Cutaneous manifestations of graft-versus-host disease (GVHD)

INTRODUCTION — Acute and chronic graft-versus-host disease (GVHD) are multisystem disorders that are complications of hematopoietic cell transplant (HCT). Skin involvement is common, and mucosal, hair, or nail abnormalities may also occur. Because these disorders share clinical and histopathologic features with a variety of other skin diseases, thorough consideration of the differential diagnosis is essential for the management of post-HCT patients with lesions suggestive of cutaneous GVHD.

The clinical and histopathologic features, differential diagnosis, and supportive therapy of cutaneous GVHD will be reviewed here. The epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prevention of acute and chronic GVHD are reviewed in greater detail separately. (See "Pathogenesis of graft-versus-host disease (GVHD)" and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Prevention of graft-versus-host disease" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease" and "Treatment of chronic graft-versus-host disease".)

CLASSIFICATION — Classically, GVHD has been divided into acute and chronic forms based upon the time of onset of disease:

●Acute GVHD – Manifestations of GVHD occurring within 100 days after hematopoietic cell transplant (HCT)

●Chronic GVHD – Manifestations of GVHD occurring more than 100 days after HCT

However, this conventional division has been challenged by the recognition that signs of acute and chronic GVHD may occur outside of these designated periods. This observation has led to increasing use of clinical findings, rather than a set time period, to differentiate between acute and chronic GVHD [1]. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Introduction'.)

ACUTE CUTANEOUS GRAFT-VERSUS-HOST DISEASE — Acute GVHD is common after allogenic hematopoietic cell transplant (HCT), and can lead to disorders of the skin, gastrointestinal tract, liver, and hematopoietic system. Cutaneous involvement is often the earliest manifestation of acute GVHD; skin lesions frequently appear within two to four weeks of HCT but may occur any time after hematopoietic cell engraftment. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

Clinical manifestations

Skin lesions — Acute cutaneous GVHD typically begins with erythematous, blanchable macules on the ears, palms, or soles (picture 1). The lateral neck, cheek, and upper back are additional common sites of early involvement [2,3]. Follicular-based lesions are present in some patients (picture 2) [3-5].

As acute cutaneous GVHD progresses, lesions become generalized, and the eruption often takes on a morbilliform (measles-like) appearance. Smooth or hyperkeratotic papules and postinflammatory hyperpigmentation may occur [2,3]. In severe cases, patients develop atypical target lesions, generalized erythroderma, bullae, or extensive skin sloughing, resembling Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (picture 3). (See 'Differential diagnosis' below and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Skin'.)

Patients with acute cutaneous GVHD may complain of pruritus or a burning sensation in the skin. In some patients, skin pain or pruritus precedes the onset of visible skin lesions [4].

As with intestinal and hepatic GVHD, a staging system is used to describe the extent of cutaneous involvement (table 1) [6]:

●Stage 1 – Less than 25 percent body surface area (BSA) involvement

●Stage 2 – 25 to 50 percent BSA involvement

●Stage 3 – Greater than 50 percent BSA involvement

●Stage 4 – Erythroderma with bullae

The combined stages of skin, liver, and gastrointestinal disease are used to determine the overall severity (grade) of acute GVHD (table 1). The presence of erythroderma and bullae (as may occur in SJS/TEN-like acute cutaneous GVHD) is sufficient to diagnose grade 4 GVHD and is associated with a poor prognosis [6]. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

Oral lesions — Erythema, erosions, ulcers, lichenoid lesions, xerostomia, and pain involving the oral cavity have been attributed to acute GVHD [4,7]. However, relatively little is known about oral acute GVHD due to difficulty in distinguishing this disorder from mucositis secondary to chemotherapy administered in preparation for HCT. Some authors have suggested that lesions that persist for longer than three weeks after HCT or involve the hard palate (an uncommon site for chemotherapy-induced mucositis) may be more likely to represent acute GVHD [4]. (See "Oral toxicity associated with systemic anticancer therapy".)

Diagnosis — In the absence of concomitant extracutaneous manifestations, making a definitive diagnosis of acute cutaneous GVHD may be challenging. The clinical findings are nonspecific and can be difficult to distinguish clinically from other skin eruptions that occur in post-HCT patients and there are no pathognomonic histopathologic features [8]. Correlation between clinical and pathologic findings is essential. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Diagnosis' and 'Differential diagnosis' below.)

A retrospective study of patients with acute cutaneous GVHD with SJS/TEN-like features (n = 15) or without these features (n = 16) found a higher rate of systemic complications, including hematologic abnormalities, hepatitis, diarrhea, renal dysfunction, and bacteremia, in patients with SJS/TEN-like acute cutaneous GVHD [9]. Moreover, patients with SJS/TEN-like acute cutaneous GVHD had higher short-term mortality (death of three patients with SJS/TEN-like features within two months compared with no patients without SJS/TEN-like features) and higher five-year mortality (hazard ratio 5.351, 95% CI 1.838-15.580).

Skin biopsy

Procedure and findings — A 4 mm punch biopsy sent for hematoxylin and eosin staining is generally sufficient to evaluate for acute cutaneous GVHD. Immunofluorescence testing may demonstrate nonspecific IgM and complement deposits at the basement membrane zone [10] but generally is not indicated.

Key histopathologic findings in acute cutaneous GVHD include interface dermatitis (vacuolization of the basal layer of the epidermis and a lymphocytic infiltrate in the superficial dermis) and epidermal apoptotic keratinocytes (picture 4). Apoptotic keratinocytes may also be present in the follicular epithelium [4,11]  

The lymphocytic infiltrate can be sparse and perivascular or more extensive. Migration of lymphocytes into the epidermis (lymphocyte exocytosis) is common. The presence of satellite cell necrosis (two or more lymphocytes surrounding an apoptotic keratinocyte) also supports a diagnosis of acute GVHD. Fulminant lesions demonstrate subepidermal clefting and full-thickness necrosis of the epidermis [4,11].

The criteria often used for categorizing the histopathologic findings in acute GVHD are as follows [12]:

●Grade 0 – Normal skin or changes not referable to GVHD

●Grade 1 – Vacuolization of the basal layer at the dermal-epidermal junction

●Grade 2 – Basal layer vacuolization, necrotic epidermal cells, lymphocytic infiltrate (picture 4)

●Grade 3 – Grade 2 changes plus cleft formation at the dermal-epidermal junction

●Grade 4 – Grade 2 changes plus separation of the epidermis from the dermis

Reliability and value — The sensitivity and specificity of skin biopsy for acute GVHD has not been definitively established. In general, a diagnosis of acute cutaneous GVHD is supported by the appearance of a consistent cutaneous eruption occurring in a time period that correlates with the return of neutrophils to the peripheral circulation (engraftment) and at least grade 2 changes on histopathologic examination [13]. Biopsies taken early in the course of GVHD may reveal nondiagnostic findings. In one retrospective study of 40 biopsy specimens from 38 patients with skin eruptions taken between 3 and 21 days after HCT, the histopathologic findings were nonspecific in all cases [14].

In addition, it is unclear whether skin biopsies influence the decision to treat or affect disease outcomes in patients with acute GVHD. Thus, the value of performing a skin biopsy, particularly early in the course of acute GVHD, has been questioned by some authors [15-18]. Few studies have investigated the role of skin biopsies. The following studies found little evidence in support of this procedure:

●A retrospective study of 187 patients who had received allogenic HCT within the preceding 30 days found that the results of skin biopsies (performed in 51 patients who developed skin eruptions suggestive of GVHD) did not influence the likelihood of patients to receive treatment. In addition, skin biopsy results failed to correlate with clinical severity of skin disease [15].

●In a retrospective study of patients with a new skin eruption who were status post allogenic HCT, 98 skin biopsies from 71 patients with clinical grade 2 or higher acute GVHD were compared with 81 biopsies from 66 patients who did not progress to clinically significant acute GVHD [18]. No single histopathologic finding was found to be a statistically significant diagnostic indicator of GVHD. The authors concluded that biopsies were of limited use for determining which patients will progress to grade 2 or higher GVHD.

Despite the lack of strong evidence to support performing a skin biopsy in patients with suspected GVHD, a biopsy may provide information that can be used in conjunction with other clinical findings to support a diagnosis of acute GVHD or to establish an alternative cause of the skin eruption. Due to the relative safety of skin biopsy procedures and the known risks associated with immunosuppressive therapy used in the management of acute GVHD, many clinicians, including ourselves, continue to perform skin biopsies in post-HCT patients with skin eruptions for which the differential diagnosis includes acute GVHD. Additional studies are necessary to investigate the utility of skin biopsy in the management of acute GVHD and the most appropriate setting and timing for skin biopsy. Potential adverse effects of skin biopsy include minor bleeding, infection, and scarring.

Differential diagnosis — Multiple other disorders may present with clinical or histopathologic features that resemble acute GVHD. The following conditions should be considered [8]:

●Drug eruptions – Differentiation of acute GVHD from a drug eruption may not be possible (picture 5). Morbilliform drug reactions typically develop 7 to 10 days after first exposure to the inciting medication; however, more rapid onset (within one to two days) may occur upon re-exposure to an offending agent. Unlike GVHD, which most commonly starts on the head, neck, and acral sites, morbilliform drug reactions typically begin on the torso and spread over several days to involve the lower extremities [19,20]. Although the presence of eosinophils on biopsy is often associated with drug eruptions, the presence of eosinophils does not rule out GVHD [21]. (See "Exanthematous (maculopapular) drug eruption".)

Antibiotics, particularly sulfonamides and beta-lactams, are the most common causes of drug eruptions in the post-HCT setting [8]. Phototoxic drug eruptions secondary to voriconazole may also be mistaken for GVHD [22].

●Viral exanthems – Viral infections (eg, human herpesvirus [HHV] 6, HHV-7, cytomegalovirus, others) can induce maculopapular or morbilliform eruptions in post-HCT patients (picture 6) [2,8,23]. Skin biopsy specimens secondary to viral exanthems often demonstrate sparse perivascular lymphocytic infiltrates. Disease-specific clinical, laboratory, or histopathologic findings (eg, intranuclear inclusions in cytomegalovirus infection), when present, may be useful for distinguishing viral diseases from GVHD.

The frequency with which viral eruptions cause skin eruptions in post-HCT patients is unclear. HHV-6B reactivation has been associated with increased risk of grades 2 through 4 acute GVHD [24].

●Eruption of lymphocyte recovery – Lymphocyte recovery describes the return of lymphocytes to the peripheral circulation following marrow ablative therapy. The eruption of lymphocyte recovery is a self-limited skin exanthem associated with transient fever that was first described following recovery of lymphocyte counts in patients treated with chemotherapy [25]. Unlike GVHD, gastrointestinal and hepatic abnormalities do not occur. Histopathologic examination typically demonstrates a superficial perivascular mononuclear cell infiltrate [25]; however, histopathologic findings resembling those of grade 1 or 2 acute GVHR also have been observed [26].

●Acral erythema – Acral erythema (also known as palmoplantar erythrodysesthesia) is a complication of chemotherapy (picture 7A-B). Like acute GVHD, acral erythema affects the palms and soles. Painful symmetrical edema and erythema occur; blistering and desquamation also may develop. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Toxic erythema of chemotherapy'.)

●Toxic epidermal necrolysis – Severe cases of acute GVHD share clinical and histopathologic features with toxic epidermal necrolysis, a severe skin reaction typically induced by a medication (picture 8A-D). Toxic epidermal necrolysis typically begins with dusky erythematous macules that rapidly progress to extensive blistering and desquamation. Histopathologic examination of established lesions reveals subepidermal bullae and full-thickness epidermal necrosis. Differentiation between severe GVHD and toxic epidermal necrolysis is sometimes impossible. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

●Engraftment syndrome – Engraftment syndrome presents with a cutaneous eruption that mimics acute GVHD, fever without identifiable infectious source, and signs of capillary leak syndrome (eg, noncardiogenic pulmonary edema with hypoxia, weight gain) [27]. Engraftment syndrome is most commonly considered a phenomenon of autologous HCT; however, it may also occur after allogenic HCT [28].

●Radiation dermatitis – Acute radiation dermatitis presents with cutaneous erythema, desquamation, blistering, or cutaneous necrosis. The histopathologic features are similar to acute GVHD, demonstrating vacuolization of the basal layer, apoptotic keratinocytes, satellite cell necrosis, and a superficial perivascular lymphocytic infiltrate. (See "Radiation dermatitis".)

●Erythema multiforme – Erythema multiforme is an immune-mediated disorder that most commonly occurs in the setting of herpes simplex virus infection (picture 9A-C). Like acute GVHD, the histopathologic findings in erythema multiforme include necrotic keratinocytes, subepidermal clefts, and vacuolization of basal keratinocytes. The clinical identification of target and targetoid lesions, suggests a diagnosis of erythema multiforme. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

CHRONIC CUTANEOUS GRAFT-VERSUS-HOST DISEASE — Chronic GVHD is a major cause of morbidity and mortality in long-term survivors of allogeneic hematopoietic cell transplantation (HCT). The skin is the most common site of involvement; however, nearly all organ systems may be affected (table 2). Chronic GVHD may occur with or without a history of acute GVHD [2,3]. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

Clinical manifestations

Skin — Traditionally, chronic cutaneous GVHD has been classified as lichen planus-like or sclerotic (resembling scleroderma); however, many different clinical presentations of chronic GVHD are now recognized, reflecting a spectrum of epidermal and dermal (sclerotic) changes.

Cutaneous and extracutaneous diagnostic criteria for chronic GVHD composed by a panel of experts in the National Institutes of Health Consensus project have been published [1]. The panel designated lichen planus-like lesions, sclerotic skin manifestations, and poikilodermatous changes in the skin as clinical features that are diagnostic of chronic GVHD.

Lichen planus-like lesions — Lichen planus-like chronic GVHD presents as erythematous to violaceous papules or plaques with a predilection for the dorsal hands and feet, forearms, and trunk (picture 10). Fine scale may be present. Lesions resemble true lichen planus. Patients may complain of pruritus. (See "Lichen planus".)

Lichen planus-like chronic GVHD also can occur in a follicular distribution, mimicking the appearance of keratosis pilaris [1]. Lesions in sites of herpes zoster scars or following Blaschko's lines have been reported [29]. Although lichen planus-like GVHD is sometimes considered an earlier form of GVHD than sclerotic GVHD, it is not a prerequisite for the development of sclerotic disease manifestations [30].

Sclerotic manifestations — Sclerosis is a common manifestation of chronic GVHD [31-33]. A retrospective study of 977 patients who received systemic treatment for chronic GVHD after a first allogenic HCT found that 20 percent of patients had sclerosis (defined by documentation of cutaneous sclerosis, fasciitis, or joint contracture in the medical record) by three years after initial systemic treatment for chronic GVHD [31].

Sclerotic skin manifestations of chronic GVHD can develop in sites of resolving lichen planus-like lesions or in areas of previously normal skin. Lesions may occur in any location. The depth at which cutaneous sclerosis occurs determines the clinical presentation [34]:

●Morpheaform – Morphea-like chronic GVHD results from sclerosis that primarily involves the dermis. This variant usually presents with firm, hyperpigmented, hypopigmented, or skin-colored plaques (picture 11). Affected skin often has a shiny appearance and demonstrates hair loss secondary to elimination of adnexal structures. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults" and "Juvenile localized scleroderma".)

Unlike systemic sclerosis, body surface area involvement in sclerotic GVHD often is discontinuous. In some cases, lesions may preferentially appear in sites of skin trauma (Koebner phenomenon) [35,36]. In one series of 58 patients with sclerotic chronic GVHD, 11 (19 percent) exhibited strikingly linear lesions in the waistband area [35]. Extensive involvement of the chest wall may lead to respiratory symptoms secondary to restricted chest expansion.

●Lichen sclerosus-like – When sclerosis occurs in the superficial dermis, lesions resemble lichen sclerosus, a dermatosis characterized by epidermal atrophy and superficial dermal fibrosis. Lichen sclerosus-like lesions are typically found on the upper back as white or gray, thin plaques with accentuated dermatoglyphics. (See "Extragenital lichen sclerosus: Clinical features and diagnosis".)

●Deep sclerosis/eosinophilic fasciitis-like – Deep sclerosis may also occur. Subcutaneous fibrosis results in a cellulite-like rippled appearance to the skin due to thickening of the fibrous septae within fat, particularly on the medial arms and thighs (picture 12). Fascial involvement tends to occur late in the chronic period, and may lead to the appearance of prominent linear demarcations, often referred to as the "groove sign," and contractures that limit range of motion (picture 13). In eosinophilic-fasciitis-like cases, these findings of deep sclerosis are often accompanied by pain and edema [34]. (See "Eosinophilic fasciitis".)

The development of bullae or ulcerations may complicate sclerotic disease [29]. (See "Pathogenesis of graft-versus-host disease (GVHD)".)

Additional studies are necessary to clarify the risk factors and prognostic implications for sclerosis in chronic GVHD. In the retrospective study of 977 patients described above, a significant increase in risk for sclerosis was observed among patients who received a mobilized blood cell graft compared with a bone marrow graft and patients who received total body irradiation (TBI) exposure >450 Gy in the conditioning regimen compared with no TBI [31]. Unexpectedly, use of an HLA-mismatched donor was associated with a reduced risk of sclerosis, as was the use of an ABO-mismatched donor. Sclerosis was not associated with risk for subsequent mortality or recurrent malignancy. A significant association between sclerotic chronic GVHD and TBI also was demonstrated in a separate study of 206 patients with primarily severe chronic GVHD [33].

Poikiloderma — Poikiloderma describes the combination of atrophy, hypopigmentation, and hyperpigmentation in the skin. Poikilodermatous skin changes in chronic GVHD appear as patches with mottled pigmentation and telangiectasias (picture 14).

Other cutaneous findings — In addition to poikiloderma, other pigment disorders may occur in chronic GVHD, including the appearance of depigmented, hypopigmented, and hyperpigmented areas. Hyperpigmentation may occur in a widespread, leopard-skin like pattern. In one series of 17 patients with sclerotic chronic GVHD, 10 (59 percent) had a history of the appearance of multiple hyperpigmented macules with fine scale prior to the development of sclerotic lesions [30].

Widespread eczematous lesions and malar eruptions resembling systemic lupus erythematosus have been reported as histopathologically confirmed manifestations of chronic GVHD in small series of patients [37,38]. An atopic dermatitis-like presentation also has been documented [39]. Other cutaneous findings associated with chronic GVHD include hypohidrosis, ichthyosis, erythema, pruritus, and maculopapular eruptions [1]. Cutaneous vascular lesions, termed "graft-versus-host disease-associated angiomatosis," as well as calcinosis cutis may develop in patients with chronic GVHD, particularly at sites of long-standing skin sclerosis (picture 15A-B) [40,41]. (See "Calcinosis cutis: Etiology and patient evaluation".)

Oral lesions — Forty-five to 83 percent of patients with chronic GVHD develop oral involvement (picture 16A-C) [7]. Lacy or reticulated white plaques that resemble Wickham's striae of lichen planus may occur on the tongue, buccal mucosa, lips, or palate. Hyperkeratotic plaques, mucosal erythema, erosions, and ulceration can also occur. Associated pain may inhibit oral intake [42]. In patients with sclerotic GVHD, perioral sclerosis can lead to restricted oral aperture, further complicating dental hygiene and nutritional status.

In addition, patients may suffer from sicca symptoms resembling those that occur in Sjögren's disease secondary to impairment of salivary gland function. Mucoceles, which are fluid-filled smooth nodules on the oral mucosa that represent accumulations of sialomucin from minor salivary glands in the oral mucosa, may also occur (picture 17). Mucoceles result from obstruction of the salivary duct, and are thought to be related to salivary gland inflammation associated with chronic GVHD [7].

Oral verruciform xanthoma (mucosal plaques characterized histologically by epithelial hyperplasia and foamy macrophages) is a rare finding that has been documented in a few patients with chronic GVHD [43]. Oral verruciform xanthomas may also occur on normal mucosa, or in the setting of oral lichen planus or other inflammatory diseases.

Hair disorders — Scarring or nonscarring alopecia or scaly papules on the scalp may occur in chronic GVHD, but are not sufficient to establish the diagnosis in the absence of other findings consistent with GVHD [1,44]. Thinning hair, patchy hair loss, coarse or dull hair, and premature graying may occur. Alopecia areata and other autoimmune skin conditions such as vitiligo have been reported in the GVHD setting [45].

Nail disorders — A variety of nail abnormalities ranging from mild nail dystrophy to total nail loss (anonychia) may occur (picture 18). Examples of associated nail abnormalities include longitudinal ridging, splitting or brittle nails, onycholysis (separation of the nail plate from the nail bed), and pterygium (abnormal adherence of the nail plate to the proximal nail fold or hyponychium).

Ocular and genital mucosa — Inflammation of the conjunctiva, pseudomembranous or cicatricial conjunctivitis, and keratoconjunctivitis sicca (dry eye) syndrome may occur in patients with chronic GVHD. Symptoms of ocular irritation, pain, or visual changes may accompany these findings. Vulvar or vaginal erosions, lichen planus-like lesions, or sclerosis leading to labial resorption or tissue agglutination may also occur in affected females. Balanitis and phimosis may develop in males.

Diagnosis — Tissue biopsy is recommended to confirm chronic GVHD in the absence of diagnostic clinical findings [1,46]. A summary of the common and diagnostic clinical features of chronic GVHD, as defined by the National Institutes of Health Consensus Project, is provided in a table (table 2). (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Diagnosis and classification'.)

The histopathologic changes in chronic GVHD vary according to the type of skin involvement. The classic findings in lichen planus-like and sclerotic lesions are discussed below:

●Lichen planus-like lesions – Lichen planus-like papules and plaques reveal findings that resemble lichen planus, with hyperkeratosis, hypergranulosis, acanthosis, saw-tooth rete, interface dermatitis, and dyskeratotic keratinocytes [46]. Periadnexal inflammation, particularly around eccrine glands is evident in some cases.

●Sclerotic lesions – Sclerotic skin involvement may or may not demonstrate overlying epidermal changes of lichen planus-like disease. Lichen sclerosus-like lesions characteristically show epidermal atrophy with edema and homogenization of collagen in the superficial dermis [2]. Morpheaform lesions demonstrate thickened collagen bundles in the dermis with loss of adnexal structures, and in the absence of epidermal changes, may be indistinguishable from specimens from true morphea or systemic sclerosis. As in these other disorders, specimens from lesions of sclerotic chronic GVHD often have a square or "box car" shape to the biopsy. Sclerotic GVHD involving the subcutaneous tissue demonstrates a lymphocytic infiltrate near the interface of dermis and fat with thickening of the septae.

A 4 mm punch biopsy is sufficient for the evaluation of lichen planus-like, lichen sclerosus-like, and most morpheaform lesions. Deep incisional biopsy may be necessary to evaluate for fascial involvement. Magnetic resonance imaging (MRI) also may have value for the diagnosis of subcutaneous disease and fasciitis [47,48]. The efficacy of MRI for long-term monitoring of disease activity is unclear.

Various scales have been used to assess the severity of skin involvement in chronic GVHD, most of which have not been validated. A multicenter prospective study that evaluated several assessment scales found that the National Institutes of Health composite 0 to 3 skin score correlated with both the clinician and patient perceptions of disease improvement or worsening [49]. The Lee skin symptom score, a scale based on the patient's assessment also correlated with these factors. Both scales were useful for assessing prognosis. In a separate study, the National Institutes of Health chronic GVHD Oral Mucosal Score was found to associate with patient-reported oral pain and sensitivity [50]. These scoring systems may be helpful tools for evaluating patients with chronic cutaneous GVHD in research trials and clinical practice.

Differential diagnosis — Several disorders share clinical and histopathologic features with chronic GVHD:

●Lichen planus-like lesions – The clinical and histopathologic features of lichen planus-like GVHD closely resemble lichen planus. Lesions of GVHD may be less angular and may have less well-defined margins than lichen planus [4]. The flexural wrists and shins are classic sites for true lichen planus (picture 19A-B). (See "Lichen planus".)

Lichenoid drug eruptions and pityriasis lichenoides chronica are additional disorders that may present with widespread erythematous papules and interface dermatitis (picture 20A-C). (See "Lichenoid drug eruption (drug-induced lichen planus)" and "Pityriasis lichenoides chronica".)

●Sclerotic lesions – Sclerotic lesions can mimic lichen sclerosus, morphea, systemic sclerosis, and eosinophilic fasciitis (picture 21A-D). Of note, the distal to proximal progression of cutaneous sclerosis on the extremities that is characteristic of systemic sclerosis typically is not observed in chronic GVHD. Radiation-induced fibrosis and nephrogenic fibrosing dermopathy can also present with induration and thickening of the skin. The possibility of nephrogenic fibrosing dermopathy should be considered in patients with renal failure. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults" and "Juvenile localized scleroderma" and "Eosinophilic fasciitis" and "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

●Poikiloderma – Poikiloderma can occur in a variety of disorders, most commonly on the lateral necks of fair-skinned individuals as poikiloderma of Civatte, a condition that is thought to be related to chronic sun exposure (picture 22). Additional disorders that may present with poikiloderma include dermatomyositis, systemic lupus erythematosus, Rothmund-Thompson syndrome, Bloom syndrome, and poikiloderma vasculare atrophicans in the setting of parapsoriasis or cutaneous T cell lymphoma (picture 23).

MANAGEMENT

Overview — Systemic therapy is generally required for the management of patients with acute GVHD. Topical corticosteroids may provide improvement in patients with limited skin disease and no internal involvement. (See "Treatment of acute graft-versus-host disease".)

Phototherapy may be an additional treatment option for acute cutaneous GVHD. In retrospective studies, psoralen plus ultraviolet A (PUVA) and narrowband ultraviolet B phototherapy have been associated with improvement in acute cutaneous GVHD that was refractory to systemic glucocorticoid therapy or that flared upon glucocorticoid tapering [51,52]. Prior to a recommendation for the routine use of phototherapy, further study is necessary to determine the long-term safety and efficacy of phototherapy in this population.

Topical corticosteroids and topical calcineurin inhibitors may have some benefit for patients with limited nonsclerotic chronic GVHD [53]. Phototherapy and systemic therapies are the mainstays of treatment for patients with sclerotic lesions. (See "Treatment of chronic graft-versus-host disease".)

Although oral ruxolitinib is used for the treatment of acute and chronic GVHD, additional study is necessary to determine the role of topical Janus kinase (JAK) inhibitors in GVHD. In a case report, treatment with ruxolitinib was associated with marked hair regrowth in a patient with alopecia universalis and chronic GVHD [54]. (See "Treatment of acute graft-versus-host disease", section on 'Ruxolitinib' and "Treatment of chronic graft-versus-host disease", section on 'Ruxolitinib'.)

Ancillary measures in chronic graft-versus-host disease — Patients with chronic cutaneous GVHD benefit from preventive skin care recommendations, including skin cancer surveillance, monitoring for adverse effects of topical corticosteroids, management of pruritus, and wound care and infection control measures [53,55]. Guidelines for ancillary therapy and supportive care of chronic GVHD were proposed by the original National Institutes of Health (NIH) Consensus Development Project and revised in 2015 [55,56]. Recommendations included:

●Photoprotection

●Regular use of emollients on intact skin

●Careful use of topical corticosteroids to reduce risk for cutaneous atrophy

●Use of topical or systemic antipruritic agents when needed

●Wound management

Cutaneous squamous cell carcinoma (SCC) is a potential long-term complication of hematopoietic cell transplant (HCT); the development of multiple cutaneous SCCs has been reported in patients chronic GVHD [57-59]. Immunosuppression, PUVA phototherapy, and chronic wounds are associated with elevated risk for cutaneous SCC, and may contribute to the development of SCC in this population. Patients should be encouraged to engage in sun protective practices, including the use of broad spectrum sunscreens, sun protective clothing, and sun avoidance [55]. In addition, patients should be examined periodically for signs of skin cancer. (See "Secondary cancers after hematopoietic cell transplantation", section on 'Prevention and screening'.)

Daily use of emollients may reduce pruritus and may be beneficial for maintaining skin integrity [55]. Ointment or creams, rather than less-occlusive lotion formulations, are preferred. Urea-containing compounds (3 to 10%) are efficacious for hydration but may be irritating to nonintact or inflamed skin and in young children [56]. Topical antipruritic agents such as pramoxine-hydrocortisone or menthol-containing lotions or creams may also be beneficial for pruritus. In patients with significant symptoms, oral antipruritics such as diphenhydramine, hydroxyzine, or doxepin may be used.

For patients with active cutaneous involvement involving the epidermis (eg, lichen planus-like lesions), medium-potency topical corticosteroids (triamcinolone 0.1% cream or ointment) can be applied on the trunk and extremities [56]. When topical corticosteroids, particularly high-potency agents, are used, patients should be monitored for signs of cutaneous atrophy. Low-potency agents, such as hydrocortisone 1 to 2.5% or desonide 0.05%, should be used on areas at high risk for atrophy (face and intertriginous areas) (table 3). (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Spontaneous ulceration can occur in patients with sclerotic chronic GVHD. Areas of skin breakdown should be assessed for the possibility of infection or malignancy and cultured, biopsied, and treated as appropriate [55]. Chronic wounds in the setting of GVHD may be challenging to heal, and referral to a wound care center may be beneficial. Plastic surgery consultation is useful in some cases. Improvement in friable lesions of GVHD-associated angiomatosis with use of topical timolol 0.5% ophthalmic solution, an effective treatment for infantile hemangiomas, has been documented in a case report [60]. (See "Infantile hemangiomas: Management", section on 'Topical beta blockers'.)

Patients should be educated regarding early signs of skin sclerosis, such as skin tightness, edema, and reduced range of motion, and should be instructed to seek care if these symptoms occur. Serial clinical photography and range of motion assessment are useful for documenting changes in skin activity over time in patients with sclerotic chronic GVHD.

Oral lesions — Topical high-potency corticosteroids are often used for the treatment of oral GVHD [7]. Solutions are used for generalized involvement, whereas other vehicles, such as gels, can be applied to individual lesions with gauze and left in place for 10 to 15 minutes. Oral candidiasis is not uncommon, and some patients may require ongoing fungal prophylaxis [56]. Supportive interventions for patients with oral chronic GVHD include encouraging good oral hygiene and utilizing of topical anesthetic agents, such as viscous lidocaine, to reduce pain and facilitate oral intake.

There are multiple reports of oral SCC in patients with chronic GVHD, and patients should be followed closely for the development of oral malignancies [61]. Leukoplakia may be a benign manifestation of chronic GVHD or a precursor to oral SCC. Leukoplakia that fails to improve or worsens despite therapy should be biopsied [55].

Patients with xerostomia may benefit from salivary stimulants (sugarless gum or candy), oral lubricants or saliva substitutes, and topical fluoride to prevent tooth decay. Cholinergic agonists to stimulate saliva production (eg, pilocarpine, cevimeline) may be useful in patients in whom the use of these agents is not contraindicated. (See "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease".)

No therapy is necessary for small, superficial mucoceles [55]. Deep lesions that cause discomfort can be surgically excised.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cutaneous graft-versus-host disease".)

SUMMARY AND RECOMMENDATIONS

●Overview – Graft-versus-host-disease (GVHD) is a common complication of hematopoietic cell transplant (HCT) that results from recognition of host antigens by immunocompetent cells from the donor. Cutaneous manifestations commonly occur in both acute and chronic GVHD. (See 'Introduction' above and 'Classification' above.)

●Acute cutaneous graft-versus-host disease:

•Clinical manifestations – Acute GVHD usually begins with erythematous macules on the ears, palms, soles, neck, face, or upper back. Lesions subsequently become more generalized; severe cases exhibit erythroderma, bullae, and extensive epidermal necrosis. Little is known about oral involvement in acute GVHD. (See 'Clinical manifestations' above.)

•Diagnosis – Characteristic histopathologic findings in acute GVHD include vacuolization of the basal layer of the epidermis, a sparse lymphocytic dermal infiltrate, and apoptotic keratinocytes. Advanced lesions demonstrate subepidermal clefts and extensive epidermal necrosis. The value of skin biopsy in acute GVHD has been questioned. Biopsies can yield nonspecific results. In all cases, histopathologic findings require clinical correlation for proper interpretation. (See 'Diagnosis' above.)

A variety of disorders, including drug eruptions, viral exanthems, and toxic epidermolytic necrosis share clinical and/or histopathologic features with acute cutaneous GVHD. The possibility of other disorders must be considered in hematopoietic stem cell transplant patients who present with clinical or histopathologic findings suggestive of acute cutaneous GVHD. (See 'Differential diagnosis' above.)

●Chronic cutaneous graft-versus-host disease – Chronic GVHD presents with various morphologies involving the epidermis, dermis, or subcutaneous tissues. Lichen planus-like lesions resemble the dermatologic disease lichen planus, whereas sclerotic involvement may resemble morphea, lichen sclerosus, or eosinophilic fasciitis. Dyspigmentation and other cutaneous, hair, or nail abnormalities have been associated with chronic GVHD. Oral involvement is common. (See 'Clinical manifestations' above.)

●Ancillary measures for chronic cutaneous graft-versus-host disease – Patients with chronic GVHD may benefit from the use of emollients, topical or systemic antipruritic agents, or topical corticosteroids. Patients should also be followed closely for the development of cutaneous or oral squamous cell carcinoma. Agents to reduce oral pain or xerostomia are useful. (See 'Ancillary measures in chronic graft-versus-host disease' above and "Treatment of chronic graft-versus-host disease".)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the National Institutes of Health or the United States Government or its components.