Cutaneous Graft-Versus-Host Disease

Autoimmune disorders

Autoimmune lymphoproliferative syndrome (ALPS)

Immune dysregulation, polyendocrinopathy, X-linked syndrome (IPEX)

Hematologic malignancy

Acute myeloid leukemia

Acute lymphoblastic leukemia

Chronic lymphocytic leukemia

Chronic myeloid leukemia

Hodgkin’s lymphoma

Multiple myeloma

Non-Hodgkin’s lymphoma

Bone marrow failure

Aplastic anemia

Diamond-Blackfan syndrome

Fanconi anemia

Dyskeratosis congenita/Hoyeraal-Hreidarsson syndrome

Myelodysplastic syndrome

Shwachman-Diamond syndrome

Immunodeficiency

Ataxia-Telangiectasia

Chediak-Higashi syndrome

Chronic granulomatous disease

Complete interferon-γ receptor 1 deficiency

DiGeorge syndrome

DOCK8 combined immunodeficiency

Familial hemophagocytic lymphohistiocytosis

GATA2 deficiency

Griscelli syndrome

Hyper-IgM syndrome

Kostmann syndrome

Leukocyte adhesion deficiency

Severe combined immunodeficiency

Wiscott-Aldrich syndrome

X-linked proliferation syndrome

Metabolic disorders

Fucosidosis

Gaucher disease

Mucopolysaccharidoses

Osteopetrosis

Other disorders

Congenital erythropoetic porphyria (Günther disease)

Essential thrombocytopenia

Histiocytoses

Idiopathic hypereosinophilic syndrome

Myelofibrosis

Polycythemia vera

Paroxysmal nocturnal hemoglobinuria

Sickle cell disease

Thalassemia

Waldenstrom macroglobulinemia

The first step in allogeneic HSCT is the identification of a suitable stem cell donor. The donor is selected based on the similarity of his/her histocompatibility antigen (HLA) profile to that of the recipient. There are three major Class I HLA antigens, HLA-A, −B, and –C, and three major Class II HLA antigens: HLA-DP, −DQ, and –DR. Because the alleles in each HLA class tend to be inherited together, there is approximately a 25 % chance that a sibling donor will be a 6/6 HLA-identical match. If no related donor is available, then a bone marrow registry will be utilized to search for an unrelated donor. International registries now contain over 9 million potential donors and identify an unrelated donor for approximately 50 % of patients [1]. The risk of GVHD is directly proportional to the degree of mismatch in major HLA alleles between donor and recipient. In addition, mismatch of minor HLA antigens is more likely to occur in the setting of unrelated donor HSCT, also contributing to the development of GVHD. Once a suitable donor is identified, the stem cells are collected from the donor’s bone marrow, or colony-stimulating factor (CSF) is administered to the donor in order to mobilize stem cells from the marrow prior to pheresis from the peripheral blood. Umbilical cord blood is a third source for stem cell transplantation but currently accounts for a small percentage of transplants performed worldwide. The source of the stem cell graft is an important factor in the development of GVHD as peripheral blood grafts may be associated with a higher risk of GVHD than bone marrow-derived grafts [2]. After harvesting, donor stem cells are selected by physical and immunologic sorting methods. Specific T-cell depletion of the graft may be utilized in order to decrease the risk of GVHD prior to transfusion.

Pre-treatment of the recipient’s marrow before transplantation is necessary in order to allow engraftment of the donor stem cells. Traditional myeloablative regimens utilize a combination of total-body irradiation and chemotherapeutic agents such as cyclophosphamide to permit engraftment. These regimens create an immunosuppressed state, preventing the host from rejecting the foreign stem cells. Myeloablative preparative regimens may also reduce tumor burden through a direct effect on the cancer; however, they are associated with a high rate of toxicity [3]. Over the last several years, reduced-intensity (nonmyeloablative) preparative regimens have resulted in less acute toxicity and have expanded the use of allogeneic transplantation to higher risk groups including older patients or those with significant organ dysfunction. Reduced-intensity regimens rely primarily on the transplanted graft for anti-cancer activity rather than the direct cytotoxicity of the preparative regimen [1].

Autologous stem cell transplantation, which utilizes the patient’s own stem cells following ablation of the hematopoietic system, is an important treatment for certain malignancies such as non-Hodgkin’s lymphoma and multiple myeloma. More than 30,000 autologous procedures are performed worldwide each year. Although the risk of GVHD and overall non-relapse mortality are greatly reduced following autologous transplantation when compared with allogeneic transplantation, autologous procedures are associated with an increased rate of malignancy relapse [4].

Acute Versus Chronic GVHD

Traditionally, the onset of GVHD symptoms before or after the 100 day mark following transplantation has been used to designate acute versus chronic GVHD, respectively. However, this temporal distinction is somewhat arbitrary, as patients may manifest classic signs of acute GVHD after day 100, and chronic manifestations may occur before 100 days post-transplantation. Whereas acute cutaneous GVHD typically presents as an exanthematous skin eruption with gastrointestinal and hepatic involvement, chronic cutaneous GVHD is remarkable for its protean skin presentation and is associated with variable but potentially widespread organ dysfunction and immunodsyregulation. Changes in transplant protocols have also impacted the onset of acute and chronic symptoms. Nonmyeloablative conditioning regimens may delay the onset of manifestations of acute GVHD until after 100 days following transplantation [5]. Similarly, the use of donor lymphocyte infusions (DLI), wherein additional stem cells are administered weeks or months following transplantation to augment the graft-versus-tumor response, may induce symptoms of acute GVHD after the 100 day period [18].

Clinical Manifestations of GVHD

Acute GVHD

Acute GVHD is a potentially life-threatening complication of allogeneic transplantation. The risk of developing acute GVHD depends on a number of factors, including HLA-compatibility, the age and sex of the donor and recipient, the GVHD prophylaxis regimen used, and the T cell composition of the graft. Without prophylactic immunosuppression, acute GVHD will develop in most allogeneic HSCT recipients. Therefore a calcineurin inhibitor (cyclosporine or tacrolimus) or other immunosuppressant regimen is commonly used in the first several weeks to months following transplantation during which time the risk of acute GVHD is greatest.

Despite prophylactic immunosuppressive therapy, nearly 30 % of HLA-identical related transplant procedures result in significant acute GVHD [6]. This risk is significantly higher in HLA-matched unrelated and mismatched transplants. Theskin is often the earliest clinical sign of acute GVHD. Long-term survival from acute GVHD is directly related to the severity of skin, liver, and gut involvement. The 1994 Consensus Conference grading for acute GVHD is demonstrated in Table 38.2 [7].

Table 38.2

Staging and grading of acute GVHD

Stage	Skin	Liver	Gut
1	Rash <25 % BSA	Bilirubin 2 mg/dL to <3 mg/dL	Diarrhea 500–1000 mL/day or persistent nausea
2	Rash 25–50 % BSA	Bilirubin 3–6 mg/dL	Diarrhea 1000–1500 mL/day
3	Rash > 50 % BSA	Bilirubin 6–15 mg/dL	Diarrhea > 1500 mL/day
4	Erythroderma w/bullae formation	Bilirubin >15 mg/dL	Severe abdominal pain with or without ileus
Grade
I	Stage 1-2	None	None
II	Stage 3 or	Stage 1 or	Stage 1
III		Stege 2–3 or	Stage 2-4
IV	Stage 4 or	Stage 4

Adapted from Przepiorka et al. [7]

Acute GVHD primarily involves the skin, liver, and gastrointestinal tract, although other organ systems may be affected less frequently. Skin involvement most often occurs within 2–4 weeks after transplantation. Cutaneous involvement may range in severity from an asymptomatic maculopapular erythematous eruption to widespread necrolysis, but most commonly presents with an exanthem-like eruption that preferentially involves the head, ears, palms, and soles (Fig. 38.1). In early GVHD, there may be involvement of the hair follicles creating a folliculocentric-appearance [8]. When severe, diffuse erythroderma or bullae with epidermal necrolysis may occur (Fig. 38.2).

Fig. 38.1

Acute GVHD of the palms

Fig. 38.2

Acute GVHD with necrolysis

Histologically, acute GVHD is characterized by widespread keratinocyte necrosis with a dermal lymphocytic infiltrate and basal cell hydropic degeneration (Fig. 38.3). Histologic changes mimicking GVHD may be found following high-dose chemotherapy or radiation therapy, in the setting of drug hypersensitivity, and with the eruption of lymphocyte recovery; therefore clinicopathologic correlation is often helpful [9]. In cases in which the clinical and histologic diagnosis of acute skin GVHD is non-diagnostic, the presence of hyperbilirubinemia or symptoms of nausea, vomiting, diarrhea, or abdominal pain are important indicators of hepatic and gastrointestinal involvement. Even in the setting of equivocal cutaneous and histological findings, the mortality associated with severe acute GVHD necessitates a low threshold for initiating empiric corticosteroid therapy.

Fig. 38.3

Scattered necrotic epidermal keratinocytes with vacuolization of the basal cell layer and lymphocytic infiltration in the papillary dermis in a patient with acute GVHD (Hematoxylin and Eosin, 20×)

Chronic GVHD

Chronic GVHD occurs in 30–80 % of allogeneic HSCT recipients and is the leading cause of non-relapse mortality in survivors more than 2 years after transplantation [10]. Skin involvement may progress directly from acute disease, following a period of disease quiescence, or de novo without a history of previous acute involvement. The greatest predictor of chronic GVHD is a history of prior acute GVHD [11]. Other risk factors include older patient age, female donor for male recipient, mismatched or unrelated donor, peripheral blood graft, T-cell replete graft, and use of donor lymphocyte infusions. A flare of chronic cutaneous GVHD may be triggered by a number of factors, most commonly tapering of immunosuppression, but may also occur following the development of a drug eruption or sunburn, or in the setting of a cutaneous or systemic infection.

One of the greatest hurdles to improving chronic GVHD management stems from the clinical and immunological complexity of the disorder. In an effort to facilitate clinical research in the field of chronic GVHD, the National Institutes of Health Chronic GVHD Consensus Project published a series of articles providing a standardized approach for diagnosis and staging [12], histopathology [13], disease biomarkers [14], response criteria [15], supportive care [16], and clinical trial design [17]. Traditionally, chronic cutaneous GVHD has been described as either “lichenoid” or “sclerodermoid” involvement. However, these terms do not accurately portray the variability in the currently recognized cutaneous manifestations of chronic GVHD [18]. The Consensus Project diagnosis and staging guidelines provide a classification system of the clinical manifestations of cutaneous GVHD (Table 38.3). Poikiloderma, lichen-planus-like lesions, and sclerotic skin changes including fasciitis are considered diagnostic features of chronic cutaneous GVHD when they occur in the setting of allogeneic HSCT. Other cutaneous features, such as ichthyosis, dyspigmentation, and alopecia are also well-recognized manifestations but are not considered diagnostic of skin involvement [12].

Table 38.3

Clinical manifestations of chronic GVHD

Dermatologic and mucosal features
Skin	Alopecia
	Angiomatous papules
	Bullae
	Erythema
	Hypo- or hyperpigmentation
	Ichthyosis-like
	Keratosis-pilaris-like
	Lichen-planus-like^a
	Lichen-sclerosus-like^a
	Maculopapular
	Morphea-like^a
	Poikiloderma^a
	Scleroderma-like^a
	Sweat impairment
	Ulceration
Nails	Brittleness
	Longitudinal ridging or splitting
	Onycholysis
	Pterygium unguis
Subcutaneous tissue	Fasciitis^a
	Panniculitis
Oral mucosa	Erythema
	Gingivitis
	Hyperkeratotic plaques^a
	Lichen-planus-like^a
	Mucocele
	Mucosal atrophy
	Mucositis
	Pseudomembrane
	Restriction of oral opening from sclerosis^a
	Ulcer
	Xerostomia
Genital mucosa	Lichen planus-like^a
	Vulvar erosions/fissures
	Vaginal scarring/stenosis^a
Other organ system involvement in chronic GVHD
Cardiovascular	Pericardial effusion
Ophthalmologic	Cicatricial conjunctivitis
	Sicca symptoms
	Confluent punctuate keratopathy
	Photophobia
	Blepharitis
Gastrointestinal	Esophageal web
	Esophageal stricture/stenosis
Hematopoeitic	Thrombocytopenia
	Eosinophilia
	Lymphopenia
	Hypo- or hypergammaglobulinemia
	Autoantibodies
Hepatic	Elevated total bilirubin
	Elevated alkaline phosphatase
	Elevated transaminases
Musculoskeletal	Myositis or polymyositis
	Edema
	Myalgia
	Arthralgia, arthritis
Neurologic	Peripheral neuropathy
	Myasthenia gravis
Pulmonary	Bronchiolitis obliterans ± organizing pneumonia
	Pleural effusion

^aDiagnostic feature; other signs and symptoms listed are not considered sufficient to establish a diagnosis of chronic GVHD without further testing or other organ involvement

Given the variety of epidermal changes associated with GVHD, the term “lichenoid” is preferred as a histologic descriptor of GVHD rather than as a clinical disease classification. Discrete lichen-planus-like violaceous papules are relatively uncommon in chronic GVHD, but may be seen most commonly on the palms and soles (Fig. 38.4). In the past, the term “lichenoid” has been used most commonly to describe cutaneous GVHD which manifests as poorly defined interconnecting erythematous papules and plaques with overlying scale. This eruption may localize to sites of previous UV exposure, such as the posterior and lateral neck, and may spare UV-protected areas such as the buttocks. Underlying sclerotic changes resembling lichen sclerosus or morphea may also be present. Resolution of this manifestation of chronic GVHD often results in a distinct reticulate pattern of hyperpigmentation, reflecting the pigment incontinence induced by the epidermal-dermal interface reaction.

Fig. 38.4

Chronic GVHD; scaling violaceous papules and plaques on the hands

Sclerotic changes associated with chronic GVHD may develop at any layer of the dermal and subcutaneous tissue. Chosidow et al. [19] estimated the incidence of sclerodermatous GVHD to be 3.6 % based on a review of 196 HSCT patients. However, the true frequency of sclerotic changes associated with GVHD may be higher if all forms of sclerosis are included. In a large NIH cohort of 206 patients enriched for severe and refractory chronic GVHD, sclerotic changes were detected in 109 (53 %) [20]. Sclerosis may be present on multiple levels on a single patient and the changes may or may not occur in the presence of overlying epidermal involvement. The most superficial level of sclerotic changes resembles lichen sclerosus and consists of atrophic gray patches with epidermal atrophy, often distributed symmetrically on the upper back. Morphea-like GVHD mimics morphea with patchy areas of prominent dermal sclerosis, often with overlying pigmentation, that results in a decreased ability to pinch the skin. Morphea-like GVHD often occurs preferentially at sites of skin friction or pressure such as the waistband area (Fig. 38.5) [21]. Scleroderma-like GVHD represents full-thickness sclerosis with the complete inability to pinch skin and with a hidebound appearance. Involvement over joints may significantly limit range of motion. In contrast to scleroderma, scleroderma-like GVHD does not begin with symmetric distal hand involvement and proceed proximally and Raynaud’s phenomenon is uncommon [18]. Chronic sclerosis may be complicated by bullae formation as well as spontaneous erosions and ulcerations (Fig. 38.6). Benign angiomatous papules and nodules may develop in patients with chronic disease (Fig. 38.7) [22].

Fig. 38.5

Tan sclerotic plaques with koebnerization at site of waistband in patient morpheaform chronic GVHD

Fig. 38.6

Hidebound sclerosis with skin ulceration in a patient with scleroderma-like chronic GVHD

Fig. 38.7

Numerous angiomatous papules and nodules in a patient with chronic sclerotic GVHD of the legs

The histologic of “lichenoid” chronic GVHD resembles that of lichen planus with a bandlike lymphoplasmocytic infiltrate. Sclerotic GVHD resembles scleroderma with homogenization of collagen and loss of adnexal structures. The level and degree of fibrosis observed histologically reflects the clinical type of sclerosis. In patients with primary rippling to the skin resembling eosinophilic fasciitis, sclerosis and inflammation will be seen primarily at the interface between the reticular dermis and the subcutaneous fat and the deeper fascia.

Chronic GVHD-Related Fasciitis

GVHD-related panniculitis and fasciitis represent sclerosis of the deep subcutaneous tissue and fascia [23]. Although GVHD-related fasciitis is thought to be an uncommon presentation, it may present in an insidious manner with resultant marked functional limitations. Patients with GVHD-related fasciitis often manifest overlapping features of both panniculitis and fasciitis and the histologic diagnosis may depend on the depth and extent of the tissue biopsy. Patients may complain of muscle pain or weakness [24], or may demonstrate limited range of motion at affected joints at the time of presentation. GVHD-associated fasciitis shares many similarities with eosinophilic fasciitis, an uncommon disorder of unknown etiology first described by Shulman in 1974 [25]. GVHD-associated fasciitis presents with prominent induration and rippling of tissue, visible grooves demarcating fascial bundles or underlying superficial veins, and decreased range of motion (Fig. 38.8). The first indications of subcutaneous involvement may be edema of the affected limb. Magnetic resonance imaging may facilitate the diagnosis of subcutaneous involvement [26, 27].

Fig. 38.8

Subcutaneous sclerosis from chronic GVHD; there is prominent rippling and nodularity of the subcutaneous tissue appreciable by deep palpation. The overlying skin is normal in texture and color

Genital GVHD

Assessment of genital involvement is important in the management of GVHD patients. Genital involvement is most commonly associated with sclerotic cutaneous disease, but may occur with other forms of cutaneous involvement, or in the absence of other cutaneous involvement. Genital tract involvement may be present in as many as 49 % of female patients two years post-transplantation and may seriously impact the quality of life of affected individuals [28]. Manifestations include burning and irritation, discharge, erosions and fissures, or vaginal stricture (Fig. 38.9). In a recent review of 155 male allogeneic transplant recipients 1 year or more after transplant, 21 (13 %) manifested inflammatory lesions, most frequently balanoposthitis (12 patients), lichen-sclerosus-like lesions (6), and phimosis (5) [29].

Fig. 38.9

Chronic vulvar GVHD; resorption of labia minora; pallor and sclerosis of vulvar vestibule; fissuring of the interlabial sulcus

Oral GVHD

The second most common organ system involved with chronic GVHD after the skin is the mouth. Chronic oral GVHD may affect the oral mucosa and salivary glands. Mucocele formation is very common but usually asymptomatic. Lichen-planus-like oral involvement manifests as erythematous hyperkeratotic plaques and erosions. Sclerosis of the skin surrounding the mouth or the frenulum can cause difficulty opening the mouth or protruding the tongue, respectively. Persistent erosions and fissures cause burning pain, particularly upon contact with acidic foods. Salivary gland involvement from chronic GVHD results in decreased saliva production and sicca symptioms. Loss of taste is also commonly reported by patients [30].