Atypical cutaneous targetoid lesions after bone marrow transplant

Abstract

A 69-year-old man with esophageal EBV-positive diffuse large B cell lymphoma status post allogeneic bone marrow transplant (BMT) five months prior presented to his oncologist with three days of maculopapular rash that was initially diagnosed as grade 1 graft-versus-host disease and started on oral prednisone. However, due to worsening of the rash, the patient presented to dermatology clinic, where skin biopsy revealed a diagnosis of erythema multiforme (EM). The patient improved with the use of topical steroids. This case highlights the atypical morphology of post-BMT EM and the potential causes for this atypical appearance.

Background

Graft-versus-host disease (GVHD) and erythema multiforme (EM) are two cutaneous conditions that may both manifest after bone marrow transplantation (BMT). In GVHD, donor T lymphocytes attack the host cells, while in EM, autoreactive T cells cause inflammation in the individual’s own tissues. Acute cutaneous GVHD may have multiple morphologies, but is most typically characterised by generalised erythematous macules, while EM classically manifests with target lesions. Both can be pruritic and demonstrate mucosal involvement.

We report a case of idiopathic EM with a component of GVHD that resulted in atypical morphology of the cutaneous lesions. This case discusses the pathogenesis of EM and GVHD, how to distinguish the two entities and highlights the uniqueness of this patient’s presentation.

Case presentation

A 69-year-old man with esophageal EBV-positive diffuse large B cell lymphoma status post allogeneic bone marrow transplant (BMT) five months prior presented to his oncologist with three days of maculopapular rash that started on his legs and spread to his arms and trunk in the setting of tacrolimus taper. Dosing of tacrolimus was reduced from 2 mg twice daily to 1 mg twice daily 1 week prior to the onset of the rash. The rash was burning and pruritic, with no fevers or systemic symptoms. The patient had not started new medications and was compliant with his current medications, which included acyclovir prophylaxis and gabapentin. He was diagnosed with grade 1 GVHD based on clinical findings and started on oral prednisone 80 mg daily.

Ten days later, he presented to dermatology for rash progression while on prednisone. On examination, there were numerous pink, raised ovoid lesions with targetoid appearance and lightly depressed dusky centres, some with central erosions or small vesicles, on the dorsal hands, extremities, chest, back, abdomen, ears and legs (figure 1). Oropharynx, groin and conjunctiva were clear.

Figure 1.

Target lesions on (A) chest and (B) dorsal hand.

Investigations

Skin biopsy showed vacuolar interface dermatitis with florid dyskeratosis (figure 2). Laboratory investigations were notable for elevated erythrocyte sedimentation rate of 29 mm/hr (normal 0–12), white blood cell count 4.9x10⁹/L (baseline 1.5x10⁹), haemoglobin of 124 g/L (normal 135–180), platelets of 86 000/uL (normal 150 000–450 000) and normal liver function tests. Serologies for acute herpes simplex virus (HSV), cytomegalovirus (CMV), varicella zoster virus (VZV), and Epstein-Barr virus (EBV) IgM were negative.

Figure 2.

Histopathological image showing vacuolar interface dermatitis with florid dyskeratosis, consistent with erythema multiforme; magnification (A) 10x, (B) 40x.

Differential diagnosis

GVHD and EM can be difficult to distinguish because of shared characteristics. Both GVHD and EM may show necrotic keratinocytes, dermal inflammatory infiltrate and subepidermal clefting on histopathology. Morphologically, GVHD may manifest as EM-like targetoid lesions.^{1 2} One helpful distinction is that GVHD is often associated with systemic symptoms, such as fever and diarrhoea, and abnormal findings on relevant clinical and laboratory investigations, such as jaundice, transaminitis, pancytopenia and marrow aplasia, while EM is not.²

The patient had an atypical appearance of EM due to ear involvement, scaling and florid dyskeratosis on histology. The patient may have had a component of acute inflammation as the graft cells were summoned to the skin in the event of EM eruption; cutaneous eruptions can therefore trigger GVHD. However, given the absence of systemic findings or laboratory abnormalities commonly found in GVHD, as well as the pronounced targetoid morphology and confirmatory histopathology, our patient’s ultimate diagnosis was EM.

Treatment

The patient was initially started on topical tacrolimus 0.1% ointment, which was switched to clobetasol propionate 0.05% ointment when he complained of burning and tingling of his hands and feet. He continued his valacyclovir and gradually tapered his prednisone from 80 mg to 20 mg in a stepwise manner within 1 month as his rash improved.

Outcome and follow-up

At follow-up dermatology appointment 1 month later, the patient showed significant improvement with only two residual and fading violaceous papules on his shoulder and knee, without signs of new lesions. Two months later, the patient was admitted to the hospital for Pneumocystis carinii pneumonia and required intubation. The patient passed away shortly thereafter.

Discussion

EM is an acute mucocutaneous eruption, characterised by target lesions. It is commonly related to underlying infections, such as herpes simplex virus, but in up to 58% of cases, the aetiology is unknown.³ Our patient had no obvious inciting factors for EM, such as drugs, infections, or autoimmune disease, suggesting that his EM was most likely idiopathic. There have been reported associations of non-Hodgkin’s lymphoma with EM⁴ as atypical cancer cells could participate in the hypersensitivity reaction.⁵ However, our patient had already undergone BMT and was without signs of active malignancy.

Despite our patient having negative HSV viral PCR and being on prophylactic acyclovir, HSV is important to consider in patients following BMT. HSV genetic fragments may localise in stem cells, which can deliver the fragments to the skin on differentiation.⁶ Reactivated HSV can also increase the risk of GVHD through its ability to stimulate T-cell proliferation.⁷ Thus, underlying viral infections triggering both EM and GVHD can cause atypical cutaneous reactions seen post-BMT.

Our patient’s case was unique in that his EM was atypical, given the scaling, substantial ear involvement and florid apoptotic keratinocytes on histology. This atypical morphology is most likely due to a component of GVHD as graft cells were recruited to the sites of inflammation. To distinguish between GVHD and EM, it is important to consider that GVHD may be associated with systemic symptoms, such as transaminitis, fever and pancytopenia, and GVHD tends to occur 30 days post-transplant. GVHD may rarely also occur in a skin-limited manner. EM can occur at any time and is more likely accompanied by pruritus.² Histologically, GVHD and EM may be affected by the medications used post-BMT. For example, immunosuppressive agents, such as the tacrolimus that our patient was on, target T lymphocytes so the inflammatory reaction in GVHD may be predominantly macrophages.⁸

This case highlights the importance of recognising atypical eruptions in patients post-BMT. Because of similarities between GVHD and EM, cutaneous reactions post-BMT may fall under a larger umbrella or spectrum of EM-reactive dermatoses.^{6 7} The timing of our patient’s eruption coinciding with the tapering of immunosuppression initially raised the possibility of GVHD, but the atypical morphology appreciated by his oncologist triggered a dermatology evaluation. The differential for post-transplant cutaneous eruptions should be broad to avoid missing correct diagnoses and appropriate treatment.

Learning points.

• The differential diagnosis for cutaneous eruptions after bone marrow transplant (BMT) is broad. It is important to keep in mind that eruptions may appear atypical due to the immunosuppression and other potential comorbidities.

• Erythema multiforme (EM) is commonly associated with cancer, viral infections (eg, HSV), bacterial infections (eg, Mycoplasma), drugs (eg, sulfonamides, phenytoin, barbiturates, allopurinol, penicillin) and autoimmune disease (eg, systemic lupus erythematosus). However, there are cases in which the EM is idiopathic, as in our patient.

• Referral to dermatology and skin biopsies may be helpful in diagnosing cutaneous eruptions in patients post-BMT.