Hydroa vacciniforme-like lymphoproliferative disorder: an EBV disease with a low risk of systemic illness in whites

Jeffrey I Cohen, Irini Manoli, Kennichi Dowdell, Tammy A Krogmann, Deborah Tamura, Pierce Radecki, Wei Bu, Siu-Ping Turk, Kelly Liepshutz, Ronald L Hornung, Hiva Fassihi, Robert P Sarkany, Lori L Bonnycastle, Peter S Chines, Amy J Swift, Timothy G Myers, Melissa A Levoska, John J DiGiovanna, Francis S Collins, Kenneth H Kraemer, Stefania Pittaluga, Elaine S Jaffe, Jeffrey I Cohen, Irini Manoli, Kennichi Dowdell, Tammy A Krogmann, Deborah Tamura, Pierce Radecki, Wei Bu, Siu-Ping Turk, Kelly Liepshutz, Ronald L Hornung, Hiva Fassihi, Robert P Sarkany, Lori L Bonnycastle, Peter S Chines, Amy J Swift, Timothy G Myers, Melissa A Levoska, John J DiGiovanna, Francis S Collins, Kenneth H Kraemer, Stefania Pittaluga, Elaine S Jaffe

Abstract

Patients with classic hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) typically have high levels of Epstein-Barr virus (EBV) DNA in T cells and/or natural killer (NK) cells in blood and skin lesions induced by sun exposure that are infiltrated with EBV-infected lymphocytes. HVLPD is very rare in the United States and Europe but more common in Asia and South America. The disease can progress to a systemic form that may result in fatal lymphoma. We report our 11-year experience with 16 HVLPD patients from the United States and England and found that whites were less likely to develop systemic EBV disease (1/10) than nonwhites (5/6). All (10/10) of the white patients were generally in good health at last follow-up, while two-thirds (4/6) of the nonwhite patients required hematopoietic stem cell transplantation. Nonwhite patients had later age of onset of HVLPD than white patients (median age, 8 vs 5 years) and higher levels of EBV DNA (median, 1 515 000 vs 250 000 copies/ml) and more often had low numbers of NK cells (83% vs 50% of patients) and T-cell clones in the blood (83% vs 30% of patients). RNA-sequencing analysis of an HVLPD skin lesion in a white patient compared with his normal skin showed increased expression of interferon-γ and chemokines that attract T cells and NK cells. Thus, white patients with HVLPD were less likely to have systemic disease with EBV and had a much better prognosis than nonwhite patients. This trial was registered at www.clinicaltrials.gov as #NCT00369421 and #NCT00032513.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
HV lesions. (A-G) Varioliform erosions on sun-exposed areas on the face of patient 4 (A), eroded papulopustules on the back of the neck of patient 1 (B), conjunctival involvement in patient 1 (C), erosions on the pinna of the ear of patient 5 (D), vesicles on the lip of patient 4 (E), bulla and healing erosions on the hand of patient 3 (F), and erosions on the neck of patient 4 (G). (H) Typical, round, punched out, varioliform scarring after healing of HV lesions on the cheek of patient 9.
Figure 2.
Figure 2.
Pathology of HV biopsy specimens. (A-B) Skin biopsy specimen from patient 5 showing multiloculated intraepidermal vesicles with reticular degeneration and necrotic epidermal keratinocytes and a mixed inflammatory reaction with neutrophils and mononuclear cells; no viral cytopathic changes were observed. The dermis showed perivascular, periadnexal, and interstitial mononuclear cells with a predominance of small lymphocytes throughout the thickness of the dermis (hematoxylin and eosin stain [(B) higher power]). (C-D) Terminal ileum and Peyer’s patches with reactive follicle (C; hematoxylin and eosin stain) and numerous EBV-positive cells (D; in situ hybridization for Epstein-Barr encoded RNA) in patient 5. (E-F) Skin biopsy specimen from patient 16 stained for CD3 (E) and Epstein-Barr encoded RNA (F; EBER). Original magnification ×100 (A,C), ×200 (D-F), ×400 (B).
Figure 3.
Figure 3.
Lymphocyte subset and EBV tetramer staining of PBMCs from patients with HV and normal controls. Tetramer staining was performed for EBV LMP2, lytic protein BRLF1, and influenza M1 (flu) with costaining for CD8 (A), CD127 (B), CD27 (C), PD1 (D), CCR7 (E), or CD57 (F). P values are shown for results that are significantly different between patients and controls. NC, normal control; pt, patient.
Figure 4.
Figure 4.
EBV protein antibody levels to gp350 (A), gH/gL (B), BHRF1 (C), BLRF2 (D), BFRF3 (E), and BMRF1 (F) in patients with HV, T-cell CAEBV without HVLPD, and healthy EBV-seropositive (EBV+) and EBV-seronegative (EBV−) blood-bank donors. Antibody levels were determined by immunoprecipitation and measured in light units.
Figure 5.
Figure 5.
Serum cytokine levels in patients with HV, T-cell CAEBV without HVLPD, and EBV-seropositive blood-bank donor controls (CTRL).
Figure 6.
Figure 6.
Serum cytokine levels in patients with systemic HV (sHV) and classic HV (cHV).

Source: PubMed

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