Dermatology Online Journal

Lichen sclerosus et atrophicus-like graft versus host disease post stem cell transplant
Jennifer L Weinberg¹, Misha Rosenbach MD², Ellen J Kim MD³, Carrie L Kovarik MD⁴
Dermatology Online Journal 15 (9): 4

1. University of Pennsylvania School of Medicine. jenniflw@mail.med.upenn.edu
2. Department of Dermatology and Department of Internal Medicine, University of Pennsylvania
3. Department of Dermatology, University of Pennsylvania
4. Department of Dermatology and the Department of Internal Medicine, Division of Infectious Disease, University of Pennsylvania

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Abstract

A major complication following hematopoietic stem cell transplantation is graft versus host disease. Cutaneous manifestations of chronic graft versus host disease (cGVHD) are varied and this condition impacts patient outcomes and quality of life. We describe two cases of lichen sclerosus et atrophicus-like cGVHD developing in patients after hematopoietic stem cell transplantation. Both patients presented clinically with patches of pigmentary changes and scaling that displayed classic histologic features of lichen sclerosus et atrophicus. The skin is a frequent target organ of cGVHD and often the presenting location of the disease, making dermatologists key in recognition and management. It has been proposed that cutaneous cGVHD is a spectrum of disease and the lesions may evolve through various stages. Lichen sclerosus et atrophicus-like cGVHD may represent a phase in this continuum or a distinct sub-type of disease. Remaining cognizant of the potential manifestations of disease is key for prompt recognition and proper treatment.

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Introduction

Hematopoietic stem cell transplantation (HSCT) is a therapy with a growing list of indications, including hematological malignancies such as lymphoma and leukemia, non-malignant hematological diseases, solid tumors such as renal cell carcinoma, and genetic disorders [1]. A major complication arising in up to 80 percent of recipients of HSCT is graft versus host disease (GVHD) [1]. A similar reaction is seen less frequently after solid organ transplantation and transfusions of non-irradiated blood products [2]. This multisystem immunological complication is a main cause of non-relapse morbidity and mortality and is becoming progressively more common as more patients undergo HSCT and mismatched transplants become more frequent [1].

Hyperacute, acute, and chronic forms of GVHD exist. Hyperacute GVHD presents within a week of HSCT, usually in the setting of unfavorably matched patients receiving insufficient immunosuppression [2]. Acute GVHD (aGVHD) most commonly develops between two and six weeks following HSCT [3]. This form of GVHD classically presents with erythematous macules and/or papules, which may coalesce into plaques, accompanied by burning and pruritis; atypical presentations have been described, including bullae, erythroderma, or a morbilliform eruption. Fever and gastrointestinal manifestations are frequent, including diarrhea, transaminitis and bile duct disruption causing cholestasis [2]. Chronic GVHD (cGVHD) can progress from acute GVHD, arise de novo, or recur after a disease-free interval [2]. Manifestations of cGVHD usually arise within three years following HSCT and may be multisystemic or limited to a single organ system with heterogeneous features that may resemble other immunologic disorders [3]. The most common morphologic types of cutaneous cGVHD are lichenoid and sclerodermoid. We report two cases of lichen sclerosus et atrophicus (LS&A)-like cGVHD.

Case reports

Patient 1

Patient 1 is a 46-year-old woman, three months status post a 10/10 HLA matched sibling donor HCST for acute lymphoblastic leukemia. She previously had GVHD, which progressed to cutaneous and oral cGVHD by one year post-transplant. The patient presented to dermatology with alopecia of the scalp, dry eyes, parched lips, redness around the eyelids, and a diffuse, dry eruption that was easily irritated. Modest improvement was noted with emollients and clobetasol gel 0.05 percent twice daily to the hands. Her systemic medications on presentation included mycophenolate mofetil 1000mg twice daily, prednisone 5mg every other day, acyclovir, fluconazole, penicillin for pneumococcal prophylaxis, trimethoprim/sulfamethoxazole, and amlodipine.

Figure 1	Figure 2
Figure 1. Hypopigmented patches on the infraorbital skin Figure 2. Histologic changes of lichen sclerosus et atrophicus, including epidermal hyperkeratosis, focal basovacuolar alteration of the dermal-epidermal junction, and homogenization of the dermal collagen in the superficial dermis (H&E, x100)

Physical examination revealed diffuse non-scarring alopecia of the scalp. The patient also demonstrated atrophic, pink and hypopigmented patches with fine, wrinkled scale of the infraorbital (Fig. 1), perioral and vulvar skin. On her arms, trunk, and legs she had hyperpigmented lichenoid papules as well as lacy white plaques in the buccal mucosa. Focal mildly indurated morpheaform linear plaques in her axillae and neck as well as diffuse scaling of her soles and toes were also noted. A punch biopsy taken from the right upper arm demonstrated an atrophic epidermis with overlying hyperkeratosis, focal basovacuolar alteration of the dermal epidermal junction, dilated vascular channels, abundant pigment-laden macrophages, and homogenization of the dermal collagen in the superficial dermis (Fig. 2). Given the clinical scenario, these findings were histolopathologically consistent with cGVHD with features of lichen sclerosus.

The patient was treated with extracorporeal photopheresis (ECP) on consecutive days once every two weeks. In addition, treatment included topical hydrocortisone 2.5 percent ointment twice a day to the face and vulva, triamcinolone 0.1 percent ointment to the body using the soak and smear regimen [4], and fluocinonide gel 0.05 percent twice a day to the oral mucosa. Following approximately four months on this treatment regimen, the patient had a 50 percent improvement in her skin and oral lesions and eye symptoms. She is currently on tacrolimus ointment 0.1 percent daily to the face, intermittent clobetasol 0.05 percent ointment to the feet, and biweekly ECP. She has been able to discontinue her prednisone and taper her mycophenolate mofetil to 500 mg daily.

Patient 2

Patient 2 is a 46-year-old man, two years status post a matched unrelated donor HSCT for acute promyelocytic leukemia. He presented with painful areas of desquamation, beginning on the feet and extending to the legs, arms, face, back and buttocks, which had initially developed shortly after he had received a donor lymphocyte infusion 15 months previously. These lesions did not respond to treatment with clobetasol 0.05 percent ointment. He was taking no other medications.

Figure 3	Figure 4
Figure 3. Periorbital, erythematous, and hypopigmented atrophic patches, as well as hyperpigmented macules on the cheeks Figure 4. Histologic changes of lichen sclerosus et atrophicus, including epidermal atrophy, basovacuolar alteration, scattered necrotic keratinocytes, and associated dermal sclerosis (H&E, x100)

On physical examination, the patient had lichenoid pink and hypopigmented atrophic patches periorbitally and hyperpigmented macules and patches on the cheeks (Fig. 3), upper arms, elbows, lateral back, buttocks, proximal thighs, and popliteal fossae. Asubtle erosion was present on the right buccal mucosa. No sclerodermoid changes were noted. A punch biopsy of the left arm revealed basal vacuolar alteration, associated dermal sclerosis, and an epidermis with hyperkeratosis and scattered necrotic keratinocytes (Fig. 4). Homogenization of superficial dermal collagen bundles, pigment incontinence, and mild lymphocytic inflammation were also identified. This combination of clinical and histologic changes is consistent with cGVHD, with features of lichen sclerosus.

The patient was treated with topical triamcinolone 0.1 percent ointment to the body and hydrocortisone 2.5 percent ointment to the face at bedtime using the soak and smear method [4]. Unfortunately, the patient did not continue further treatment for his cGVHD due to the development of a relapse of his leukemia in his small intestine. He is currently undergoing radiation therapy to address this relapse.

Discussion

Because of broadened transplantation inclusion criteria and lengthened recipient survival, the incidence of cGVHD has increased to around 80 percent from near 40 percent in 1990 [5]. The risk of GVHD post-HSCT varies based on certain patient characteristics. Disparate human leukocyte antigens (HLA) between donor and recipient negatively impact survival and are major risk factors for GVHD, with a single allele-level mismatch associated with an 8-12 percent reduction in five-year survival in one series [6]. Improved outcomes are reported when alleles are matched for HLA-A, -B, -C and DRB1 with additional benefit garnered by also matching HLA-DQB1 and HLA-DPB1 [5]. Mismatched sex is another factor which influences outcomes, leading to more prevalent and severe GVHD in cases of host-recipient sex mismatch. In addition, recipient and donor age impact the incidence of GVHD, with higher rates of cGVHD in older recipients [5].

Although the pathogenesis of cGVHD is not fully understood, it is believed to be mediated by mature donor CD4+ and CD8+ T cells from the transplanted graft; these clonally expand in an antigen-specific manner upon recognition of non-self HLAs expressed on nucleated cells in an immunosuppressed host [1]. This expansion is permitted to continue unrestricted because of impaired immunological self-tolerance in the setting of ineffective thymic and peripheral deletion mechanisms. Mismatch in major histocompatibility locus antigens is often involved, although minor histocompatibility antigens are believed to be important in some cases [2]. The overlap in clinical and laboratory presentation of several autoimmune disorders and some presentations of GVHD has lead to the suggestion that dysfunctional humoral immunity and persistently activated donor T cells, which induce cytolytic attack, fibrosis, B-cell activation and production of inflammatory cytokines, may also be involved [1, 5]. Whereas initial acute disease seems to involve Th1 pathways, cGVHD appears to be mediated by Th2 cytokine responses, with increased levels of IL-4, IL-5, transforming growth factor beta and eosinophils found in many such cases [1].

Cutaneous manifestations of cGVHD are varied and related topatient outcomes and quality of life. Before the development of classical cutaneous findings, initial skin manifestations may be subtle. Patients may develop xerosis, ichthyosis, follicular prominence, annular lesions or papulosquamous, psoriasiform, eczematous or pityriasis-rosea-like changes [1]. Classically, cutaneous cGVHD is separated into two clinical subtypes, which may occur independently, in succession or simultaneously [3]. The lichenoid subtype typically presents with violaceous or erythematous flat-topped plaques and papules on the palms, soles, dorsal trunk and forearms, which may resemble lichen planus [2]. The other classic subtype, sclerodermoid cGVHD, may mimic morphea or show features similar to lichen-sclerosus. Morpheaform sclerodermoid cGVHD features indurated plaques of dermal sclerosis, fibrosis, and joint contractures. In contrast to typical morphea, the histology of sclerodermoid GVHD shows prominent sclerosis in the papillary versus the reticular dermis [3]. Lichen sclerosus-like plaques present as the most superficial variant of sclerodermoid GVHD with a predilection for the neck, upper trunk and sites of freshly removed central venous catheter [3]. Hypopigmented, atrophic, scaling plaques and follicular plugging are characteristic cutaneous manifestations [1]. Histological features of lichenoid eruptions include epidermal atrophy, basovacuolar changes, perivascular lymphohistiocytic infiltration and a sub-epidermal zone of homogenized collagen, which lacks elastic fibers [3]. In addition eosinophilic fasciitis has been reported as a manifestation of sclerodermoid cGVHD. This variant favors the extremities, but spares the most distal acral areas, and presents with indurated "pseudo-cellulite" plaques, which are preceded by acute edema and pain [3]. Edema, fibrosis, and thickening of the fascia and subcutaneous septae with an infiltrate of lymphocytes, eosinophils, and histiocytes are seen on histology [3].

We present two cases of LS&A-like cGVHD. Only a few reports of LS&A-like cGVHD have previously been described in the literature. In a series of 17 patients with sclerodermoid GVHD presented by Penas et al. [7], 8 patients showed LS&A-like lesions. An additional six patients with sclerodermatous cGVHD presenting with LS&A-like lesions were described by Schaffer et al. [8]; 2of those patients progressed to develop eosinophilic fasciitis. A patient reported by Cordoba et al. [9] developed chronic lichenoid GVHD progressing from acute GVHD after an allogenic bone marrow transplant from her HLA- identical sister and subsequently developed LS&A-like plaques. Saxana et al. [10] reported a case of LS&A-like cGVHD in a 28-year-old female who was status post allogenic stem cell transplant; she presented with atrophic white and hyperpigmented macules and patches on the trunk that histologically showed vacuolar changes at the dermo-epidermal junction with edema, sclerosis and melanophages in the papillary and upper reticular dermis. LS&A-like chronic GVHD skin lesions may appear very similar to classic LS&A both clinically and histopathologically, emphasizing the need for clinical-pathologic correlation in making the diagnosis. Schaffer et al. [8] suggested that LS&A-like GVHD microscopically demonstrates an interface dermatitis near adnexal structures deep in the reticular dermis but lacks a prominent interstitial mononuclear infiltrate, helping to distinguish it from inflammatory LS&A.

Modification of patients' immunosuppression is the mainstay treatment of chronic GVHD and should be approached cautiously, taking into account disease extent and severity as well as the threat of relapse of the primary malignancy. Prednisone alone or combined with a calcineurin inhibitor has been shown to increase survival in patients with extensive cGVHD by 26 percent or 52 percent respectively [8]. Salvage treatment generally aims at blocking the expansion of donor T lymphocytes, the key mediators of chronic GVHD, with agents such as daclizumab, sirolimus, pentostatin, mycophenolate mofetil or ECP [8]. Additional strategies have focused on B lymphocyte blockade using medications such as rituximab [8]. Other proposed approaches include methods to induce tolerance against specific host antigens and/or deplete the host of alloreactive T cells, via expansion of regulatory T cells or introduction of mesenchymal stem cells and immature dendritic cells [8].

The skin is a frequent target organ of GVHD and often the presenting location of the disease, making dermatologists key in recognition and management of this major cause of morbidity and mortality in recipients of HSCT. It has been proposed that cutaneous cGVHD is a spectrum of disease with lesions that may evolve through various stages. LS&A-like GVHD may represent a phase in this continuum of cutaneous cGVHD or a distinct sub-type of disease. Remaining cognizant of the potential manifestations of disease is key to prompt recognition of cGVHD and the need for proper treatment.

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