Epstein–Barr Virus–Associated Adrenal Smooth Muscle Tumors and Disseminated Diffuse Large B-Cell Lymphoma in a Child With Common Variable Immunodeficiency

Abstract

This article reports the clinical and the histological features in a 7-year-old girl affected by common variable immunodeficiency (CVID) who developed multiple Epstein-Barr virus-associated tumors, represented by bilateral adrenal smooth muscle tumors (EBV-SMT) and multifocal diffuse large B-cell lymphoma. The EBV-SMTs showed features compatible with a benign or at least a low-malignant potential neoplasm. A peculiar feature observed in both EBV-SMTs was the occurrence of numerous lymphocytes intermingled with the spindle cells, which consisted of CD3+ CD5+ T-cells, with a predominant cytotoxic CD8+ component. Interestingly, EBV status differed in the neoplasms, since the EBV-SMTs were negative for LMP1 and positive for EBER, whereas the B-cell lymphoma expressed both EBV markers. Furthermore, EBV-LMP1 deletion was positive only in the EBV-SMTs, thus indicating that these tumors were the consequence of 2 distinct, EBV-dependent transformations. Similarly, lymphocyte clonality assay also showed different clonal bands in different sites (skin and nasal cavity), suggesting the development of intratumoral mutations. Finally, the authors review all 127 previously reported EBV-SMT, with discussion of their clinical and pathological features.

Epstein-Barr Virus-Associated Smooth Muscle Tumours after Transplantation, Infection with Human Immunodeficiency Virus and Congenital Immunodeficiency Syndromes

“…EBV-positive smooth muscle tumours (SMT) are not specific for transplant patients but are associated with any patients on long-term immunosuppression. Similar tumours can manifest in patients who suffer from human immunodeficiency virus (HIV) infection (HIV-SMT) or congenital immunodeficiency syndromes (CI-SMT) [3,4,5,6,7,8,9,10,11]. Among HIV patients and patients with rare congenital defects, the exact frequency of tumour manifestation is not known, but is most likely <5%.…”

“…In a case with PTSMT and PTLD, both tumour types showed the same 30-bp deletion in the LMP1 gene but TP53 mutation only in the PTLD and not the PTSMT, indicating that the same EBV species induced two unrelated tumours [17]. In contrast, in a patient with CI-SMT and a high-grade B cell lymphoma which were both EBV-positive, LMP1 deletion was present only in the CI-SMT and not in the unrelated lymphoma [8]. …”

“…There is no gender-specific risk increase regarding any of the three tumour types [2,3,4,5,6,7,8,9,10,11]. In transplant patients, the type of immunosuppressive drug, the transplant organ and the manifestation of PTLD are not associated with PTSMT manifestation [2].…”

“…Only a few CI-SMT cases have been described (all children) and in these cases at least, no association with a particular type of immune defect was evident, i.e. immunodeficiencies predisposing to severe EBV-associated complications like X-linked lymphoproliferative disease or CD27 deficiency do not seem to have an impact on CI-SMT development [6,7,8,9,10,11]. Furthermore, some patients with congenital immunodeficiency syndromes have undergone bone marrow transplantation and have then developed EBV-positive SMT (overlap between PTSMT and CI-SMT) [2,12,13].…”

“…in the cerebral sinus, the tumour founder cell is thought to be derived from an aberrant myogenous venous wall cell [2,14]. Almost all PTSMT and CI-SMT are EBV-positive while up to 30% of HIV-SMT are EBV-negative (therefore, in these latter HIV-SMT cases, the proliferation cannot be linked to EBV) [2,3,4,5,6,7,8,9,10,11]. In lymphoid diseases, EBV infects B cells by using C3d/EBV receptor CD21 [1].…”