Although GVHD is a multisystem disease, the skin and mucosal tissues are the most commonly affected organs. Cutaneous signs and symptoms typically develop early; therefore, they often hold the key to diagnosis. Liver and intestinal involvement is the second most common source of signs. Thus, skin rash, elevated bilirubin levels, and diarrhea form the characteristic clinical triad.13

Skin symptoms may present as the dysesthesia, itching, erythema, or edema that develop into a progressive morbilliform or generalized folliculotropic rash that is found mainly on the trunk, spreads centrifugally, and becomes confluent. A rash on the palms, soles and skin behind the ear is typical (Fig. 2). In severe eruptions, blisters (dermal-epidermal detachment) may form. Also typical is oral, genital, nasal, or ocular mucositis.

Figure 2.

Signs and symptoms of acute graft-vs-host disease. A, Confluent, foliculotropic macular rash on the trunk. B, Eruption behind the ear. C, Close view of the rash. D, Palmar involvement.

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GVHD is staged (0 to 4) according to signs and symptoms and the percentage of body surface area (BSA) involved.13 Liver involvement is also staged from 0 to 4 according to blood and intestinal bilirubin levels and the severity of diarrhea.

Acute GVHD is considered classic if onset occurs within 100 days of HSCT, persistent if it lasts beyond 100 days, recurrent if it resolves but reappears after 100 days, and late-onset if symptoms start after 100 days (Table 1 and Fig. 1).5

The diagnosis of acute GVHD is based on clinical evidence of the characteristic triad (skin rash, elevated bilirubin levels, and diarrhea), although all organs are not necessarily involved.

In the early phase following HSCT, other common complications that also present with rash must be considered. Adverse drug reactions affecting the skin and infectious rashes (often viral) must be included in the differential diagnosis.14 Palmar-plantar erythrodysesthesia, syringometaplasia, and toxic epidermal necrolysis are relatively common toxic drug reactions in these patients and must be distinguished from GVHD. When viral rashes develop after HSCT, the usual culprits are reactivated cytomegalovirus, Epstein-Barr virus, herpes simplex virus types 1 and 2, varicella zoster virus, and human herpesvirus types 6, 7 and 8.

The diagnosing physician should bear in mind the clinical context and timing of lesion appearance, drugs taken and other systemic manifestations. Nevertheless, differentiating these processes is often dauntingly difficult.

Histopathologic evaluation of a skin biopsy can aid the diagnosis of acute GVHD, but there is no specific finding that confirms the diagnosis.15 It is helpful to include hair follicles in the biopsy. Characteristic findings are vacuolar interface dermatitis with necrotic keratinocytes surrounded by lymphocytes (Fig. 3). When the condition is advanced, dermal-epidermal detachment and subepidermal blisters can be seen.

Figure 3.

Histopathology of cutaneous GVHD.

A and B, Acute GVHD. Hematoxylin and eosin (H&E), original magnification ×200 and H&E, original magnification×400, respectively. Interface dermatitis with necrotic keratinocytes surrounded by lymphocytes (lymphocyte satellitosis). C and D, Chronic GVHD. H&E, original magnification×100 and H&E, original magnification×200. Interface dermatitis with dermal-epidermal detachment and follicular involvement.

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Histopathologic observations are graded from 0 to 4 (similarly to clinical signs) according to the degree of dermal-epidermal involvement.16

The same obstacles are encountered in histologic diagnosis as in clinical diagnosis: essentially acute GVHD must be distinguished from toxic drug reactions and infectious rashes. Certain histopathologic features can be helpful. Whether or not eosinophil counts are useful for differential diagnosis is controversial.15,17 A finding of adnexal involvement would favor a diagnosis of GVHD, whereas the presence of spongiosis, a dense inflammatory infiltrate, and extravasation of blood would point to a drug reaction. Enzyme-linked immunosorbent assay findings have demonstrated elafin overexpression throughout the epidermis,18 and this biomarker might therefore prove useful for the differential diagnosis of drug reactions, in which only the granular layer would stain.

Chronic GVHD can appear as an extension of acute GVHD (the progressive chronic form), or it can follow a disease-free period (the quiescent form) or develop without prior GVHD signs (the de novo form).2,3

The classic presentation (with the distinctive signs and symptoms of chronic GVHD but with no limits on timing) is distinguished from overlap syndrome (where acute and chronic signs and symptoms are both present).5

Chronic GVHD is a multisystem disease that can affect any organ, either one or several at a time. The involvement of the skin and oral mucosa is most common.22 Other affected organs in decreasing order of frequency are the liver, the eyes (dry-eye syndrome), the intestines, and the lungs.

Cutaneous signs and symptoms affecting skin, mucosal tissue, or adnexa can vary greatly. Sclerodermiform and nonsclerodermiform manifestations are distinguished.23,24 The first type comprises (from superficial to deeper signs) lichen sclerosus et atrophicus, morphea, and fasciitis. The second includes lichen planus, poikiloderma, and keratosis pilaris. Other less common clinical presentations are panniculitis, changes in pigmentation and sweating, erythema, rash, pruritus, ulceration, vitiligo and alopecia areata, among others25 (Fig. 4). Lichenoid lesions tend to appear earlier and may evolve into sclerotic lesions, although not all such lesions have a lichenoid derivation, nor do all lichenoids evolve in this way.14 It is not unusual for lesions to appear on skin previously damaged by burns, radiotherapy, or herpes infection (isotopic response) or where there has been repeated trauma (isomorphic response).23

Figure 4.

Signs of chronic cutaneous and mucosal graft-vs-host disease.

A, Poikiloderma. B, Nongenital lichen sclerosus et atrophicus. C, Lichenoid eruption. D, Morphea. E, Fasciitis. F, Keratosis pilaris. G, Oral lichen planus. H, Oral erosion and ulcers. I, Hyperkeratosis and fissures.

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Although nail involvement is of relatively little importance, it affects half of patients with chronic GVHD. Manifestations might take the form of nail dystrophy, thickening, thinning onycholysis, vertical striae, or pterygium. Similarly, the scalp is often involved, through alopecia (scarring or nonscarring), although the root causes are usually multiple (e.g., chemotherapy, radiotherapy, hormone changes, deficits, GVHD).23

Oral mucosa may be affected by oral lichen planus, hyperkeratosis, sclerosis, xerostomia, mucocele, mucosal atrophy, pseudomembranes, and ulcers, among other conditions23 (Fig. 4).

Genital mucosal involvement is less common and the patient does not usually ask about it spontaneously. Direct questioning and a complete physical examination is therefore required to rule out this manifestation, which is often an obstacle for sexual relations. Genital lichen planus, vaginal stenosis, erosions, fissures, or ulcers may be present.23

Table 2 lists the cutaneous and mucosal signs and symptoms of chronic cutaneous GVHD.

Chronic GVHD is graded in order to indicate severity and evaluate response to treatment. Grading systems are available for specific organs or to evaluate GVHD globally according to type and number of organs involved and severity. The most widely used system in clinical practice, because assessment is rapid and simple, is that of the US National Institutes of Health (NIH).26–28 A severity level of 0 to 3 assigned for each affected organ takes into consideration the impact on function. Table 3 shows the NIH grading system for the skin and oral and genital mucosa. Other more complex scales are available for use in clinical trials, although comparative studies have not demonstrated they are superior to the NIH's for determining disease activity, the physician and patient's perception, or relation to survival.29,30

The signs and symptoms of chronic GVHD are classified by type as follows31:

• -

  Diagnostic: sufficient to establish a diagnosis of chronic GVHD without resort to other tests

• -

  Distinctive: insufficient alone for establishing a firm diagnosis without complementary tests or evidence of lesions on other organs

• -

  Other features, or unclassified ones: also insufficient for establishing a diagnosis

• -

  Common features: seen in both chronic and acute GVHD

Table 2 summarizes skin and mucosal signs and symptoms according to these categories.

A diagnosis of chronic GVHD requires the following findings31:

• -

  The presence of at least 1 diagnostic sign or symptom, or the presence of at least 1 distinctive sign or symptom plus histologic confirmation

• -

  The exclusion of other possible diagnoses

• -

  Differential diagnosis with acute GVHD

It is important to remember that not all skin lesions in patients who have undergone HSCT are signs of GVHD. Like other patients, graft recipients can also develop drug reactions, inflammatory lesions, infections, benign or malignant tumors, or other conditions. Therefore, the physician must consider the correlation of clinical and pathologic features and timing when diagnosing any skin lesion.

A skin biopsy is recommended to confirm diagnosis, although it is not absolutely necessary if the patient has a sign or symptom considered diagnostic. Biopsies are suggestive but not specific for either chronic or acute GVHD, although a histologic report that findings are “compatible with” or “diagnostic for” GVHD is sufficient to confirm the diagnosis if the patient has manifestations classified as distinctive.31 The minimum histologic criteria that must be met for diagnosis are the presence of apoptosis in the basement membrane of the epidermis or the external root sheath of a hair follicle or the acrosyringium. These findings may be accompanied by a lichenoid infiltrate, vacuolar changes or lymphocytes surrounding necrotic keratinocytes (lymphocyte satellitosis). There are additional specific criteria according to type of chronic GVHD32 (Fig. 3).

Following HSCT, all patients should keep skin well hydrated, undertake moderate exercise, and avoid sun exposure by using sun blockers and sun glasses.23

Dry mouth and genitalia are very common symptoms of GVHD and can be alleviated through topical and oral medications33:

• -

  Dry mouth syndrome: artificial saliva and oral pilocarpine (5mg every 6–8h)34

• -

  Dry genitals: humectants and hormonal therapy.

Given that acute GVHD is a multisystem disease that appears in immunocompromised patients, and customarily presents during hospitalization for HSCT, the treating physician is usually a hematologist. The first line of therapy is methylprednisolone, and if there is no response, a second drug (e.g., antithymocyte globulin, mycophenolate mofetil, anti-tumor necrosis factor agents, or sirolimus) can be added, using departmental regimens and a tailored approach.35 However, the main approach to acute GVHD is to prevent it, through the use of corticosteroids, ciclosporin, and/or methotrexate.36

Topical treatments for skin manifestations of GVHD are inadequate. Phototherapy may be useful in cases that are resistant to conventional treatment.37–42

Dermatologists play a more important role in managing and treating chronic GVHD. Certain issues must be considered before choosing an approach. Once again, we should recall the multisystem nature of the disease and always investigate the involvement of other organs. It is also important to distinguish sclerodermiform and nonsclerodermiform types, verify depth (epidermal, dermal, or subcutaneous involvement), note the extension of manifestations (localized vs generalized), and consider location when evaluating cutaneous signs. Manifestations involving more than 50% of the BSA predict a poor prognosis.43

Physical Therapies

• 1.

  Phototherapy. Psoralen plus UV-A (PUVA), UV-A1, UV-B, and narrow-band UV-B phototherapies have been used.52 These alternative therapies can be useful for patients with generalized lesions that are refractory to other measures, or they can be used as a corticoid-sparing strategy.53 The choice of type of phototherapy is based mainly on the depth of lesions and the patient's concomitant conditions. Sclerotic lesions respond best to PUVA, whereas superficial lesions respond to narrow-band UV-B treatment. A finding of ocular GVHD would contraindicate PUVA. The dermatologist should take care to investigate any photsensitizing drugs (especially voriconazole) the patient might be taking as well as a positive antinuclear antibody test result.54

• 2.

  Extracorporeal photopheresis. This therapy is particularly appropriate for cutaneomucosal forms of GVHD and patients who have become dependent on corticosteroids or have hepatic or pulmonary involvement.55,56 The technique requires placement of a central venous catheter for apheresis of white blood cells and platelets from whole blood. After treatment with PUVA, the concentrated collected blood is reinfused. The procedure, which is repeated twice a week for several months, is time-consuming. Although few side effects develop during treatment, risk of infection and sepsis is present.

Figure 5 shows a flow chart of available treatments for chronic cutaneous GVHD.

Figure 5.

Flow chart for treatment of chronic cutaneous GVHD.

GVHD refers to graft-vs-host disease; CT, clinical trial; PUVA, psoralen plus UV-A; NB-UV-B, narrow-band UV-B.

Adapted from Hymes et al.23

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No validated, standardized criteria are available for measuring response to therapy for chronic cutaneous GVHD. This situation complicates the management of this condition and the design of clinical trials.

Disease activity must be measured at 2 time points in order to quantify and compare response. It is important to assess skin lesions, depth of involvement (epidermis, dermis, or subcutaneous tissue), and BSA expressed as a percentage.

Definitions for complete response (all lesions have disappeared), partial response (only improvement can be perceived), and progression (the condition has worsened) have been proposed.31 However, the definitions are subjective and reproducibility is a problem. Furthermore, clinical manifestations are varied (dry mouth, sclerotic cutaneous lesions, etc.) and the fact that some are irreversible makes it difficult to standardize response criteria.

Acute GVHD continues to represent the main limiting factor affecting the use of allogeneic HSCT. Biomarkers for early risk assessment and diagnosis are needed.57 The treatment of acute GVHD is less than optimal, and we need new approaches to prevention and management that preserve the antitumor effects of the graft.

The pathogenesis of chronic GVHD is still poorly understood. Interest in the role of cytokines in the development of clinical signs and their influence on severity has increased given that greater understanding might suggest potential therapeutic targets.58

Assessing response to chronic GVHD therapy is one of the greatest challenges we face. Available grading systems are unable to assess disease extension and severity or measure the effect of treatment. There are no clinical or laboratory findings that can distinguish active chronic GVHD from residual fibrosis.

Nor is there a laboratory test for a biomarker that can predict risk of developing chronic GVHD, response to treatment, or survival. Such biomarkers are essential for identifying risk and initiating treatment early as well as for closely monitoring response. They can also be helpful for measuring disease activity and the balance between chronic GVHD and the antileukemia effect of the graft. Biomarkers are currently being developed and their use validated, but none have been applied routinely in clinical practice.59,60