Clonality Of Multiple Distinct Lymphoproliferative Disorders Occurring Within Individual HIV+ Patients

Lymphoma is usually considered a monoclonal process that can be present at one or more anatomic sites in a patient. In the setting of combined Epstein Barr virus (EBV) infection and immunosuppression, clonally distinct lymphoproliferative disorders (LPDs) may arise within a single individual. In the area of solid organ transplant, it has been previously described that multiple LPDs arising simultaneously or sequentially in the same patient, including those in the same anatomic site, can be of different genetic composition (Cancer 1995 75:2747). Furthermore, histologic morphology does not necessarily correlate with molecular clonality. HIV+ patients are another population who are immunosuppressed and often infected with EBV. However, whether multiple LPDs (reactive and/or neoplastic) occurring in an individual HIV+ patient are of identical or disparate clonal content, or whether they are clonally consistent with morphology, has not been fully studied. We previously reported data from 10 patients (Modern Path 2013 26(S2):340A) which suggested that recurrence or progression of lymphoma, regardless of site, is usually of the same clone. However, the vast majority of these cases involved specimens obtained fewer than 2 years apart, and half were only 6 months or less. Data on an additional 8 patients are now presented, with 5 cases representing greater than 2 years of follow-up.

DNA from touch preparations or formalin-fixed, paraffin-embedded tissue of 2-3 LPDs from 8 HIV+ patients (6 males/2 female; ages 32-62 yrs) was amplified using BIOMED-2 primer sets for heavy, kappa and lambda immunoglobulin loci (Invivoscribe). Tests performed were dependent on available material. Samples were assessed for quality using a specimen control size ladder primer set. PCR products were analyzed by capillary electrophoresis. The data was analyzed using GeneMapper software, and monoclonality was defined as a peak > 3 times the height of the third highest peak in the appropriate region. EBV was detected by in situ hybridization with an EBER probe.

Clonal populations were seen in almost all specimens regardless of morphology. One reactive lymph node was polyclonal, but all lymphomas were monoclonal and three non-neoplastic –appearing lesions also contained clonal populations. Four patients had the same clone present in multiple locations at various times, ranging from 1 week to 2 years. In three cases with a longer time lapse between presentations (5-9 years), different clones were identified.

(D)LBCL – (diffuse) large B cell lymphoma; LN – lymph node; MZL – marginal zone lymphoma; PEL – primary effusion lymphoma

The current data indicate that HIV-associated LPDs can contain clonal populations regardless of morphology. This may suggest either the presence of a benign reactive subpopulation, which could be transient, or of low-level visually-undetectable involvement by a neoplastic process. As was previously shown, the recurrence or redevelopment of lymphoma within 2 years of original diagnosis is usually of the same clone, and may therefore warrant a change in strategy for successful treatment. However, LPDs which appear more than 5 years from initial presentation generally represent a new disease and may not necessarily imply nonresponsiveness to a similar therapeutic regimen.

No relevant conflicts of interest to declare.