DISCUSSION
PEL-like or HHV8 and EBV-negative PEBL is a rare B-cell neoplasm that
typically presents as a malignant serous effusion in
non-immunocompromised patients. In the last decade, several reports of
HHV8-negative effusion lymphomas have been published demonstrating
remarkably similar cytomorphologic characteristics to PEL but
differences in immunophenotype, demographics, response to treatment and
clinical outcome; suggesting that PEL-like is a distinct entity. As
mentioned before, to date only HHV8-positive PEL is a recognized entity
in the current WHO classification1; but HHV8 and
EBV-negative PEBL has been recently suggested as a provisional entity by
the International Consensus Classification of Mature Lymphoid
Neoplasms.2
Our case is of particular interest because of the Caucasian origin of
the patient as most of the published data are case series reported from
Japan6. Despite its different origin, the other
characteristics are similar to those described in the Japanese cases.
Its prevalence is unknown and its diagnosis is challenging (especially
because it has not been described in the current WHO classification).
HHV8 and EBV-negative PEL is considered to have a distinct
etiopathogenic mechanism than HHV8-positive PEL. Different theories have
emerged with no conclusive data to date. Kobashi et
al7 suggested in 2007 that immunosenescence related to
age could play a major role, as most of the patients were older (median
age of 70 years) compared with PEL individuals. In the same line,
Ohshima et al8 concluded that multi-step genomic
abnormalities found in PEL-like cases could be related to age. In their
study, most of the patients were elderly men with all cases showing
complex karyotypes but without identification of a driver genomic
abnormality. Suggested mechanisms of lymphomagenesis in HHV8 and
EBV-negative PEL include impaired immune surveillance and dysregulatory
haemopoietic pathway. Unlike PEL, in which HHV8 acts as an exogenous
stimulus for local B-cell expansion, no viral mechanism has yet been
identified in PEL-like lymphomas. In our case, Epstein-Barr
virus-encoded small RNA in situ hybridization was negative but the
patient had seropositivity for EBV. In the literature, around one third
of cases of PEL-like lymphomas are infected with EBV.9However, whether EBV is simply a prior infection or a trigger of
PEL-like lymphoma remains unclear and further investigation is needed.
Regarding HCV infection in PEL-like lymphomas, there is a slightly
higher prevalence of its infection among these patients (30% to 40% of
patients). Association between HCV and B-cell non-Hodgkin lymphoma is
well reported in the literature. Thus, it has been suggested that fluid
overload related to cirrhosis due to HCV infection plays a role in
PEL-like lymphomas. Moreover, underlying medical condition leading to
fluid overload has been observed too in almost one-half of the
patients.7 The ICC also recognizes chronic serosal
stimulation by fluid overload in its pathogenesis.2Although this last hypothesis needs further confirmation and not all the
authors agree on that.6
Tumor cells in HHV8 and EBV-negative PEL express pan-B-cell markers and
they are negative for plasma cell markers in contrast with PEL. CD45
antigen expression is present in both neoplasms indicating hematological
derivation of the effusion cells.10
According to the reported series, the site of the effusion varies but
the most common location was pleural, followed by ascites and being the
pericardial one the less common.7 Nonetheless,
approximately 40% of the cases showed multiple body cavity lesions
including pericardial in all of them.6 In our case,
probably both pericardial and pleural effusions had a neoplastic
involvement according to images from PET scan (figure 2b). Nonetheless,
the reason why this B-cell neoplasm is exclusively confined to serous
membranes without developing tumor masses is still non-explained.
Diffuse Large B-cell lymphoma associated with chronic inflammation is
another B-cell neoplasm which also arises in the serous membranes but
unlike our case, the pathogenic mechanism and localization of this
entity is well understood. Chronic inflammation causes local
immunosuppression permitting EBV-infected memory B-cells evade
immunosurveillance, accumulate genetic alterations and evolve to
lymphoma.11
There is no standard treatment for this entity due to the small number
of cases although the majority of them are treated with chemotherapy
including anthracycline and rituximab (as tumor cells express CD20). In
a retrospective study conducted by Kaji et al, 86% of patients received
CHOP-like regimens.6 Other systemic treatments
consisted of rituximab in monotherapy or in combination with etoposide.
Perhaps, due to the introduction of rituximab, the prognosis seems to be
better in PEL-like lymphomas.12 In this study
conducted in Japan6, the 2-year overall survival was
84.7% (95% confidence interval, 71.3-92.1) compared to 1-year overall
survival of 30% in PEL. Moreover, there are some cases that were
successfully treated only with drainage of the
effusion.13 Its survival might be conditioned by the
advanced age at diagnosis and patients’ comorbidity.14