Diagnostic Dilemmas in Dermatology
Section Editor: Jason Emer, MD
This month’s column by: Jason Emer, MD; Shaily Pandey, BS;
Brian J. Marciniak, BS; Harleen Sidhu, MD;
Robert Phelps, MD
Dr. Emer, Ms. Pandey, and Mr. Marciniak are from Mount Sinai School of Medicine, Department of Dermatology, New York, New York. Drs. Sidhu and Phelps are from Mount Sinai School of Medicine, Department of Pathology, New York, New York. Disclosure: The authors report no relevant conflicts of interest.
A 14-month-old infant with a past medical history of hemophagocytic lymphohistiocytosis was admitted to the pediatric intensive care unit (ICU) 18 days after a perfectly human leukocyte antigen (HLA)-matched allogeneic bone marrow transplantation for sudden onset of generalized itchy bumps on the skin. Lesions initially presented on both arms and quickly spread to the trunk and extremities. The mother also described small “water blisters” on the dorsum of both feet. Review of systems was significant for fever, shortness of breath, lack of appetite, diarrhea, and yellowing of the skin and sclera. On total body skin examination, many hyperpigmented macules and patches along with erythematous to brown follicular papules were noted on the trunk and extremities (Figure 1). Papules were most prominent on flexural surfaces, such as the axillae, groin, and wrists (Figure 2). An intact, tense, bullae was appreciated on the medial side of the left foot; Nikolsky’s sign was negative (Figure 3). The mucous membranes were spared and there was no associated lymphadenopathy, but examination revealed palpable hepatosplenomegaly. Initial laboratory studies revealed hyperbilirubinemia and pancytopenia with negative blood, urine, and stool cultures. A punch biopsy was obtained from the left axilla in an area of prominent follicular papules and sent for histological analysis (Figures 4–6).
Bullous graft-versus-host disease (GVHD)
Microscopic Findings and Clinical Course
A skin biopsy from the left axillae revealed a mild interface dermatitis with hemorrhage and mild cytologic atypia of keratinocytes (Figures 4 and 5). Hydropic change was present and also extended around the sweat ducts (Figure 6). These features favored a diagnosis of GVHD. Subepidermal clefting with bulla formation is present in the bullous form of GVHD, and although not present on our biopsy sample, the clinical findings were suggestive of this pathological state.
The patient was started on potent topical corticosteroids (betamethasone 0.05% ointment twice daily for two weeks) and topical tacrolimus 0.03% ointment twice daily. Intravenous (IV) methlyprednisolone and oral tacrolimus were started for disease involving the liver, pulmonary and gastrointestinal systems. After a week of therapy and continued deterioration, other immunosuppressants were tried without success including mycophenolate mofetil, etanercept, and infliximab. Extracorporeal photophoresis was unable to be delivered due to difficulties with IV access. Despite all attempted measures, the patient became neutropenic and developed Klebsiella pneumoniae sepsis. On hospital day 37, the patient passed away from an asystolic episode.
GVHD is the most common complication of allogenic hematopoietic cell transplantation (HCT), the result of immunocompetent donor cells recognizing host tissue as foreign. Up to 80 percent of HCT patients suffer from GVHD, producing significant morbidity and mortality since many organ systems are affected including the skin (most common), gastrointestinal, and hepatic systems.
The diagnostic criteria of GVHD includes the following: 1) the graft must have immunologically competent T-cells; 2) there must be an antigenic difference between the donor and host tissue; and 3) the host must demonstrate incompetence to reject the graft. Although the prevalence increases with the degree of HLA mismatch, 40 percent of perfectly HLA-matched patients will have manifestations of GVHD following bone marrow transplantation, suggesting that minor histocompatibility complexes and cytokine polymorphisms are important in disease pathogenesis.
Acute GVHD (aGVHD) manifests with pruritus, edema, erythema, and dysesthesia. This presentation can evolve into a morbilliform eruption commonly starting on the trunk, often with follicular accentuation, and becoming confluent with progression (Figures 7A and 7B). As seen in the authors’ patient, the presence of bullae or Nikolsky’s sign heralds the onset of severe disease, as does mucus membrane involvement. In contrast, chronic GVHD (cGVHD) manifestations include poikiloderma, lesions resembling lichen planus or lichen sclerosis, morphea-like sclerosis, and deep sclerosis/fasciitis (Figure 8). These manifestations often occur at sites of earlier injury, such as an area of previous varicella zoster infection or in pressure prone areas, such as the waistline, buttock, or intertriginous sites.
Bullous lesions have been documented in both aGVHD and cGVHD; however, the exact etiology remains unknown. Some authors report lymphatic stasis surrounding the bullae as a suggested possible etiology. They are commonly found on acral sites including the ears and fingers. There are reports of concurrent bullous dermatoses, such as bullous pemphigoid (BP), epidermolysis bullosa acquisita, mucous membrane pemphigoid, and pemphigus with GVHD that are direct immunofluorescence (DIF) positive. Interestingly, transplant patients with GVHD have been found to have increased antibodies to basement membrane zone (BMZ) proteins including collagen VII, collagen XVII, BP230, and p200 when compared to transplant patients who do not have GVHD. However, not all patients with anti-BMZ antibodies had bullous lesions and some patients with bullae did not have detectable antibodies.
The morbilliform eruption commonly seen in aGVHD lends itself to a wide differential diagnosis including drug hypersensitivity reactions, viral exanthems, and other toxic infectious conditions, such as staphylococcal scalded skin syndrome or disseminated herpes zoster. Atypical targets of palmar involvement may suggest erythema multiforme (EM) and the addition of mucous membrane involvement, skin fragility, or blister formation suggest Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Hyperpigmented acral skin changes and nail findings are seen as consequences of bone marrow ablation agents given pre-transplant, such as busulfan and cyclophosphamide. One case report suggested papular lesions of early aGVHD may resemble psoriasis vulgaris and described an instance of GVHD being misdiagnosed as contact dermatitis in an infant that ultimately proved fatal. Atopic-like dermatitis and urticarial plaques have also been reported as uncommon presentations of disease (Figure 9).[8,9] The differential diagnosis of cGVHD as mentioned above include scleroderma, morphea, and eosinophilic fasciitis. In one case report, lichenoid changes of cGVHD were initially thought to be a recurrence of cutaneous lymphoma.
Histological criteria for GVHD include early vacuolization of the basal layer (Grade 1), the added presence of dyskeratotic keratinocytes (Grade 2), focal clefting of the basal layer (Grade 3), and bulla formation with total separation of the epidermis from the dermis (Grade 4). Grade 4 disease can progress into a TEN-like reaction and the prognosis is very poor with an estimated survival rate of five percent over five years. The exocytosis, spongiosis, and lymphocytic infiltrate at the BMZ makes it difficult to distinguish GVHD from an adverse drug reaction; however, the presence of eosinophils make the latter more likely. The cutaneous eruption of lymphocyte recovery also has a spongiosis, a dermal vascular infiltrate, and dyskeratotic keratinocytes. Epidermal changes, such as interface dermatitis and satellite cell necrosis, seen can also resemble radiation dermatitis or EM. However, the stratum corneum in EM is often normal basket-weave and keratinocyte apoptosis is accompanied by a heavy superficial dermal lymphohistiocytic infiltrate. In radiation dermatitis, the epidermis can show acanthosis or atrophy with underlying hyalinization of dermal collagen and associated dermal fibrosis, ectatic vessels, and characteristic bizzare-shaped (radiation) fibroblasts. Viral exanthems also have basal vacuolization and dyskeratotic keratinocytes and are often difficult to differentiate histologically from early GVHD.
Prophylaxis with immunosuppressive agents, such as cyclosporine, methotrexate, and/or tacrolimus, may help prevent the occurrence of GVHD in stem cell transplant patients.[11,12] Once the diagnosis of cutaneous GVHD has been established, the first step in treatment is discussion with the transplant team of a need for change in the oral immunosuppressive therapy and/or the addition of high-dose systemic corticosteroids as well as the initiation of topical treatment with super-potent topical corticosteroids and emollients. Topical calcineurin inhibitors (tacrolimus, pimecrolimus) are particularly helpful in refractory cases requiring long-term topical corticosteroids or for involvement in areas with a high risk of skin atrophy from corticosteroids, such as intertriginous locations or the face. However, caution should be exerted in areas of significant skin breakdown as there is a risk of systemic absorption.
For patients who fail treatment with corticosteroids, there is no single proven therapy that is best. Phototherapy with both ultraviolet A (UVA) and B (UVB) light have shown benefit in refractory cases of cGVHD. Numerous drugs including methotrexate, mycophenolate mofetil, cyclosporine, sirolimus, daclizumab, etanercept, infliximab, alefacept, rituximab, imatinib mesylate, and anti-thymocyte globulin, as well as extracorporeal photophoresis have been tried as second-line therapies; none has proven superior. Further, information concerning serious adverse reactions or an increase in mortality is lacking for each of these therapies and risks of infections (immunosuppressives), cancer (UVA phototherapy), and venous thrombosis (extracorporeal photophoresis) are of real concern. The current literature does not differentiate treatment of bullous disease from other forms of GVHD, and most algorithms follow conventional separation between generalized and local skin involvement to guide a treatment course with further differentiation between sclerotic and non-sclerotic skin lesions to individualize distinct treatments.
Skin involvement is a significant morbidity in patients with GVHD, thus dermatologists need be familiar with this entity and its varied presentations. Performing skin biopsies when confronted with disease is essential to obtain the diagnosis. Both the psychological and functional impact of cutaneous disease is extremely significant and the early initiation of treatment with systemic, topical, and/or light therapies may be of tremendous benefit in specific cases even though most treatments have not shown an increased benefit if the condition is unresponsive to first-line oral corticosteroids. Although rare, bullous lesions in GVHD predispose an increased mortality and are suggestive of the need for a more aggressive intervention when confronted. Increased research in both the pathogenesis of GVHD and treatment options is needed to better formulate treatment guidelines and recommendations.
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