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.     

Chronic Graft-Versus-Host Disease Mimicking Psoriasis in a Patient with Hemophagocytic Lymphohistiocytosis

Graft-versus-host disease (GVHD) is a common complication of bone marrow transplantation (BMT) that can be classified as acute or chronic. Chronic GVHD, which usually occurs more than 3 months after BMT, includes typical lichenoid or sclerodermatous lesions. Psoriasiform eruption is a rare clinical manifestation of chronic GVHD, and there have been no reports of psoriasiform chronic GVHD associated with hemophagocytic lymphohistiocytosis. A 33-year-old woman who was diagnosed with hemophagocytic lymphohistiocytosis 10 years ago visited our outpatient clinic with psoriasiform eruption over her entire body. She underwent allogeneic BMT 7 months previously from her sibling. Skin biopsy was performed on the lesion, and the histological features suggested GVHD. The psoriasiform lesions improved with narrow-band ultraviolet B phototherapy, with secondary vitiligo remaining on the corresponding locations.     

Lichenoid graft vs. host disease following liver transplantation

BACKGROUND: Graft vs. host disease (GVHD) is a common complication of bone marrow transplantation (BMT) but is rarely seen after solid organ transplantation. METHODS: We report a case of lichenoid GVDH arising in a 60-year-old man 10 weeks after orthotopic liver transplantation. RESULTS: Skin biopsies revealed changes suggestive of lichenoid GVHD, but histological features differed from those described in post bone marrow (stem cell) transplant GVHD, in that a dense lymphoid infiltrate was present. The brisk infiltrate contained eosinophils that initially led to concern for a lichenoid drug eruption. The patient developed multiorgan GVHD after reduction in immunosuppression. The diagnosis of chronic GVHD was confirmed by the demonstration of chimerism in the patient's peripheral blood. The generalized cutaneous eruption and systemic manifestations responded to salvage therapy including intravenous immunoglobulin infusion, increased immunosuppression with high-dose steroids, mycophenolate mofetil, and systemic and topical tacrolimus. CONCLUSIONS: In interpreting skin biopsies, it is important to recognize that brisk inflammation may be seen in GVHD in the setting of solid organ transplantation, in contrast to the more sparse inflammation typical of GVHD following BMT. The clinical and histologic differential diagnosis included the eruption of lymphocyte recovery, drug reaction, and viral exanthem. We provide a conceptual framework for evaluating generalized cutaneous changes that may occur post transplantation.     

Hyperacute graft-versus-host disease: histological assessment of skin biopsy specimens from 19 cases

Background. Hyperacute graft‐versus‐host disease (GVHD) is defined as GVHD occurring within 14 days after haematopoietic stem‐cell transplantation (HSCT). Aim. To evaluate the usefulness of skin biopsy in assessing hyperacute GVHD. Methods. We examined 19 cases of hyperacute GVHD from a total of 134 consecutive HSCT cases at Shinshu University Hospital between 1999 and 2008. Results. Exanthemas were seen in all patients, which were mainly disseminated maculopapular erythemas, commonly present in acute GVHD as well. Most patients presented with a high fever, and a few had mild hepatic dysfunction and/or diarrhoea. The clinical grade of GVHD was 1–2 in all patients; there were no cases of clinical grades 3–4. The histological findings of skin biopsy were divided into three groups: (i) eight had grade 2 changes, characterized by diffuse vacuolization of basal cells, with dyskeratotic bodies; (ii) five had grade 1 changes, characterized by vacuolization of epidermal basal cells (all these cases were diagnosed as acute GVHD with grade 2 histological changes at subsequent biopsy); (iii) and six had no significant changes (these cases were also diagnosed as acute GVHD with grade 2 (four cases) or grade 1 (one case) histological changes on the second biopsy). Many of the patients developed acute and later chronic GVHD. Conclusion. Skin biopsy should be considered when eruption develops after HSCT even before engraftment, especially when other organ involvement is minimal. If the first skin biopsy is inconclusive, follow‐up biopsy within a short time is helpful in the diagnosis of hyperacute GVHD.     

Tissue eosinophils and the perils of using skin biopsy specimens to distinguish between drug hypersensitivity and cutaneous graft-versus-host disease

Graft-versus-host disease (GvHD) is a frequent and serious complication of bone-marrow transplantation (BMT), and carries a high morbidity and mortality if not promptly recognized and treated. The rash of acute GvHD is often difficult to distinguish clinically from a drug eruption, and skin biopsies are often performed in an attempt to render a diagnosis. Histologically, eosinophils are classically associated with hypersensitivity reactions, and their presence in inflamed tissue is considered suggestive of a drug-induced dermatitis. We present 3 cases of acute exanthema in BMT recipients in whom the presence of eosinophils on skin biopsy specimen led to an initial diagnosis of drug eruption over GvHD. As a result, these patients experienced delays in the institution of definitive immunosuppressive therapy for GvHD. We review the growing literature suggesting that no single or combined histologic feature, including tissue eosinophils, is useful in differentiating GvHD from drug eruptions in BMT recipients. Indeed, in most cases, the cause of a new-onset blanchable erythematous rash in a BMT recipient is most accurately determined by close examination and follow-up of the clinical features without a skin biopsy.     

Papular urticaria and transfer of allergy following bone marrow transplantation

Skin rashes following allogeneic hone marrow transplantation are common. The majority are either drug reactions or manifestations of acute or chronic graft-versus-host disease (GVHD). We describe a previously unreported manifestion of a donor allergic response pattern in the recipient of an allogeneic hone marrow transplant who presented with papular urticaria in the post-transplant period.     

Chronic Graft-versus-Host Disease with Follicular Involvement

The clinical and histopathological findings in a 25-year-old Japanese male patient who suffered from chronic graft-versus-host-disease (GVHD) with follicular involvement are described. The patient had been diagnosed as aplastic anemia and underwent an allogeneic bone marrow transplant (BMT). In the eighth month thereafter, pruritic follicular red papules developed over his trunk and extremities. A biopsy specimen revealed histological exocytosis of lymphocytes into the hair follicles and basal-cell vacuolization of the follicular epithelium. Analysis of T-lymphocyte subpopulations in the dermis revealed a predominance of CD4 positive cells. To our knowledge, several cases of acute follicular GVHD have been reported (1, 2); however, the occurrence of chronic GVHD with follicular involvement (chronic follicular GVHD) has not been clearly documented.     

La biopsia cutánea en la urticaria crónica: cuándo realizarla,qué buscar y dónde hacerlo

Chronic urticaria is a relatively common condition in dermatology and is usually diagnosed on clinical grounds. Skin biopsy, however, may be indicated in certain cases to confirm diagnosis and rule out other conditions that can cause hive-like rashes. We review histopathologic findings seen in both chronic urticaria and other entities in the differential diagnosis. We then propose an algorithm of indications for skin biopsy in patients with hive-like rashes and suggest possible diagnoses based on the histopathologic findings.     

恙虫病皮肤损害的特征

目的 分析恙虫病皮肤损害的临床特征。方法 分析17例住院恙虫病患者的皮肤损害及临床特征。结果 恙虫病有88.2%（15/17）的患者出现皮肤焦痂及溃疡,有64.7%（11/17）的患者伴有皮肤出疹。焦痂出现在发热后4 ～ 10 d,其发生部位不一,数量为1个,平均直径1.2 cm（0.5 ～ 3.0 cm）,表面干燥呈黑色,周边绕以环形红晕,不伴疼痛及瘙痒,于出现后5 ～ 9 d焦痂脱落形成浅溃疡。出现焦痂者中有80.0%的患者伴有焦痂附近浅表淋巴结肿大。66.7%的患者首诊时未发现焦痂。伴有皮肤出疹者为充血性丘疹（45.5%）和斑丘疹（54.5%）,不伴瘙痒,于出疹后2 ～ 5 d消退。结论 恙虫病的皮肤损害包括皮肤焦痂和皮疹。皮肤焦痂是本病的重要特征,为临床诊断的主要依据。     

Histochemical and ultrastructural study of diffuse melanoderma after bone marrow transplantation

Summary Hyperpigmentation is a well-recognized feature of cutaneous graft-versus-host disease (GVHU). and is usually restricted to sites where lichenoid or sclerodermiform lesions have occurred. Since 1975, two of 745 patients treated by allogeneic bone marrow transplantation in our institution have developed diffuse melanoderma which differed considerably from the classic presentations. They both developed acute GVHD. then lichen planus-like chronic lesions and diffuse melanoderma. Histology of biopsies of the pigmented skin showed intense pigment deposition in the basal and suprabasal layers, and in dermal macrophages. On split-dopa, melanocyte counts were 98 and 93 per Held, respectively. Electron microscopy showed melanocytes protruding into the dermis, and dark melanosomes in all epidermal layers and in macrophages. These findings were suggestive of post-inflammatory hyperpigmentation. In bone marrow recipients, de nova melanoderma is a rare event which could represent a feature of cutaneous GVHD in pigmented subjects.     

Reply

In regard to the recent report, "The specificity of histopathology in erythrodernia" by Zip, Murray and Walsh (j cutaneous Pathology 1993: 20: 393) 1 would like to Comment on the conclusions drawn from our previous article (Ref. #8, Southern Medical J 1986: 79: 1210). We reported that 43% of skin biopsies were highly suggestive or truly diagnostic and did not "aver that it [skin biopsy] is of little or no value" (Discussion, p. 395). We do not agree that the diagnostic value ol skin biopsies in erythrodermic patients is in question as both positive and negative data are highly relevant. Skin biopsies are helpful and the results are accurate in the setting described, but the clinical population was very different from that likely to be evaluated by pathologists in a general hospital setting.     

Clinical, laboratory, and histopathologic indicators of the development of progressive acute graft-versus-host disease.

Graft-versus-host disease (GvHD) is the major cause of morbidity and mortality following bone marrow transplantation (BMT). The goal of this study of 69 cyclosporin-treated, allogeneic BMT patients was to identify early clinical, laboratory, or histopathologic indicators of the development of progressive, fatal GvHD. Peak values within 100 d of allogeneic BMT for total bilirubin, stool volume in a day, clinical stage of cutaneous GvHD (based on extent of rash), and overall clinical stage of GvHD (based on a combination of graft-versus-host reactions in the skin, liver, and gastrointestinal tract) were most useful (p less than 0.05, by logistic regression) in identifying those patients with clinically progressive and fatal GvHD. Peak values for each of these parameters were reached an average of 40 d or less after BMT. Each unit increase in peak clinical stage of rash (e.g., stage 2 versus stage 3) was associated with an odds ratio incremental risk of 5.8 for clinical progression of GvHD, and each tenfold increase in peak total bilirubin (e.g., 2 mg/dl versus 20 mg/dl) or stool output in a day (e.g., 100 cm3/d versus 1000 cm3/d) was associated with an incremental risk of 8.4 and 10.6, respectively, for a fatal outcome from GvHD. Number of exocytosed lymphocytes and dyskeratotic epidermal keratinocytes (DEK) per linear millimeter of epidermis, the presence of follicular involvement, and the degree of dermal perivascular lymphocytic infiltration in 121 skin biopsy specimens were not associated with the development of progressive or fatal GvHD. Pretransplant total body irradiation was associated (p = 0.03, by Mann-Whitney U testing) with an increased number of DEK in skin biopsy specimens taken less than 20 d after BMT. This study demonstrates that monitoring of total bilirubin, stool output, extent of rash, and overall clinical stage of GvHD is most useful during the first 40 d after BMT in formulating the prognosis of early acute GvHD in allogeneic BMT patients receiving cyclosporin.     

Immunohistochemical Study of Graft-versus-Host Reaction (GVHR)-Type Drug Eruptions

Skin biopsies of graft-versus-host reaction (GVHR)-type drug eruptions in the acute phase were compared immunohistochemically with those in the chronic phase and also with non-GVHR type drug eruptions in the acute phase. Predominance of CD8⁺ T cells in the epidermal infiltrates, reduction in the number of epidermal OKT6⁺ dendritic cells (Langerhans cells), and increased expression of HLA-DR and ICAM-1 on keratinocytes were observed in the acute phase of GVHR-type, but not in either the chronic phase of GVHR-type or the acute non-GVHR type. These findings were similar to those of previous reports on skin lesions of acute GVH disease (GVHD) seen after bone marrow transplantation. Therefore, immunohistochemistry is not useful for differential diagnosis between acute GVHR-type drug eruptions and acute cutaneous GVHD. These findings also indicate that similar immunomechanisms may be involved in the pathogenesis of both GVHR-type drug eruptions and cutaneous GVHD.     

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.     

The role of nerve biopsies in the diagnosis and management of leprosy

Skin and nerve biopsies from 81 patients clinically suspected to have leprosy were studied. Histologically 54% of the patients showed leprosy. Both nerve and skin biopsies were histologically diagnostic of leprosy in 64% of these cases while 32% were diagnostic in the nerve but not skin biopsy. In the 11 patients with multibacillary leprosy (BI greater than or equal to 2) a multibacillary picture was seen in all nerve biopsies while 8 patients exhibited a paucibacillary leprosy of the skin and a multibacillary leprosy in the nerve. The present results emphasize that leprosy is a disease of peripheral nerves and that diagnostic criteria other than skin parameters is important to reach a proper diagnosis. The evident possibility of having patients with a multibacillary leprosy in peripheral nerves and paucibacillary in skin emphasize the need of clinical studies to clarify the criteria for the diagnosis of paucibacillary leprosy and the drug regimen for this group of patients.     

Extra-domain-A fibronectin: a new marker of fibrosis in cutaneous graft-versus-host disease

One of the major complications that limit the success of allogeneic stem cell transplantation is graft-versus-host disease (GVHD). The major target organ in GVHD is the skin. Cutaneous GVHD can eventually lead to fibrosis of the skin. Fibronectin mediates a variety of cellular interactions with the extracellular matrix. The molecular and functional diversity of fibronectin (FN) arises from alternative splicing of pre-mRNA. In normal circumstances endothelial cells and fibroblasts synthesize FN without the ED-A domain. In tissue repair and pathologic circumstances such as fibrosis, the ED-A domain is expressed. We hypothesize that expression of ED-A FN is upregulated in patients with cutaneous GVHD. In frozen skin biopsies the expression of ED-A FN was measured at the protein level by immunohistochemistry and at the mRNA level by quantitative real-time PCR (qPCR). In normal control skin, immunohistochemistry showed slight deposits of ED-A FN just under the basal layer. The expression of ED-A FN significantly increased in acute cutaneous GVHD (p<0.05) and ED-A FN was strongly deposited in chronic cutaneous GVHD (p<0.001). Quantitative PCR also showed increased expression of ED-A FN mRNA in acute and chronic cutaneous GVHD compared with normal control skin (p=0.07 and 0.039, respectively). The expression of ED-A FN is increased in the skin of patients with cutaneous GVHD measured both with immunohistochemistry and qPCR. ED-A FN is a new marker of fibrosis in the skin of patients with cutaneous GVHD.     

Atypical acute graft-versus-host disease

Acute graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic bone marrow transplantation. It is important to recognize the dermatologic manifestations of acute GVHD, as skin is often the initial organ of involvement. We present a case of acute GVHD characterized by rare clinical and histopathologic findings as only two erythematous nodules clinically and abrupt follicular wall necrosis histopathologically.     

Cutaneous graft-versus-host reaction: prognostic features seen by light microscopy

Acute graft-versus-host disease (GVHD) is a severe complication of bone marrow transplantation. The diagnosis may be made and its course followed by serial skin biopsies. The degree of epidermal change has been used as a guideline in grading each biopsy, but great variation may be found within each grade, especially grade 2 (basal cell vacuolization and dyskeratosis). To find a histologic parameter that is prognostic of more severe acute GVHD, we examined retrospectively the serial biopsies of 54 patients. When we studied early cutaneous graft-versus-host reaction (GVHR), represented by the grade 2 biopsies, the number of dermal and epidermal mononuclear inflammatory cells correlated positively with the probability of developing more severe acute GVHD. In addition, the patients who had more severe acute GVHD tended to have an earlier appearance of cutaneous histologic changes. None of the other histologic parameters examined in these grade 2 biopsies were found to be predictive of GVHD progression. In addition, no histopathologic parameters in these grade 2 biopsies were predictive of the subsequent development of chronic GVHD.