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DOI: 10.1111/jdv.12737

ORIGINAL ARTICLE

Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease €usermann,2 D. Massi,3 A. Janin,4 D. Wolff,5 A. Lawitschka,6 H. Greinix,7 R. Meyer,8 U. Hillen,1,* P. Ha 9 M. Ziemer 1

Department of Dermatology, University Hospital of Essen, Essen, Germany Department of Dermatology, University Hospital of Basel, Basel, Switzerland 3 Department of Surgery and Translational Medicine, University of Florence, Florence, Italy 4 , Paris, France Laboratoire de Pathologie, University Paris Diderot, Sorbonne Paris Cite 5 Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany 6 SCT Outpatient Clinic, ST. Anna Children’s Hospital, Vienna, Austria 7 Department of Internal Medicine I, BMT, Medical University of Vienna, Vienna, Austria 8 Department of Hematology, Oncology, and Pneumology, University Medical Center Mainz, Mainz, Germany 9 Department of Dermatology, University Hospital Leipzig, Leipzig, Germany *Correspondence: U. Hillen. E-mail: [email protected] 2

Abstract Background Histopathological diagnosis including selection of lesions, the determination of the best point of time for biopsy and workup is not trivial in cutaneous graft-versus-host disease (GvHD). Objectives To develop interdisciplinary recommendations on performing, the laboratory work up and reporting of the results of skin biopsies in patients with suspected cutaneous GvHD. Methods A working group consisting of dermatopathologists, dermatologists, transplant-physicians and transplantpathologists prepared recommendations for performing skin biopsies, laboratory workup and evaluation of tissue samples, and reporting of the results in patients with cutaneous GvHD. After achieving a consensus within the working group, a survey that comprised the core issues of the recommendations was electronically sent out to 72 alloHSCT centres within Germany, Austria, and Switzerland and their Departments of Pathology. The answers were discussed in a Consensus Conference and final recommendations were established. Results Twenty-five centres responded to the clinical and 17 centres to the histopathological survey. Questions addressed to the clinicians comprised the indication for skin biopsy in chronic GvHD (cGvHD) and acute GvHD (aGvHD) and the appropriate point of time for skin biopsy. Eighty-eight per cent agreed that the skin biopsy is generally indicated in patients with suspected cGvHD lacking diagnostic features. In contrast, with suspected aGvHD, only 62% of respondents felt that skin biopsy was necessary even if GvHD had not been confirmed in another organ. Although restricted due to the fact that immunosuppression is often applied in an emergency setting most centres supported skin biopsies before initiation of topical or systemic immunosuppression. The majority of pathologists agreed that in non-sclerotic GvHD a punch biopsy is adequate, whereas in sclerotic GvHD a scalpel biopsy is preferred. Conclusion While a consensus on the need for biopsies in cGvHD was reached the value of skin biopsies in aGvHD and subsequent biopsies during therapy requires further evaluation. Received: 19 March 2014; Accepted: 4 August 2014

Conflicts of interest None.

Funding sources None.

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Introduction In graft-versus-host disease (GvHD) skin biopsy may be of special diagnostic interest because skin is the organ most frequently affected and skin is easily accessible for biopsy. Although skin biopsy itself is a minimally invasive, low-risk, and technically easy procedure, selection of the lesion, and determination of the best point of time for biopsy is not trivial. The aim of the work presented here, was to develop interdisciplinary recommendations [based on the Diagnosis and Staging Working Group Report and the Pathology Working Group Report of the National Institute of Health (NIH)]1,2 on performing skin biopsies, the laboratory work up evaluation of tissue samples and reporting of the results in patients with suspected cutaneous GvHD. GvHD is a potentially life threatening complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). GvHD may have diverse clinical features and is sometimes difficult to discriminate from other diseases. It has been shown earlier that 7% of patients treated for clinically diagnosed GvHD had another disease.3

Methods (Table S1, Table S2) A consensus conference on the histopathology of GvHD was held in November 2010 under the auspices of the German Working Group on Bone Marrow and Blood Stem Cell Transplantation (DAG-KBT) and the Austrian Working Group for Blood and Marrow Transplantation (ASCT) of the German and Austrian Societies of Haematology and Oncology (DGHO and OEGHO), the Swiss Blood Stem-Cell Transplantation Group, and the German-Austrian Working Group on Paediatric Bone Marrow and Blood Stem-Cell Transplantation (PAED-AG-KBT). During five additional meetings between 2011 and 2013, the participants of the Cutaneous Pathology Group performed a literature search using the Pubmed database (considering English written literature published until May 2013), and discussed the diagnostic histological criteria as well as the prerequisites for evaluation of skin biopsies in patients after alloHSCT in clinical practice. The Cutaneous Pathology Group consisted of dermatopathologists, dermatologists and transplant-pathologists. All meetings were supported by at least one haematologist or oncologist with special expertise in clinical management of alloHSCT patients. The aim of the meetings was to prepare recommendations for performing skin biopsies, laboratory workup and evaluation of tissue samples, and reporting of the results in patients with GvHD. After achieving a consensus within the working group, a survey was performed within German, Austrian and Swiss transplant centres to reinsure consensus of the proposed guidelines. The survey comprised the core issues of the recommendations and was electronically sent out to 72 alloHSCT centres within Germany, Austria, and Switzerland and their Departments of Pathology in July 2012. The survey consisted of three questions (Table S1) addressed to the clinicians and 15 questions (Table S2) addressed to the pathologists respectively. Clinicians and

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pathologists were asked to answer with ‘I agree’ or ‘I don’t agree’. In case of non-agreement, the respondents were asked to provide reasons for disagreement. After presentation and discussion of the survey results during the Consensus Conference in November 2012 (Basel, Switzerland), the recommendations were finalized.

Results Of 72 alloHSCT centres, 22 German, three Austrian centres and one Swiss centre (all together 36%) responded to the clinical survey, representing 36% (Germany), 35% (Switzerland) and 48% (Austria) of alloHCT activity within the participating countries in 2012. Among the responding centres, five (19%) were paediatric centres. The histopathological survey was answered by 17 centres (all together 24%), among them 15 German centres, one Austrian and one Swiss centre. Clinician’s survey (Table S1)

Questions addressed to the clinicians comprised the indication for skin biopsy in cGvHD (question 1) and aGvHD (question 2) and the appropriate point of time for skin biopsy (question 3). Twenty-three centres (88%) agreed that skin biopsy is generally indicated in patients with suspected cGvHD lacking diagnostic features (question 1). Disagreeing centres stated to perform skin biopsies dependent on the clinical course (e.g. only if a therapy is intended and/or if patients do not respond to current therapy). Question 2 reached only an agreement of 62%. Ten centres disagreed for the following reasons: (i) Three centres perform skin biopsies dependent on the stage and on the clinical course of aGvHD respectively; (ii) Five centres consider skin biopsies dispensable because of the characteristic clinical features of aGvHD and perform skin biopsies only in cases of atypical clinical features or for exclusion of other diagnoses and (iii) Two centres disagreed because in their experience skin biopsy does not assure distinct discrimination between aGvHD and other diagnoses and thus, is not generally indicated. Finally, the Consensus Conference concluded to recommend skin biopsy in aGvHD although this statement has not been unanimously accepted. Twenty-one (82%) centres agreed to question 3. Performing a skin biopsy prior to initiation of therapy was considered unfeasible by two some centres, two centres only perform skin biopsies for exclusion of other diagnoses if patients do not respond to immunosuppressive therapy. Based on the discussion during the Consensus conference, it is recommended that skin biopsy should be performed before initiation of any therapy including topical one. Detailed information is given in Table S1. Pathologist’s survey (Table S2)

Agreement was 100% in five (questions 5,11,13–15), 94% in seven questions (1,2,4,6,7,9,12), 88% in two (questions 3,8) core

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issues, respectively, and 77% (question 10) in one core issue. Questions 1–4 and 11 requested the adequate kind of biopsy. In non-sclerotic GvHD, the majority considered a punch biopsy as adequate. Most of the pathologists preferred at least a 6 mm punch biopsy, whereas clinicians tended to a smaller biopsy size. During the Consensus Conference agreement was reached that at least a 4 mm punch biopsy is required. A scalpel biopsy was considered adequate by most pathologists in sclerotic GvHD. The Consensus Conference concluded that in situations where a scalpel biopsy is not available, a (6–) 8 mm punch biopsy may be performed. Only one pathologist considered a shave biopsy as adequate under certain conditions. Reporting of histological grading was recommended by three pathologists despite the fact that histological grading does not predict disease severity in aGvHD to improve standardized evaluation. Detailed information is given in Table S2.

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Checkbox 1 Consensus recommendations i

ii

Consensus recommendations

The recommendations are depicted in Checkbox 1.

Discussion

iii

Skin biopsy may have an important impact on treatment decisions in GvHD. In a recently published retrospective study, a total of 430 biopsies were performed in 192 of the 439 HSCT recipients. The clinical and histopathological diagnoses differed in 240 episodes (56%) and biopsy led to management modifications in 69 (16%) of them, underlining the significance of cutaneous biopsy.4 Indication for skin biopsy

The rationale for obtaining biopsy samples in patients with GvHD and the limitations have been extensively discussed in the Pathology working group of the NIH.2 However, recommendations for skin biopsy were focused on cGvHD and use in clinical trials. Biopsies were recommended for confirmation of active cGvHD, in patients without diagnostic but only distinctive clinical features of cGvHD and for exclusion of other diagnoses.2 Nevertheless, also patients who present clinically with so called ‘other features’ (according to the classification of signs and symptoms of the Diagnosis and Staging Working Group of the NIH) – e.g. keratosis pilaris – may have (active) GvHD. Moreover, also in patients with aGvHD skin biopsies may be of diagnostic significance, especially, as no diagnostic signs as in cGvHD have been established. Our survey revealed that in aGvHD indication for skin biopsy was not as unequivocal as in cGvHD. Some centres perform skin biopsies only dependent on the clinical course or in case of atypical presentation. Moreover, the role of subsequent biopsies to assess treatment response has not been determined. Also, the utility of screening biopsies in asymptomatic patients who are still taking immunosuppressive medications is controversial.2 Nevertheless, there was a consensus that in patients refractory to immunosuppressive therapy a

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iv

v

Indication for biopsy: Taking into consideration that skin biopsy is a minimally invasive, low-risk and technically easy procedure we recommend that biopsies be obtained in all patients lacking diagnostic features of cGvHD. Clinical information The clinician should present relevant information to the histopathologist.20 Information required is: patient’s age and gender, disease duration/duration of the lesion, history of previous treatments, distribution, configuration and arrangement of lesions, morphology of the individual lesion, localization and type of biopsy, suggested clinical diagnosis and differential diagnosis. A clinical information form for pathologists has been developed and is available online (www. gvhd.eu). Kind of lesion for biopsy The sample should be obtained from a fully developed lesion (without secondary changes). a In cases of sclerotic changes, biopsies from the back should be avoided, as the reticular dermis physiologically is very thick in this localization. b In general, the lower legs should be spared to prevent impaired wound healing. c It may be helpful to take several or sequential biopsies, in particular if primary lesions are present in different stages of evolution. d In cases of vesicular or bullous lesions, or even widespread epidermolysis, biopsy should be performed at the periphery of the blister/bulla, including larger parts of the surrounding erythema. Type of biopsy to be performed a In non-sclerotic GvHD, a punch biopsy is adequate. The biopsy punch should penetrate up to the subcutaneous adipose tissue. At least a 4 mm punch is necessary. b In sclerotic GvHD, a scalpel biopsy (elliptical biopsy) is recommended, which should include the deep subcutis, and if necessary the fascia. In cases in which a scalpel biopsy is refused or impracticable a (6–) 8 mm punch biopsy may be performed instead. Fixation The specimen should be put into 4% or 10% buffered formalin (formaldehyde). The amount of formalin should exceed the volume of the specimen by about 20 times.

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vi Number of slides and routine stainings a Number of slides Each laboratory should use its own standard. If histopathological characteristics of GvHD are not present or if GvHD cannot be excluded, further sections have to be performed in order to fulfil the NIH recommendations.2 b In routine, no stainings beyond H&E are obligatory. vii Items of the pathological report a The descriptive morphological section and a morphological diagnosis based on a pattern diagnosis b A final diagnosis according to the NIH categories (not GvHD, possible GvHD, consistent with GvHD, GvHD) c Presence of criteria for active disease according to the Pathology Working Group Report2 d Possible differential diagnosis (diagnoses) e Reporting of aGvHD grading is not generally recommended.

Checkbox 2 Type and localization of biopsy

• Non-sclerotic GvHD Kind of biopsy: at least 4 mm punch biopsy. Localization: preferentially from an infiltrated lesion Depth of biopsy: epidermis, dermis and parts of the subcutis • Sclerotic GvHD Kind of biopsy: scalpel biopsy, alternatively (6–) 8 mm punch biopsy Localization: sclerotic skin, if possible avoid lower leg Depth of biopsy: epidermis, dermis and subcutis, and, where necessary, parts of the fascia.

of biopsies in these situations may be restricted to selected cases to rule out concomitant diseases. Type of biopsy (Checkbox 2)

subsequent biopsy may provide additional and clinically relevant information. Point of time, appropriate lesions for and localization of biopsy

As histopathological features may be substantially influenced by systemic immunosuppressive and topical anti-inflammatory therapy, the majority of centres affirmed that biopsy should ideally be performed before initiating any therapeutic intervention, including topical therapy. In clinical routine this is not always feasible when patients are in urgent need of treatment. Histopathological changes of early aGvHD are non-specific, and may also occur in early phases of viral or drug-induced rashes and cutaneous eruption of lymphocyte recovery (ELR).5,6 It has been supposed that ELR does not reflect an own entity but rather a different presentation of autologous GvHD.7 Horn and Haskell8 reported that donor lymphocytes are rarely seen in the epidermis prior to 14 days post alloHSCT, Therefore, it has been suggested that biopsies should not be performed prior to 21 days after transplantation.9 However, it has been stated that performing a skin biopsy may help consolidate the diagnosis in the presence of other tests, such as liver function tests.10 Systematic investigations for sensitivity of skin biopsies for early detection of aGvHD with clinical–histopathological correlation are still pending.5,6 There was a consensus that in sclerotic changes biopsies from the back and the leg should be avoided because especially biopsies from the lower legs are prone to impaired wound healing. Nevertheless, if the most representative lesion is located on the lower leg, biopsy from that site was regarded to be justified. As sclerotic changes are regarded as diagnostic in cGvHD, the use

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There was an intense discussion between clinicians and pathologists regarding the size and depth of biopsies. Pathologists in general always advocate for larger biopsies. Therefore, four questions addressing this issue were sent to the pathologists. If only small or superficial biopsies (e.g. 3 mm punch) are performed, changes important for the diagnosis may be missed (e.g. focal interface dermatitis, changes at the skin adnexae if the biopsy does not include hair follicles or sweat glands, changes in the deep dermis and subcutis). Most pathologists agreed that a punch biopsy (preferred size at least 6 mm) is sufficient in nonsclerotic GvHD, however, in sclerotic GvHD scalpel biopsy was considered adequate (Checkbox 2). Staining and number of sections

In our survey all responding pathologists agreed that each lab should use its own standard (e.g. five sections) as a first step. If histopathological characteristics of GvHD are not present or if GvHD cannot be excluded, further sections should be prepared to fulfil the NIH-recommendations. In routine, no stainings beyond H&E [such as periodic-acid-Schiff (PAS), Elastica van Gieson] are obligatory, but can be helpful to discriminate other diagnoses. Only one pathologist advocated for additional stainings for routine work up. Histopathological features of acute and chronic GvHD

After the so called ‘endothelial phase of aGvHD’ interface changes, especially vacuolar degeneration within the tips of epidermal rete ridges and adnexae are observed.11,12 Apoptosis within the epidermis, follicular and/or eccrine epithelium are observed, eventually leading to ‘satellitosis’, ‘cytotoxic infundibular folliculitis’ or ‘cytotoxic syringitis’.6,12,13 By the time, some hyperkeratosis

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have been found frequently in cases of GvHD and likely do not serve as a valuable differential criterion for drug-induced exanthemas.5,17 Nevertheless, systematic analysis of this feature is still missing. Characteristically (but not obligatory), both epidermis and stratum corneum are thickened. Early maturation of epidermal layers typically present with hypergranulosis, similar to that seen in idiopathic lichen planus. Thorough search for interface changes and apoptotic keratinocytes reveals follicular and other adnexal involvement. Moreover, lichenoid cGvHD may show focal parakeratosis and scaling, which is hardly ever found in authentic lichen planus. These features can be summarized as ‘the hallmark changes in cGvHD’ of lichen planus-like type, which were accepted by 94% of responding pathologists. Indeed, these are mainly also the hallmark changes of aGvHD, although mostly they are less distinctive in the acute form of the disease. All pathologists surveyed agreed that therefore discrimination of aGvHD form cGvHD is

and hypergranulosis develop, although these may be observed also in asymptomatic patients after alloHCST.14 In 40% of patients with late-onset aGvHD concomitant histological features of chronic lichenoid chronic GVHD may be observed, who subsequently are at higher risk to progress to fully developed cGVHD.15 cGvHD has traditionally been divided into epidermal (lichen planus-like) and dermal (sclerotic) types. However, biopsies frequently present hybrid features with alterations of epidermal and dermal or subcutaneous structures or even fascia. In some cases, epidermal alterations can manifest earlier, and eventually be followed by dermal sclerotic forms.16 Epidermal changes in cGvHD are generally less subtle than those observed in the acute form. The lymphoid infiltrate is usually not sparse, and may fill the papillary dermis in a bandlike lichenoid manner; in addition, a lymphoplasmacytic inflammation around eccrine coils may be seen. Eosinophils Table 1 Clinicopathological correlations based on pattern diagnoses Clinical criteria

Predominate pattern

Histopathological findings

Maculopapular exanthema [maculopapular rash]

Interface - vacuolar

- minimal epidermal changes: ○ possible acanthosis ○ possible hypergranulosis ○ vacuolar degeneration with apoptotic keratinocytes in the lower epidermal layers - involvement of adnexal epithelia (infundibula, acrosyringia) possible - sparse to moderate lymphocytic infiltrate, some eosinophils possible

Lichen planus-like eruption [Lichen planus-like-features]

Interface - lichenoid

- epidermal changes: ○ hyperkeratosis ○ hypergranulosis ○ acanthosis ○ lichenoid infiltrate and vacuolar interface changes ○ apoptotic keratinocytes in the lower epidermal layers - involvement of adnexal epithelia (infundibula, acrosyringia) - sparse to moderate band-like lymphocytic infiltrate -solitary melanophages in papillary dermis

Poikiloderma [Poikiloderma]

Mixed

Time dependent changes: residual lichen-planus-like features, melanophages and variable changes connective tissue of the papillary dermis, dilated vessels in superficial dermis

Keratosis pilaris [Keratosis pilaris]

Follicular interface - lichenoid - vacuolar

- lichenoid infiltrate and vacuolar interface changes around infundibula or deeper parts of the hair follicle* - apoptotic keratinocytes in the infundibular or deeper follicular epithelium*

Sclerotic GvHD

Sclerosing dermatitis with or without panniculitis (mostly septal) dermal changes - papillary - reticular - both subcutaneous changes - septal - lobular - combined

Changes of connective tissue: - collagenous deposition with thickening, homogenization and dense packing of fibres ○ throughout the papillary dermis ○ and/or reticular dermis ○ and/or subcutis with residual interface changes most often in terms of melanophages in the papillary dermis sparse or no lymphocytic infiltrate variable numbers of fibroblasts and mast cells

Fasciitis

Fibrous thickening of fascia with adjacent inflammation

[Lichen sclerosus-like features] [Morphaea-like sclerotic features] [Sclerotic features]

Fasciitis [Fasciitis]

[] Terminology according to the ‘Diagnosis and Staging Working Group’ report.1 *based on limited published data of histopathological findings.

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challenging. Other changes may include epidermal spongiosis and minimal compaction and fibrosis of the perifollicular papillary dermis, eventually leading to discrete superficial sclerosis. Early dermal alterations include a perivascular and interstitial lymphoplasmacellular infiltrate in the reticular dermis. Late stages present homogenized and broadened collagen, often without significant inflammation with adnexal structures being frequently atrophic or completely absent. Sclerotic changes may be seen in the very superficial dermal layers (then resembling lichen sclerosus), or be located much deeper with involvement of subcutaneous structures or even muscular fascia (then resembling morphaea profunda or eosinophilic fasciitis/Shulman syndrome).5,16 Fibrotic disease often has a top-down progression. Histopathologically, sclerotic GvHD may have features not occurring in morphaea/systemic sclerosis (scant vacuolar alteration, apoptotic keratinocytes, melanophages in the papillary dermis). Hallmark features for ongoing GvHD activity are residual apoptotic changes in the epidermis or epithelia of appendages.5,6,16 However, although the majority agreed, two pathologists surveyed believed that apoptoses are not a conditio sine qua non for active disease. Minimal criteria for cutaneous sclerotic cGvHD need homogenization of most of the papillary or reticular dermis2 which reached a consensus of 100% in the survey. Description of clinical and pathological findings

In Table 1, the predominant morphological pattern for each clinical sign of cutaneous cGvHD is listed (with the exception of erythema, sweat impairment and pruritus). Maculopapular rash is a manifestation of cutaneous GvHD. The histological pattern is vacuolar interface dermatitis. Scleroderma may manifest on different levels of the cutis/subcutis; the pattern is sclerosing dermatitis. In the pathological report, the different anatomic levels of the cutis and/or subcutis affected by sclerosis should be described. In poikiloderma, changes depend on the point of time when biopsy is performed. On microscopic examination, residual lichen planus-like features, melanophages, variable changes in connective tissue of the papillary dermis, and dilated vessels in superficial dermis may be observed. Thus, as we are not able to describe a uniform pattern, it is ‘mixed’. GvHD which manifests clinically as keratosis pilaris shows predominantly lichenoid interface dermatitis at the follicular epithelium and follicular hyperkeratosis. Depigmentation occurring after alloHSCT may affect the entire skin including the hair or may be patchy. Histopathologically, a loss of melanocytes is observed.18,19 It has been assumed that in GvHD, similar to vitiligo, melanocytes are destroyed by cytotoxic T-lymphocytes.18,19 However, vitiligo occurring after alloHSCT may also be drug-induced or caused by transfer from the donor to the host, which cannot be discriminated solely by routine histology. Depigmentation may become apparent after GvHD has resolved, thus, only residues of active GvHD may be

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Checkbox 3 Clinical information required for pathological examination of skin biopsies in GvHD

• • • • • • •

Age and gender of the patient Duration of disease/biopsied lesion History of previous treatments Distribution, configuration and arrangement of lesions Morphology of the individual lesion Localization and type of biopsy Suggested clinical diagnosis and differential diagnosis

observed in the biopsy. However, at the moment there is not enough published data to define a pattern for ‘hyperpigmentation’, ‘hypopigmentation’, ‘depigmentation’ and ‘ichthyosis’. In addition, GvHD, which becomes clinically apparent as keratosis pilaris (keratosis pilaris-like features), awaits more detailed histopathological characterization. Pathology report

We propose that the pathological report be composed of: (i) the descriptive morphological section and a morphological diagnosis based on a pattern diagnosis; (ii) a final diagnosis according to the NIH categories2 (should be superscript) (not GvHD, possible GvHD, consistent with GvHD, GvHD); (iii) presence of criteria for active disease according to the Pathology Working Group Report and (iv) possible differential diagnosis (diagnoses). The morphological diagnosis, (e.g. sclerosing dermatitis in the deep reticular dermis), may be easily correlated with clinical findings and ‘translated’ into a clinical diagnosis (e.g. morphaealike features, if induration of the skin is circumscribed). The prerequisite for a proper final diagnosis is the correlation of the pathological and clinical findings, e.g. on routine histology, morphaea and morphaea-like lesions of cGvHD cannot be discriminated, but this is trivial if clinical information (patient after alloHSCT or not) is available. Thus, the category GvHD (yes, without equivocation) according to NIH can only be reached in the pathology report if clinical information is available and clinical and pathological findings are congruent. Especially in inflammatory skin diseases, clinico-histopathological correlation is crucial for correct diagnosis which has recently been shown in an interobserver comparison of GvHD skin biopsy samples.17 Clinical information being crucial for the pathologist is listed in Checkbox 3 and an information form for pathologists has been developed and is available online (www. gvhd.eu). Histological grading of aGvHD does not predict disease severity.5 Nevertheless, severity reporting was advocated by four pathologists because it improves standardized evaluation

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of histopathological changes and is often requested by clinicians. In summary, the participants of the consensus process agreed on the importance of histopathological confirmation of GvHD in the absence of diagnostic changes in clinical routine including standardized work-up and reporting and underlined the importance of prospective evaluation of the impact of histopathology in cutaneous GvHD.

References 1 Filipovich AH, Weisdorf D, Pavletic S 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: 945–956. 2 Shulman HM, Kleiner D, Lee SJ et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graftversus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 2006; 12: 31–47. 3 Jacobsohn DA, Montross S, Anders V, Vogelsang GB. Clinical importance of confirming or excluding the diagnosis of chronic graft-versushost disease. Bone Marrow Transplant 2001; 28: 1047–1051. 4 Paun O, Phillips T, Fu P et al. Cutaneous complications in hematopoietic cell transplant recipients: impact of biopsy on patient management. Biol Blood Marrow Transplant 2013; 19: 1204–1209. 5 Wagner JM. Pathology and pathogenesis of cutaneous graft-vs.-host disease. Marcel Dekker, New York, 2005. 6 Karrer S. Graft-versus-Host disease der Haut. Hautarzt 2003; 54: 465–480. 7 Nellen RG, van Marion AM, Frank J et al. Eruption of lymphocyte recovery or autologous graft-versus-host disease? Int J Dermatol 2008; 47(Suppl 1): 32–34. 8 Horn TD, Haskell J. The lymphocytic infiltrate in acute cutaneous allogeneic graft-versus-host reactions lacks evidence for phenotypic restriction in donor-derived cells. J Cutan Pathol 1998; 25: 210–214. 9 Kuykendall TD, Smoller BR. Lack of specificity in skin biopsy specimens to assess for acute graft-versus-host disease in initial 3 weeks after bonemarrow transplantation. J Am Acad Dermatol 2003; 49: 1081–1085. 10 Firoz BF, Lee SJ, Nghiem P, Qureshi AA. Role of skin biopsy to confirm suspected acute graft-vs-host disease: results of decision analysis. Arch Dermatol 2006; 142: 175–182.

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11 Sale GE, Beauchamp M. Parafollicular hair bulge in human GVHD: a stem cell-rich primary target. Bone Marrow Transplant 1993; 11: 223– 225. 12 H€ausermann P, Walter RB, Halter J et al. Cutaneous graft-versus-host disease: a guide for the dermatologist. Dermatology 2008; 216: 287– 304. 13 Lerner KG, Kao GF, Storb R et al. Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc 1974; 6: 367–371. 14 Vassallo C, Brazzelli V, Alessandrino PE et al. Normal-looking skin in oncohaematological patients after allogenic bone marrow transplantation is not normal. Br J Dermatol 2004; 151: 579–586. 15 Bridge AT, Nelson RP Jr, Schwartz JE et al. Histological evaluation of acute mucocutaneous graft-versus-host disease in nonmyeloablative hematologic stem cell transplants with an observation predicting an increased risk of progression to chronic graft-versus-host disease. Am J Dermatopathol 2007; 29: 1–6. 16 Shulman HM, Sullivan KM, Weiden PL et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217. 17 Ziemer M, Haeusermann P, Janin A et al. Histopathological diagnosis of graft-versus-host disease of the skin - an interobserver comparison. J Eur Acad Dermatol Venereol 2014; 28: 915–924. 18 Sanli H, Akay BN, Arat M et al. Vitiligo after hematopoietic cell transplantation: six cases and review of the literature. Dermatology 2008; 216: 349–354. 19 Williams JS, Mufti GJ, du Vivier AW et al. Leucoderma and leucotrichia in association with chronic cutaneous graft-versus-host disease. Br J Dermatol 2008; 158: 172–174. 20 Weyers W. Diaz C [Basic principles of skin biopsy]. Pathologe 2002; 23: 4–8.

Supporting information Additional Supporting Information may be found in the online version of this article: Table S1. Survey: core issues clinicians Table S2. Survey: core issues pathologists

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Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease.

Histopathological diagnosis including selection of lesions, the determination of the best point of time for biopsy and workup is not trivial in cutane...
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