. Bone Marrow Transplant.
2005;35:515-9. It is also important to
have in mind that these patients have increased risk of secondary malignancies of the
skin or mucosa including squamous cell carcinoma and melanoma, therefore dermatological
screenings are recommended throughout life.33. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW,
et al. Comparative analysis of risk factors for acute graft-versus-host disease and
for chronic graft-versus-host disease according to National Institute of Health
consensus criteria. Blood. 2011:117:3214-9.
,
1010. Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ.
Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin
Oncol. 2006;24:1119-26.
REFERENCES
-
1Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550-61.
-
2Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease. Part I. Pathogenesis and clinical manifestation of graft-versus-host disease. J Am Acad Dermatol. 2012;66: 515. e1-18.
-
3Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institute of Health consensus criteria. Blood. 2011:117:3214-9.
-
4Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SF, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945-55.
-
5Hymes SR, Turner ML, Champlin RE, Couriel. DR . Cutaneous manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2006;12:1101-13.
-
6Silva MM, Bouzas LFS, Filgueira AL. Tegumentary manifestations of graft-versushost disease in bone marrow transplantation recipients. An Bras Dermatol. 2005;80:69-80.
-
7Hymes SR, Alousi AM, Cowen. EW. Graft-versus-host disease: part II. Management of cutaneous graft-versus-host disease. J Am Acad Dermatol. 2012;66:535.e1-16.
-
8Gruandmann-Kollmann M, Martin H, Ludwig R, Klein S, Boehncke WH, Hoelzer D, et al. Narrowband UV-B phototherapy in the treatment of cutaneous graft versus host disease. Transplantation 2002;74:1631-4.
-
9Weitzing T, Sticherling M, Simon JC, Hegenbart U, Niederwieser D, Al-Ali HK. Medium dose long-wavelenght ultraviolet A (UVA-1) photherapy for the treatment of acute and chronic graft-versus-host disease. Bone Marrow Transplant. 2005;35:515-9.
-
10Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. 2006;24:1119-26.
-
Financial funding: None
-
*
Work performed at the Department of Dermatology and Radiotherapy. Botucatu Medical School, São Paulo State University "Júlio de Mesquita Filho" (FMB-UNESP) - Botucatu (SP), Brazil.
Publication Dates
-
Publication in this collection
Oct 2013
History
-
Received
15 Sept 2012 -
Accepted
15 Oct 2012