Acute follicular graft-vs-host reaction. A distinct clinicopathologic presentation

Human graft-vs-host disease (GVHD) is a life-threatening complication that may occur following allogeneic bone marrow transplantation. In acute GVHD, skin involvement is frequent, and the skin is often the initial organ involved. The rash typically is a blanchable, erythematous macular eruption. We present the first report of follicular cutaneous GVHD. Three patients developed follicular papules simulating bacterial or fungal folliculitis as a major clinical expression of cutaneous involvement in acute GVHD following allogeneic bone marrow transplantation. In each case, histopathologic examination demonstrated features of acute graft-vs-host reaction involving hair follicles. This suggests that follicular epithelium may be an early target in acute GVHD.     

Life-threatening graft-vs-host disease

Hematopoietic stem cell transplant (SCT) is considered standard therapy for a variety of malignant and nonmalignant diseases. Graft-versus-host disease (GVHD) still represents today a major complication of hematopoietic SCT. Two types of GVHD have traditionally been recognized on the basis of the time of onset following transplantation, distinct pathobiological pathways, and different clinical presentations. The acute form commonly breaks out 2 to 6 weeks after transplantation, affecting up to 60% of patients receiving allogeneic transplants from HLA identical donors. Transfer of immunocompetent donor T cells contained in the graft may undergo alloreactivity against recipient cells because of major or minor histocompatibility antigens disparities between the donor and the immunosuppressed host. Target specificity in acute GVHD involves preferential injury to epithelial surfaces of the skin and mucous membranes, biliary ducts of the liver, and crypts of the intestinal tract. Chronic GVHD affects approximately 30% to 80% of patients surviving 6 months or longer after stem cell transplantation and is the leading cause of nonrelapse deaths occurring more than 2 years after transplantation. Chronic GVHD is a multiorgan syndrome with clinical features suggesting some autoimmune diseases, and possibly both alloreactive and autoreactive T cell clones are involved in its pathophysiology. Although GVHD may convey beneficial graft-versus-leukemia/lymphoma effects, it also entails a significant risk of morbidity and mortality. Patients with mild GVHD need only minimal, if any, immunosuppressive treatment, whereas prognosis of patients with extensive disease or resistant to standard immunosuppressive treatment may be dismal. Early recognition of GVHD followed by prompt therapeutic intervention may prevent the progression to higher-grade disease and improve the outcome for patients receiving hematopoietic SCT.     

Late appearance of acute graft-vs-host disease after suspending or tapering immunosuppressive drugs

BACKGROUND: Graft-vs-host disease (GVHD) is divided into acute and chronic phases based on time and clinical and histological features. The criterion of 100 days after transplantation for separating acute GVHD from chronic GVHD has been challenged on the following points: (1) the lichenoid rash of chronic GVHD may be observed as early as day 31 and acute GVHD may persist after day 100 in some cases, and (2) specific histological features do not consistently separate acute from chronic GVHD defined as the number of days after transplantation. However, the appearance of acute cutaneous GVHD after day 100 is not well established. OBSERVATIONS: Three patients developed a rash with clinical and histological features of acute GVHD between days 153 and 192 after allogeneic bone marrow transplantation or peripheral blood stem cell transplantation. In all patients, the late flare of acute GVHD occurred after tapering or suspending the immunosuppressive regimen with cyclosporine or corticosteroids, and was accompanied by stigmata of chronic GVHD in other target organs. CONCLUSIONS: The rash of acute GVHD may be observed as late as 192 days after transplantation, especially after tapering or suspending the immunosuppressive drugs, and should be considered in the differential diagnosis of late erythematous eruptions after transplantation.     

Role of skin biopsy to confirm suspected acute graft-vs-host disease: results of decision analysis

OBJECTIVE: To estimate the value of skin biopsy in the evaluation of suspected acute cutaneous graft-vs-host disease (GVHD) after allogeneic stem cell transplantation. DESIGN: Decision analysis using parameters specified by expert opinion for skin biopsy characteristics, prevalence of acute GVHD, and value of potential outcomes. One-, 2-, and 3-way sensitivity analyses were performed. SETTING: Major stem cell transplantation centers in the United States. PATIENTS: Hypothetical cohort of patients with suspected acute cutaneous GVHD after stem cell transplantation. INTERVENTIONS: The following 3 interventions were compared: treat immediately for GVHD without performing a skin biopsy, perform a skin biopsy and treat immediately but stop treatment if skin biopsy specimen findings are inconsistent with GVHD, and perform a skin biopsy and await results of the skin biopsy specimen before treating. MAIN OUTCOME MEASURES: Number of patients appropriately and inappropriately treated with each intervention, consistency of physician-reported behavior, individualized decision analyses, and preferred intervention based on the aggregate estimates of respondents. RESULTS: The decision to treat immediately for GVHD without performing a skin biopsy yielded the best clinical outcome for the specified clinical setting and under the parameters specified by expert opinion. One-way sensitivity analyses showed that these conclusions are robust if the prevalence of acute cutaneous GVHD in stem cell recipients with rash is greater than 50%, if the sensitivity of skin biopsy specimen is less than 0.8, and the specificity of skin biopsy specimen is less than 0.9. Only 25% of physicians interviewed chose an intervention consistent with their estimates of prevalence, test characteristics, and outcome evaluations, indicating an opportunity to improve management of this important clinical condition. CONCLUSIONS: This decision analysis modeling technique predicts that in patient populations in which the prevalence of GVHD is 30% or greater (typical for allogeneic stem cell transplantation), the best outcomes were obtained with treatment for GVHD and no skin biopsy. In populations with prevalence of GVHD of 30% or less, obtaining a skin biopsy specimen to guide treatment was predicted to provide the best patient outcomes.     

PUVA therapy for chronic cutaneous graft-vs-host disease

Chronic graft-vs-host disease (GVHD) is an immunologic disorder frequently occurring as a late sequelae of allogeneic bone marrow transplantation and characterized in the skin with lichenoid or sclerodermoid lesions. Systemic immunosuppressive agents such as corticosteroids or cyclosporine are usually required to control the disease. Therapy with psoralen and UVA (PUVA) has recently been shown to be effective for skin and oral mucosa in a few cases of GVHD. We present our experience with PUVA in six patients, five with lichenoid and one with sclerodermoid GVHD. None of these patients had significant systemic involvement. All five patients with lichenoid GVHD showed clinical improvement after PUVA therapy. Three of these patients had complete clearance of skin lesions. Clinical clearance of the disease was accompanied by microscopic clearance. The patient with sclerodermoid GVHD did not respond to therapy. No significant complications or exacerbation of systemic disease occurred. We confirm that PUVA is an effective and safe therapy for the cutaneous manifestations of lichenoid chronic GVHD. We postulate that PUVA therapy clears chronic lichenoid GVHD by selective cytotoxicity for the activated lymphoid cells in the inflammatory infiltrate.     

Chronic cutaneous graft-versus-host disease simulating hypertrophic lupus erythematosus--a case report of a new morphologic variant of graft-versus-host disease

The spectrum of clinical and histopathologic features associated with chronic graft-versus-host disease (GVHD) is broad, with recognized variants simulating scleroderma, lichen sclerosus, eosinophilic fasciitis, and de novo diffuse melanoderma. We report a case of a patient with multiple myeloma who presented approximately 1 year after his allogeneic hematopoietic stem cell transplantation with lesions of chronic lichenoid GVHD that harbored features of hypertrophic lupus erythematosus (LE) and that was initially mistaken for a superficial well-differentiated squamous cell carcinoma (SCC). However, in 4 years of follow-up, the patient failed to develop any evidence of cutaneous or systemic LE, actinic damage, or SCC, and the lesions cleared with topical and systemic treatments appropriate for chronic GVHD. For proper interpretation of the histologic findings of GVHD, it is important for the dermatopathologist to be aware of unusual manifestations. Knowledge of the occurrence of hypertrophic LE and familiarity with its histologic features is also important to avoid an erroneous diagnosis of SCC in immunosuppressed patients.     

Tacrolimus ointment in the treatment of chronic cutaneous graft-vs-host disease: a case series of 18 patients

BACKGROUND: Tacrolimus (formerly FK 506) is an immunosuppressive drug that works by inhibiting calcineurin, a calcium-dependent protein phosphatase required for immune function. Tacrolimus has been shown to be effective topically in atopic dermatitis and systemically in psoriasis and graft-vs-host disease (GVHD). However, its efficacy in treating cutaneous GVHD when applied topically has not been reported. OBJECTIVE: To assess the therapeutic efficacy of 0.1% tacrolimus ointment on chronic cutaneous GVHD in patients with symptoms refractory to systemic corticosteroid therapy. RESULTS: Tacrolimus ointment effectively treated pruritus and/or erythema in 13 (72%) of 18 patients with chronic GVHD. Responding patients had a rapid effect within several hours to days. Effectiveness was measured by means of patient report, results of physical examination, side-by-side comparisons of tacrolimus vs a vehicle control, and temporal flares of the cutaneous symptoms of the disease in the context of stopping tacrolimus ointment therapy. Because of the progression of GVHD and in 2 cases, loss of drug efficacy, all patients eventually went on to receive more aggressive treatment, including increases in steroid dosage, psoralen-UV-A therapy, and extracorporeal photopheresis. CONCLUSIONS: This case series suggests that tacrolimus ointment has efficacy in treating the erythema and pruritus of steroid-refractory, chronic cutaneous GVHD in most patients. The rapid response of tacrolimus ointment may provide a useful therapeutic bridge to systemic therapies that have slower onset, such as psoralen-UV-A therapy or extracorporeal photopheresis.     

Long-term remission after allogeneic hematopoietic stem cell transplantation for refractory cutaneous T-cell lymphoma

BACKGROUND: Allogeneic hematopoietic stem cell transplantation has proved to be an effective therapeutic option in various hematologic neoplastic disorders. Because patients with advanced cutaneous T-cell lymphoma have a poor prognosis, with minimal possibilities of sustained remission, we studied the therapeutic potential of hematopoietic stem cell transplantation. OBSERVATIONS: Three young patients with refractory tumor stage mycosis fungoides underwent allogeneic HLA-matched sibling transplantation with combined marrow and CD34-enriched peripheral blood stem cell transplantation after cytoreductive chemotherapy and total-body irradiation. Complete and sustained clinical and histologic remission was achieved in 2 patients, and both remain disease free 4(1/2) years and 15 months later. One patient was in complete remission for 9 months, followed by limited cutaneous recurrence. Mild graft-vs-host disease and graft-vs-tumor effect have contained the recurring disease as a low-grade process. CONCLUSIONS: Allogeneic hematopoietic stem cell transplantation has the potential for sustained remission and the possibility of cure for young patients with advanced and recalcitrant cutaneous T-cell lymphoma. Even in the absence of complete remission, an allogeneic graft-vs-tumor effect may provide an immune mechanism to control the malignant T-cell process and alter the natural history of disease.     

Cutaneous graft-versus-host disease: a guide for the dermatologist

Graft-versus-host disease (GVHD) is defined by the aggregation of clinical and pathological manifestations in a recipient of allogeneic stem cells or bone marrow transplantation in which specific immunological as well as nonspecific phenomena lead to characteristic features. GVHD is one of the major complications after hematopoietic stem cell transplantations and responsible for posttherapeutic morbidity, mortality and decrease in quality of life of those patients. GVHD is critically induced and maintained by donor immunocompetent cells that particularly attack epithelia of fast proliferating tissues such as those from the liver, gastrointestinal tract and skin. On the basis of the time of presentation, cutaneous GVHD has been originally divided into an acute and chronic disease. The latter has traditionally been further subclassified into a more epithelial or lichenoid and a predominantly dermal or sclerodermoid form. With respect to the growing importance of this therapeutic procedure and increasing numbers of outpatients presenting with chronic GVHD, this article summarizes the updated knowledge on this disease focused for the dermatologist, and additionally it emphasizes the recent consensus documents on the various aspects of chronic GVHD of the National Institute of Health.     

Eczematous graft-vs-host disease: A report of three cases and review of the literature

Graft-vs-host disease (GVHD) is the most common complication following hematopoietic cell transplantation, which affects skin frequently. Acute and chronic forms of GVHD manifest commonly as maculopapular to morbilliform eruptions and sclerotic or lichen-planus-like lesions, respectively; however, atypical presentations such as eczema-like GVHD may occur at times. We describe three cases of GVHD with diverse and polymorphous cutaneous eruptions including pompholyx-like and vasculitis-like rash as well as erythematous plaques and papulosquamous eruptions, with skin biopsy showing unifying histopathological findings with concurrent changes of spongiotic dermatitis and vacuolar interface reaction with apoptotic keratinocytes. In addition, the clinical and pathological features of previously reported cases of eczema-like GVHD are reviewed. It is emphasized that the course of the disease can be variable and successful management often involves a combination of multiple therapeutic modalities including immunosuppression with or without ultraviolet therapy. These cases highlight the importance of meticulous clinicopathological correlation with careful exclusion of mimicking conditions to arrive at the correct diagnosis.     

Squamous cell carcinoma of the sole in a patient with chronic graft-vs-host disease

Chronic graft-vs-host disease (GvHD) is a common, severe complication of bone marrow transplantation that often results in sclerodermoid skin changes with chronic and recurrent skin ulceration. We describe a case of cutaneous squamous cell carcinoma presenting as an ulcer on the sole of a 20-year-old woman with chronic GvHD. Although such an association has not been previously described, we discuss why features of chronic GvHD could be expected to place affected patients at increased risk for cutaneous squamous cell carcinoma.     

硬皮病样皮肤移植物抗宿主病24例临床特征分析

目的:分析异基因造血干细胞移植后硬皮病样皮肤移植物抗宿主病（GVHD）的临床特征和危险因素。方法:回顾2014—2019年间就诊于北京大学人民医院皮肤科硬皮病样皮肤GVHD患者24例的临床资料,分析临床特征、治疗、预后及发展为硬皮病样皮肤GVHD的可能因素。结果:24例硬皮病样皮肤GVHD患者中男11例,女13例,年龄...     

Clinical significance of skin biopsies in the diagnosis and management of graft-vs-host disease in early postallogeneic bone marrow transplantation

OBJECTIVE: To determine the value of skin biopsies in the management of suspected graft-vs-host disease (GVHD) within 30 days of allogeneic bone marrow transplantation (BMT). DESIGN: Retrospective study based on review of a BMT database. SETTING: Leukemia/BMT ward of a tertiary care, university teaching hospital. PATIENTS: One hundred and eighty-seven consecutive patients who received allogeneic BMT between January 1, 1994, and June 30, 1997, at Vancouver General Hospital, Vancouver, British Columbia. MAIN OUTCOME MEASURES: (1) Skin biopsy frequency for patients with rashes suggestive of acute GVHD; (2) clinical significance of skin biopsy in the management of patients with suspected acute GVHD after BMT; (3) relationship between severity of clinical GVHD and the likelihood to receive GVHD therapy; and (4) relationship between biopsy status or biopsy result and outcome of BMT (acute and chronic GVHD, transplant-related mortality, and overall and event-free survival). RESULTS: During the early post-BMT period (<30 days after BMT), 88 patients had rashes suggestive of acute GVHD; of these, 51 (58%) underwent skin biopsy to confirm the diagnosis. Skin biopsies were performed more often for higher clinical stages of cutaneous GVHD. There was no significant difference between the patients with positive biopsy findings and those with negative findings, either in the clinical severity of acute GVHD or in likelihood to receive treatment for GVHD. Most (85%) of the patients who underwent biopsies and received GVHD therapy had treatment initiated before skin biopsies were performed or before the results were available. The higher the clinical grade of overall acute GVHD, the more likely it was that the patients were treated for GVHD (P<.001). The outcome of BMT was not influenced by the skin biopsy status or biopsy result. CONCLUSIONS: The biopsy findings correlated poorly with the clinical severity of skin rash suggestive of acute GVHD soon after BMT. The decision to treat suspected acute GVHD depended not on skin biopsy findings but rather on clinical severity of acute GVHD. In this regard, skin biopsy has a limited role in the management of patients early after allogeneic BMT.     

Risk factors and clinical characteristics of acute and chronic cutaneous graft-versus-host disease in pediatric patients undergoing hematopoietic stem cell transplantation

Acute and chronic cutaneous graft-versus-host disease (GVHD) are common complications following hematopoietic stem cell transplantation (HSCT) in pediatric patients. In this retrospective study, we explored the risk factors and clinical characteristics of acute and chronic cutaneous GVHD in a case series of children undergoing HSCT at a tertiary referral hospital. We found that 36% of acute cutaneous GVHD was severe and these patients were more likely to have an unrelated donor, and that children with acute cutaneous GVHD who progressed to chronic cutaneous GVHD had a higher proportion of malignant diseases, total body irradiation, and bronchiolitis obliterans compared to those who did not progress to chronic cutaneous GVHD. Our study highlights the importance of identifying and monitoring these high-risk patients to improve the clinical management and outcomes of cutaneous GVHD in pediatric HSCT recipients.     

The changing face of graft-versus-host disease

Despite advances in the procedure and posttransplantation immunosuppressive therapy, more than half of allogeneic hematopoietic stem cell transplant (HSCT) recipients develop graft-versus-host disease (GVHD), which remains a major cause of morbidity and mortality. Modern HSCT protocols have resulted in substantial alterations in the timing and relative incidences of acute and chronic GVHD, making traditional classification schemes obsolete. This article reviews major changes in HSCT during the past decade, evolving concepts of acute and chronic GVHD (including new diagnostic criteria) and the expanding spectrum of cutaneous GVHD. It focuses on observations that have led to a better delineation of the full constellation of skin findings in chronic cutaneous GVHD, including lichen sclerosus, morpheaform lesions, and eosinophilic fasciitis. Recent insights into pathogenesis of GVHD, lessons from GVHD arising in settings outside HSCT, and therapeutic advances also are highlighted.     

Infantile vitiligo and alopecia in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is characterized by failure to thrive, severe chronic diarrhea, neonatal type 1 diabetes or thyroiditis, and eczematous dermatitis. We report a patient with infantile onset IPEX syndrome who developed vitiligo, alopecia, and chronic diarrhea. Awaiting stem cell transplant, he had multiple episodes of sepsis and succumbed at the age of 10 months. The constellation of symptoms is important to prompt clinicians to suspect this rare syndrome as early hematopoietic stem cell transplantation is the only cure for IPEX patients.     

Acute graft-vs-host disease. Development following autologous and syngeneic bone marrow transplantation

Graft-vs-host disease (GVHD) is a frequent complication of allogeneic bone marrow transplantation but has been infrequently reported following autologous or syngeneic bone marrow transplantation. Ninety-six autologous and 19 syngeneic marrow transplants were performed at our institution between July 1977 and March 1984. We report acute cutaneous GVHD occurring in seven patients who received autologous marrow and two patients who received marrow from an identical twin. All nine patients had clinically detectable eruptions and had skin biopsy specimens with histologic changes of grade 2 acute GVHD. Although most cases were mild and self-limiting, four patients required systemic corticosteroids to treat their disease. Thus, acute cutaneous GVHD was seen in approximately 8% of patients receiving autologous or syngeneic bone marrow transplants at our institution.     

A Case of Eczematoid Graft‐Versus‐Host Disease

A 13‐year‐old boy underwent allogeneic hematopoietic stem cell transplantation (HSCT) for underlying acute lymphoblastic leukemia and achieved neutrophil engraftment 28 days after HSCT. He developed ichthyosis 6 weeks after HSCT and then keratotic follicular papules, palmoplantar keratoderma, and a seborrheic dermatitis–like eruption 18 weeks after HSCT. From skin biopsies he was diagnosed with eczematoid graft‐versus host disease (GVHD), which showed spongiosis with scattered necrotic keratinocytes. He responded to oral and topical steroids and an increase in cyclosporine dose. Although uncommon, eczematoid GVHD must be considered in children who have undergone HSCT and then develop an atypical eczematous eruption, especially in the absence of a history of atopy.