The face of CD4⁺ Hydroa Vacciniforme-Like Lymphoproliferative Diseases: The Shadow of Systemic T-Cell Lymphoma

Dear Editor:

A 32-year-old female presented with multiple brownish crusts on the face and scalp, first noticed 3 months previously (Fig. 1). Her skin lesions were painful and pruritic, and appeared after intermittent high fever. Atypical lymphocytes were found on peripheral blood smear. Polymerase chain reaction (PCR) quantification of Epstein-Barr virus (EBV) in serum yielded a count of 7,585,775 copies/ml. Scalp-skin biopsy revealed scattered medium-sized dermal lymphocytes with epidermal separation and subepidermal edema (Fig. 2A, B). Immunohistochemical staining showed positivity for CD3, CD4 and negativity for CD8, CD56 (Fig. 2C, D). A monoclonal T-cell receptor (TCR)-gamma gene rearrangement was not proved on PCR. In situ hybridization identified the presence of EBV-encoded RNA. Bone marrow biopsy revealed EBV⁺ lymphoid cells that were positive for CD3, CD4, and CD8 but negative for CD56. PCR revealed a monoclonal TCR-beta F1 gene rearrangement. Lymph node biopsy in right the middle third of internal jugular vein, below the hyoid bone (right level 3) revealed systemic EBV⁺ T-cell lymphoma evidenced by EBV in situ hybridization (Fig. 2E, F). Immunohistochemical staining showed positivity for CD4, CD8 and weak positivity for CD56 (Fig. 2G~I). PCR did not reveal the clonality of TCR-beta F1 gene rearrangement. A diagnosis of hydroa vacciniforme (HV)-like lymphoproliferative disease (LPD) was finally made with collective data. The patient was treated with sunscreen and tetracycline 500 mg twice daily for 14 months. The skin lesions improved after 3 months and were stable at 12 months follow-up.

Fig. 1. (A~C) Multiple brownish papules and crusts are presented on the nose and left temple (A) forehead (B) and scalp (C) consistent with hydroa vacciniform-like eruptions.

Fig. 2. (A, B) Skin biopsy showed scattered small- to medium-sized lymphoid cells with epidermal erosion, consistent with hydroa vacciniforme-like lymphoproliferative disorders (H&E: A, ×40; B, ×200). (C, D) Immunohistochemical staining showed positive reactivity for cytoplasmic CD4 (C) and negative reactivity for CD8 (D) (C, D, ×100). (E, F) Lymph node biopsy showed polymorphic diffuse infiltration of small- to medium-sized neoplastic cells, consistent with systemic Epstein-Barr virus (EBV⁺) T-cell lymphoma (H&E: E, ×100; F, ×400). (G~I) Immunohistochemical staining showed positive reactivity for cytoplasmic CD4 (G) (×200) and CD8 (H) (×100). These cells were also positively reactive in EBV in situ hybridization (I) (×200).

HV is usually self-limited and benign. When it is proved to have TCR monoclonality, it implies HV-like lymphoma¹. The World Health Organization reclassified all disease entities showing HV-like eruptions into an umbrella term: HV-like EBV⁺ LPDs. These EBV⁺ LPDs had been shown to progress to overt systemic lymphoma with a rate of 10% to 12%². The present case did not match the typical disease progression, suggesting the complicated characteristics of EBV⁺ LPDs. Recent studies³ reflected the complex relationship between HV-like LPD and EBV⁺ LPDs. Paik et al.³ categorized EBV⁺ LPD into 4 categories and reported 10 cases of systemic EBV⁺ LPD that could not be classified. In view of this, the present case demonstrated the difficulty of classifying EBV⁺ LPD and predicting its clinical course. Moreover, the immunopositivity for CD4 is noteworthy. The present case showed adult onset and an abrupt clinical course of HV eruption without scarring, which is atypical. In previous reports, CD4⁺ HV-like LPD was more aggressive and had an abrupt clinical course. Yang et al.⁴ reported 2 cases of CD4⁺ HV-like lymphoma that progressed to systemic lymphoma as fast as 1 and 2 years, respectively. One study with mouse xenografts proved the excellent proliferative ability of EBV-infected CD4⁺ T-cells in engraftment, explaining why patients with CD4⁺ T-cell lineage diseases showed poor prognosis⁵.

In conclusion, facial HV-like LPD should be examined for further underlying systemic lymphomas irrespective of the TCR rearrangement. Clinicians should not overlook HV-like disease to potentially reveal any systemic lymphoma.

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