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

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.

Ethnic disparity in primary cutaneous CD30+ T-cell lymphoproliferative disorders: an analysis of 1496 cases from the US National Cancer Database.

Primary cutaneous CD30+ T cell lymphoproliferative disorders (PCLPD), the second most common type of primary cutaneous T cell lymphomas, accounts for approximately 25-30% of cutaneous T-cell lymphoma cases. However, only small retrospective studies have been reported. We aimed to identify prognostic factors and evaluate the overall survival (OS) of patients with PCLPD stratified by ethnicity. We identified 1496 patients diagnosed with PCLPD between 2004 and 2014 in the US National Cancer Database. Chi-square test and anova were used to evaluate differences in demographic and disease characteristics, socioeconomic factors and treatments received. OS was evaluated with the log-rank test, Cox proportional hazard regression analysis, and propensity score matching. The study included 1267 Caucasians, 153 African Americans (AA), 43 Asians, and 33 of other/unknown ethnicity. Older age, higher Charlson-Deyo score, higher clinical stage and receipt of chemotherapy were predictors of shorter OS. Primary disease site on a lower extremity was associated with shorter OS, while a head and neck location was associated with longer OS. AA patients had shorter OS when compared to Caucasian patients on multivariate analysis. This ethnic disparity persisted on propensity-score matched analysis and after matching Caucasian and AA patients on demographic and disease characteristics, socioeconomic factors and treatments received, and age and gender-matched relative survival analyses.

Risk factors and clinical outcomes of pediatric liver transplant recipients with post-transplant lymphoproliferative disease in a multi-ethnic Asian cohort.

BACKGROUND: We aimed to evaluate clinical characteristics, risk factors, and disease outcomes for liver transplant recipients (LTR) with post-transplant lymphoproliferative disease (PTLD) at our center. METHODS: Retrospective review of data of all pediatric LTR (1991-2015) was conducted. RESULTS: The overall incidence of PTLD was 16.4% (18/110), the majority (13/18) were early lesions, while 3/18 were polymorphic/monomorphic PTLD. The risk factors significant on univariate analysis were as follows: mean age (years) at transplant (1.66 vs 4.76, P = .006); age <2 years at transplant (odds ratio [OR] 3.53 [95% confidence interval [CI]: 1.16-10.73], P = .026); cytomegalovirus (CMV) primary infection (OR 11.39 [95% CI: 3.44-37.7], P < .001); recipient CMV seronegativity (OR 7.50 [95% CI: 2.02-27.78], P = .003); presence of CMV end-organ disease (OR 4.00 [95% CI: 1.22-13.16], P = .022); Chinese ethnicity; and higher mean duration of intravenous ganciclovir prophylaxis. In multivariate analysis, CMV primary infection (OR 5.22 [95% CI: 1.25-21.87], P = .024), CMV seronegativity (OR 5.91 [95% CI: 1.13-30.90, P = .035]), and having acute cellular rejections (ACR) prior to PTLD (OR 5.53 [95% CI: 1.43-21.48, P = .013]) were significant risk factors for PTLD, with the latter two factors having a synergistic effect in increasing PTLD risk in a stratified analysis. The final multivariate model in predicting the risk of PTLD, utilizing CMV primary infection, recipient CMV seronegativity, and ACR before PTLD as predictive variables, was statistically significant (likelihood ratio chi square statistic = 25.18, P < .0001 with df = 3). CONCLUSIONS: We report a unique clinicopathologic and risk factor profile in our cohort-early lesion PTLD accounts for the majority and the incidence of monomorphic PTLD remains low. In addition, we show a synergism between CMV naivety and ACR on PTLD risk, a higher prevalence of gastrointestinal manifestations, and a lack of significant association with Epstein-Barr virus seronegativity.

Dysgammaglobulinemia Associated With Glu349del, a Hypomorphic XIAP Mutation.

BACKGROUND: X-linked lymphoproliferative syndrome type 2 is a rare hereditary immunodeficiency caused by mutations in the XIAP gene. This immunodeficiency frequently results in hemophagocytic lymphohistiocytosis, although hypogammaglobulinemia and dysgammaglobulinemia are also common. OBJECTIVE: We identified 17 patients from 12 Japanese families with mutations in XIAP. The Glu349del mutation was observed in 3 patients, each from a different family. Interestingly, these patients exhibited dysgammaglobulinemia but not hemophagocytic lymphohistiocytosis. We conducted an immunological study of patients carrying Glu349del and other mutations to elucidate the pathogenic mechanisms of dysgammaglobulinemia in patients with mutations in the XIAP gene. PATIENTS AND METHODS: We performed an immunological study of 2 patients carrying the Glu349del mutation and 8 patients with other mutations. RESULTS: Flow cytometry showed that the percentage of memory B cells in patients with a mutation in XIAP was lower than that observed in the healthy controls. The patients with the Glu349del mutation had a lower percentage of memory B cells than those with other mutations. Ig production was reduced in patients with the Glu349del mutation. Increased susceptibility to apoptosis was observed in the patients with other mutations. Susceptibility to apoptosis was normal in patients with Glu349del. Microarray analysis indicated that expression of Ig-related genes was reduced in patients with the Glu349del mutation and that the pattern was different from that observed in the healthy controls or patients with other mutations in XIAP. CONCLUSIONS: Patients carrying the Glu349del mutation in the XIAP gene may have a clinically and immunologically distinct phenotype from patients with other XIAP mutations. The Glu349del mutation may be associated with dysgammaglobulinemia.

IgG4-related Mikulicz's disease is a multiorgan lymphoproliferative disease distinct from Sjögren's syndrome: a Caucasian patient and literature review.

OBJECTIVES: This paper aims to report a case of IgG4-related Mikulicz's disease with a systematic review. METHODS: The relevant English literature was searched using the keywords 'Mikulicz's disease' and 'IgG4'. Original and review articles were reviewed, and the clinical scenarios were exemplified with a case report. RESULTS: A 49-year-old Caucasian man presented with axillary lymphadenopathy and bilateral parotid/submandibular enlargement. A chest computerized tomography showed mediastinal lymphadenopathy, with low metabolic activity on the position emission tomography. A histopathological study showed an IgG4/IgG ratio of 75% in the plasma cells of the submandibular glands, associated with high levels of total serum IgG and IgG4. He had dry mouth, but minor salivary gland biopsy was negative without xerophthalmia. He had nasal obstruction and dyspnea, notably with supine position/cervical rotation, which substantially improved with glucocorticoid treatment. He had newly diagnosed diabetes mellitus with hyperlipasaemia and diffuse pancreatic swelling supportive of autoimmune pancreatitis. CONCLUSIONS: Our case report supports the literature that there are similarities between IgG4-related Mikulicz's disease and Sjögren's syndrome, but the differences are significant. IgG4-related Mikulicz's disease is a multi-organ lymphoproliferative disease distinct from Sjögren's syndrome.

Fatal atypical T-cell proliferation associated with Epstein-Barr virus infection.

We report the case of a young Caucasian man who presented with polyneuropathy and severe, ultimately fatal, congestive heart failure in the context of a chronic active Epstein-Barr virus (EBV) infection. Post-mortem examination revealed both monoclonal and polyclonal proliferation of EBV-positive atypical T lymphocytes within different organs. Predominant infiltration of the nervous system and heart with extensive myocardial scarring accounted for the clinical symptoms. The remarkable features of this case are (i) the occurrence in a Caucasian patient, (ii) the absence of detectable immunodeficiency, and (iii) the myocardial destruction by EBV-infected monoclonal T cells.

A population based, case control study of non-Hodgkin's lymphoma in patients with rheumatoid arthritis.

OBJECTIVE: Epstein-Barr virus (EBV) associated lymphoproliferative disorders (LPD) similar to those that occur in immunosuppressed solid organ recipients have been reported in patients with rheumatoid arthritis (RA). These LPD cause significant morbidity and/or mortality in a state of sustained immunosuppression, but may spontaneously regress if immunocompetence is restored. We determined the population based frequency of EBV associated LPD relative to all non-Hodgkin's lymphomas (NHL) that occur in the general population of patients with RA. METHODS: Forty-two case patients with NHL and RA and 49 control patients with NHL and no RA were identified in a population based, case control study of NHL that occurred in a 6 county Northern California area during the years 1988-94. The lymphoma tissue specimens were reviewed and the diagnosis of NHL was confirmed. In addition, the specimens were analyzed for NHL grade, histologic subtype, histopathologic features associated with immunosuppression, immunophenotype, and the presence of EBV genome in the tumor cells. RESULTS: No significant differences were identified between NHL in the RA case group and the control group (no RA) with respect to any variables investigated. One patient (2%) in the case group and one (2%) in the control group developed LPD containing EBV. CONCLUSION: Our findings reveal that EBV associated lymphomas represent only a small fraction of all NHL in the general RA patient population. EBV associated LPD should be recognized when they occur because they require a special approach to patient management. However, these data indicate that the majority of NHL that occurs in patients with RA is probably coincidental with RA and not the result of significant immunosuppression.