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cells. Contrasted whole-body computed tomography as well
as contrasted magnetic resonance imaging of the brain are also
suggested, though a high level of false-negative results has been
reported (5). [18F]ﬂuorodeoxyglucose positron emission tomography also carries a high false-negative rate for IVLBCL, with
only a 29% detection rate of pathologically conﬁrmed lesions
(13), likely due to the diﬀuse nature of IVLBCL and lack of
adenopathy contributing to a lower volume of regional tumor.
Random skin biopsies of the abdomen and extremities may also
be an option in the workup of IVLBCL, with a small series
showing a 36% rate of diagnosis (14).
IVLBCL cells are large, with increased nuclear-to-cytoplasmic
ratios, irregular nuclear contours, hyperchromatic, condensed
chromatin with occasionally prominent nucleoli, and scant
cytoplasm. Mitotic ﬁgures are markedly increased, and Ki-67
staining is usually above 50%. By immunohistochemistry,
IVLBCL is virtually always immunoreactive for CD20 and
CD79a (7) (Figure 1). Interestingly, the lymphoma cells lack
cell surface proteins critical to lymphocyte transvascular migration, which is thought to contribute to a deﬁciency in the ability
to migrate out of the microvasculature (15, 16).
The introduction of rituximab has dramatically improved
the outcome of IVLBCL. In one of the largest retrospective
studies on IVLBCL treatment, patients receiving rituximabbased chemotherapy regimens had longer progression-free
survivals and overall survivals compared to patients receiving
non-rituximab-based therapies (2-year progression-free survival
of 56% vs. 27% and 2-year overall survival of 66% vs. 46% for
rituximab-based vs. chemotherapy alone groups, respectively)
(17), with chemotherapy being predominantly cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) or
CHOP-like regimens. Other studies have also demonstrated
improved complete remission and survival rates with rituximabbased regimens in the Western variant (18), and there have
even been reports of single-agent rituximab inducing long-term
remission in disease refractory to anthracycline-based therapy
(19). The choice of speciﬁc cytotoxic chemotherapeutics in
IVLBCL is less clear, particularly in the setting of disease associated with HLH. While etoposide-based regimens have been
used successfully for HLH (6), there are no studies to date on
the use of the HLH-94 protocol in the treatment of IVLBCL.
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