Hydroa Vacciniforme-Like Lymphoma with Systemic Symptoms: Two Case Reports.

Two Chinese children presented with relapsing papules, vesicles, ulcers on the face and limbs with systemic symptoms being caused by mosquito bite. Lesion biopsy revealed atypical lymphocyte in the dermis and subcutis. Immunohistochemistry identified cells as positive for CD3, CD45RO, TIA-1 and EBER. Taken together, both the patients were diagnosed with hydroa vacciniforme-like lymphoma. Two patients showed significant improvement in clinical symptoms after being treated with acyclovir, low dose predisone and IFN-α. Copyright:

Introduction

Hydroa vacciniforme-like lymphoma (HVLL) is an uncommon, EBV infection-associated lymphoproliferative disorder in children.[1] To date, there are approximately 30 related reports of HVLL, only a few of which referred to mosquito bite as playing a key role in the onset. We report two cases of HVLL in Chinese children with systemic symptoms being caused by mosquito bite

Case Reports

Case 1

A 5-year-old girl presented with recurrent attacks of red papules, papulovesicles, necrotic ulcers with black crusts, and vacciniforme scarring on her face, hip, bilateral arms, and legs for 2 years. Symptoms got worse after mosquito bite which resolved spontaneously. She was admitted to our hospital for further investigations because of multiple red edematous plaques, necrotic ulcers with crusts on her sun-exposed areas, fever, hepatosplenomegaly, and systemic lymphadenopathy for 2 months.

Physical examinations: Body temperature was at 39.4°C. Lymphadenopathy was noted on both sides of the jaw, neck, axilla, and groin. The liver was enlarged about 3.5 cm under the costal arch, and the spleen was enlarged with its lower edge 3 cm below the left costal margin.

Cutaneous examinations: Lesions were located on the face, limbs, and hips, mainly manifested as various sizes of edematous erythema, papules, nodules and vacciniforme pitting, some with vesicles, or pustules at the center [Figure 1].

Figure 1

(a) Edematous erythema, red papules, papulovesicles, blisters, ulceration and atrophic scars on the face. (b) Edematous erythema, red papules, papulovesicles, blisters, ulceration and atrophic scars on lower legs

Laboratory tests: No atypical lymphocytes in peripheral blood smears were found. Liver function test and serum immunoglobulin analysis were within normal range. Serological examinations for human immunodeficiency virus and syphilis were negative. Result for bone marrow biopsy was normal. Skin biopsy revealed diffuse infiltrate of lymphoid cells with atypical nuclei in superficial and deep perivascular and periadnexal dermis as well as the subcutis [Figure 2]. Immunohistochemistry identified cells as positive for CD45RO [Figure 3a], CD99, CD3, and CD8 [Figure 3b]; strongly positive for TIA-1 [Figure 3c]; but negative for CD30, CD56, CD20, TDT, and CD79. In situ hybridization staining for Epstein–Barr virus (EBV)-encoded, small, nonpolyadenylated RNA (EBER)-1 was positive [Figure 3d].

Figure 2

(a) Histopathology: Dense nodular infiltration of atypical lymphocyte in dermis, subcutis and periadnexal with the involvement of epidermis (H and E, ×100). (b) Histopathology: Dense nodular infiltration of atypical lymphocyte in dermis, subcutis and periadnexal with the involvement of epidermis (H and E, ×400)

Figure 3

(a) Immunohistochemist CD8 positive. (b) Immunohistochemist CD45RO positive. (c) Immunohistochemist TIA-1 positive. (d) Epstein-Barr virus-encoded RNA detection by in situ hybridization were strong positive

Case 2

An 11-year-old boy was admitted to our hospital with recurrent itchy edematous red papules, plaques, vesicles, and ulcers on the face and limbs for 6 years. Lesions were caused by mosquito bite and some healed without treatment. He had irregular intermittent fever when rashes were severe.

Physical examinations: Several enlarged, smooth, soft, and nontender lymph nodes were found in the neck; other organs did not reveal obvious abnormality. Cutaneous examinations: Lesions were located on the face, the edge of the right opisthenar, and the skin around knee joints, mainly manifested as various sizes of edematous erythema, nodules with ulceration and dark crust on the surface, and vacciniforme pitting spread over the face and limbs [Figure 4].

Figure 4

(a) Edematous erythema, nodules, part with ulceration and dark crust on the face. (b) Edematous erythema, nodules, part with ulceration and dark crust on the edge of right opisthenar

Laboratory tests: Serological examinations for HIV and syphilis were negative; no abnormality was found in the bone marrow examination. Skin lesion biopsy: Diffuse infiltration of atypical lymphocytes in the dermis, subcutis, and lower epidermis were revealed [Figure 5]; immunohistochemistry showed positive for CD45RO [Figure 6a], CD43 [Figure 6b], and CD3; strong positive for TIA-1 [Figure 6c]; but negative for CD30, CD56, and CD20. In situ hybridization staining for EBV-encoded, small, nonpolyadenylated RNA (EBER)-1 was positive [Figure 6d].

Figure 5

(a and b) Dense infiltration of atypical lymphocyte in dermis (H and E, ×100), subcutis and lower epidermis (H and E, ×400)

Figure 6

(a) Immunohistochemistry: CD43-positive (×100) (b) CD45RO-positive (×200) (c) TIA-1-positive (×200) (d) Epstein-Barr virus-encoded RNA detection by in situ hybridization were positive (×200)

Taken together, both the patients were diagnosed with hydroa vacciniforme-like lymphoma (HVLL). They were treated with alpha-interferon for 1 × 106 units daily, low dosage of prednisone (20 mg/day), bacille Calmette–Guerin (BCG) polysaccharide, and nucleic acid injection (1 ml/day), as well as prevention of mosquito bite. Lesions and system symptoms resolved several months after initiation of treatment.

Discussion

HV is a photosensitive disorder characterized by recurrent necrotic papulovesicle on the sun-exposed area, which may be self-healing in adolescence or young adulthood. HVLL has a similar rash and vulnerable population as HV, but it spread to both sun-exposed and nonsun-exposed areas; it may have systemic manifestations and has been reported having an intimate relationship with EBV infection. HVLL is included in chronic active EBV infection according to the 2016 World Health Organization (WHO) classification of lymphoid neoplasms[2] and occurs with increased frequency in Asians, as well as in indigenous populations from Central and South America.[34] Although HVLL mainly occurs in children, there is a report showing an adult-onset HVLL.[5] This reminds us to pay more attention to the recurrent necrotic papulovesicles that occur in both sun-exposed and sun-protected areas, in the case of misdiagnosis.

Hypersensitivity to mosquito bites is known to be associated with Epstein–Barr virus infection and natural killer cell leukemia/lymphoma. However, mosquito bite has been reported to trigger anaplastic lymphoma, kinase-positive anaplastic large-cell lymphoma, nodal marginal zone lymphoma, and mantle-cell lymphoma, originating from T-cell or B-cell.[678] The mosquito bite was significantly related to morbidity in the children with HVLL.[9] These two cases of HVLL also had an obvious history of hypersensitivity to mosquito bite. Severe mosquito bite allergy was classified as chronic EBV infection as well as HVLL according to the 2016 WHO classification of lymphoid neoplasms, which is characterized by intense local skin symptoms, such as erythema, bullae, ulcers, and scarring. However, skin biopsy does not show atypical lymphocytes, but infiltrated small lymphocytes (parts of them are EB positive) are extending from the dermis to the subcutis.

In these two cases, rashes mainly spread over the sun-exposed areas such as face and limbs, accompanied by intermittent fever, or hepatosplenomegaly. Skin biopsy showed diffuse infiltration of atypical lymphocytes in the dermis, subcutis, and lower epidermis; immunohistochemistry showed positive for CD8, CD45RO, CD3, CD43 and TIA-1; and EBER-1 detection by in situ hybridization was positive. Based on the medical history, clinical feature, and auxiliary examination results, these two patients were diagnosed with HVLL.

As for HVLL, its prognosis is unclear and optimal treatment is not defined. Antiviral treatment (interferon-gamma [IFN-γ] and acyclovir) is the most common therapy, and corticosteroid is usually used to control the symptoms; only parts of the patients have response to chemotherapy. EBV-cytotoxic T-lymphocyte immunotherapy has demonstrated efficacy in systemic EBV + HV-like T-cell lymphoma.[10] Treatment for both the patients included low dosage of prednisone, IFN-γ, BCG polysaccharide, and nucleic acid, also prevention of mosquito bite. Several months later, lesions and system symptoms resolved. A 2 year follow-up showed no recurrence. Because mosquito bite was the initiation of these two cases, the therapy to prevent mosquito bite played a crucial role in the prognosis.

Declaration of patient consent

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Conflicts of interest

There are no conflicts of interest.