Paraneoplastic erythroderma: unusual presentation secondary to diffuse large B cell lymphoma

Abstract

A 34-year-old HIV-positive man presented in clinic with generalised erythroderma, having been lost to follow-up for the previous 3 years. He was CD4 lymphopenic (100×10⁶/L) and was antiretroviral therapy naive. Initial histology from a skin punch biopsy was non-specific and he was treated with topical steroids and emollients for a suspected eczema. However, the erythroderma worsened with development of cervical lymphadenopathy and significant weight loss over a 6-week period. An incisional biopsy from the left tonsil confirmed a diagnosis of diffuse large B-cell lymphoma. The erythroderma was considered to be a paraneoplastic skin phenomenon. The patient received rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone (CHOP) immunochemotherapy with gradual but complete resolution of the erythroderma. Paraneoplastic dermatoses can manifest as first clinical sign of underlying malignancy, heralding a cancer diagnosis. This is particularly important in people living with HIV given the increased incidence of malignancy in this patient group.

Background

Our case report describes one of the rare dermatological presentations of a lymphoma. Although paraneoplastic manifestations are not uncommon, erythrodermic presentation of diffuse large B-cell lymphoma (DLBCL) is exceptionally rare with only one case reported in the literature. Notably, this was in the context of CD4 lymphopenia due to untreated HIV infection and initially presented with isolated erythroderma.

Malignancy is one of the most common causes of death in HIV infection. With advances in antiretroviral therapy (ART), people with HIV can expect a near-normal life expectancy, but accumulating literature demonstrate that malignancies (both AIDS defining and non-AIDS defining) are common causes of morbidity and mortality. It is crucial that clinicians test for HIV in patients with newly diagnosed malignancy and, importantly, to have a low threshold for investigating for malignancy in patients with known HIV presenting with new symptoms.

Case presentation

A 34-year-old HIV-positive Polish man presented to clinic with widespread, erythematous and scaly skin changes. He was diagnosed HIV in 2012 with a CD4 count of 418×10⁶/L but was subsequently lost to follow-up. Examination findings revealed a generalised erythrodermic rash on the trunk, upper and lower limbs, face and dorsum of hands and feet (figures 1 and 2). There was no mucosal involvement. His nails appeared brittle and there was severe palmoplantar involvement.

Figure 1.

Initial presentation of erythroderma of left arm prior to immunochemotherapy.

Figure 2.

Initial presentation of erythroderma of both legs prior to immunochemotherapy.

He was otherwise clinically well without signs of systemic upset. He offered no previous history of eczema, psoriasis or any other skin conditions. His CD4 count was 100×10⁶/L with a HIV viral load of 700 767 copies/mL. Serological tests were negative for hepatitis B and C. However, Epstein-Barr virus (EBV) PCR level was 13 225 IU/L. His renal and liver biochemistries were within normal limits.

He had an urgent dermatology review and underwent punch biopsy of the skin. Histology demonstrated focal spongiosis with perivascular inflammation including lymphocytes, histiocytes and plasma cells in the dermis. The clinical and histological impression at that time was most consistent with a widespread eczematous process causing spongiotic dermatosis. He was prescribed emollients and momethasone ointment 0.1%. However, over the following weeks, he developed significant cervical lymphadenopathy, lost >10% of his body weight and became anaemic (haemoglobin 115 g/L) with no improvement of the skin rash.

Investigations

Initial imaging with contrast-enhanced CT imaging of chest, abdomen and pelvis revealed hepatosplenomegaly with extensive lymphadenopathy in cervical, axillary and mediastinal areas (figure 3). This was highly suggestive of an underlying lymphoma.

Figure 3.

Widespread lymphadenopathy in CT chest, abdomen and pelvis.

A histological diagnosis was subsequently confirmed following biopsy from an enlarged tonsil. This demonstrated DLBCL, which was EBV positive with only focal CD20 expression in a minority of cells. He had stage III disease with a slightly high lactate dehydrogenase (LDH) but had good performance status and was of a young age.

Differential diagnosis

The initial clinical and histological impression of the skin biopsy was consistent with a widespread eczematous process.

However, as the erythroderma persisted and the patient developed systemic symptoms (weight loss, cervical lymphadenopathy), CT chest, abdomen and pelvis suggested an underlying malignancy.

Treatment

He initially received oral prednisolone (1 mg/kg) prior to starting definitive chemotherapy. However, the skin erythema did not respond to corticosteroids alone.

Antiretrovirals were given concurrently—tenofovir alafenamide, emtricitabine and raltegravir. This combination was chosen to mitigate drug interactions given the expectation of chemotherapy.

Following the diagnosis of DLBCL, he was treated with rituximab-CHOP immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) for six cycles.

Outcome and follow-up

The treatment was uneventful and he achieved a complete metabolic remission on positron emission tomography–computed tomography (PET-CT). His HIV viral load was undetectable within 12 weeks after initiating ART. There was minimal improvement in his skin despite ART. His EBV viraemia also quickly resolved following ART and rituximab-based therapy.

His widespread skin erythema progressively improved throughout his course of immunochemotherapy, with full resolution noted after 4 months of therapy (figures 4 and 5). It was concluded that the erythroderma was a paraneoplastic skin phenomenon secondary to DLBCL and unlikely to be directly related to HIV.

Figure 4.

Resolution of erythroderma of right flank postimmunochemotherapy.

Figure 5.

Resolution of erythroderma of back postimmunochemotherapy.

Discussion

Paraneoplastic dermatoses are skin manifestations associated with neoplasms but without any direct invasion or involvement by the tumour cells.¹ The concept was first suggested by Hebra in 1868 and subsequently more widely described and characterised.² The concept It is thought to be caused by an off-target immunological response to the neoplasm, mediated through inflammatory or metabolic processes via polypeptides, hormones, cytokines and antibodies.¹ Recognition of these dermatoses is important to facilitate earlier diagnosis and management of underlying malignancies.³

There are no evidence-based guidelines for diagnosis and management of paraneoplastic dermatoses. Curth, in 1976, proposed certain criteria to assess the relationship between systemic malignancy and cutaneous lesions (as shown in box 1).¹

Box 1. Curth’s postulates.

• The malignancy and the skin disease occur concurrently.

• The malignancy and the skin disease run a parallel course. If the malignancy is treated successfully or recurs, the dermatosis follows a similar course.

• The relation between the skin disease and malignancy is uniform. A specific malignancy is consistently associated with a specific dermatosis.

• Based on sound case–control studies, there is a statistically significant association that exist between the malignancy and dermatosis.

• There is a genetic association between malignancy and dermatosis.

Paraneoplastic skin disorders associated with malignancy can be classified into two main types³:

1. Hyperkeratotic dermatoses.

   1. Acanthosis nigricans, sign of Leser-Trelat, tripe palm, ichthyosis, palmoplantar keratoderma.
2. Inflammatory dermatoses.

   1. Sweets syndrome, dermatomyositis, erythroderma, erythema gyratum repens, necrolytic migratory erythema, pancreatic panniculitis.

Erythroderma manifests as widespread erythema accompanied by a variable degree of scaling, typically involving over 90% of the body surface area. It is most commonly caused by atopic dermatitis, psoriasis as well as hypersensitivity reactions to drugs. Cases of erythroderma associated with malignancy tend to be presented as Sezary syndrome which is a type of cutaneous T cell lymphoma.^{4 5} Less commonly, paraneoplastic erythroderma is associated with acute myeloid leukaemia and solid tumours.⁶

Paraneoplastic erythroderma associated with DLBCL is exceptionally rare with only one case reported.⁷ In the published report, Yang et al described a case of generalised erythema with severe scaling and right neck mass, with confirmed DLBCL on biopsy. In this case, it was noted that the erythroderma was initially resistant to standard treatment of topical steroids, antifungals and emollients and only subsided alongside with treatment of the underlying malignancy.

HIV infection is associated with increased risk of AIDS defining malignancies (Kaposi’s sarcoma, high-grade B cell non-Hodgkin’s lymphoma and invasive cervical cancer), as well as other malignancies.⁸ With the advent of ART, although people with HIV can expect near-normal life expectancy, malignancy is one of the common causes of morbidity and mortality.⁹

Learning points.

• Paraneoplastic conditions most commonly cause endocrine abnormalities but a significant proportion present with skin manifestations, with erythroderma being a rare phenomenon.

• Paraneoplastic dermatoses can occur before or concurrent with the underlying malignancy. Skin histology may show non-specific inflammation without evidence of neoplastic involvement.

• Paraneoplastic dermatoses are often resistant to standard treatment and typically only respond to treatment of the underlying malignancy.

• Early recognition of paraneoplastic dermatoses is crucial to expedite diagnosis and appropriate management of the underlying disease.

• HIV-positive patients are at increased risk of a range of malignancies and clinicians should adopt a low threshold for investigating new and unexplained symptoms.