TO THE EDITOR: Lymphomas with villous morphology are uncommon, and the rarest type
is the splenic diffuse red pulp small B-cell lymphoma (SDRPL). Few SDRPL cases have
been reported in the literature. There is considerable overlap with lymphomas that
display villous lymphocytes in blood and splenomegaly, such as the rare variant hairy-cell
leukemia, and splenic marginal zone lymphoma. Nonetheless, recent studies have produced
clear, differentiating features regarding clinical, morphological, and immunophenotypical
data. We highlight the case of a middle-aged male patient with massive splenomegaly
and villous lymphocytes, diagnosed with SDRPL based on splenic histology and a characteristic
immunoprofile. Diagnosis of SDRPL rests mainly on the exclusion of other lymphomas
and on a correlation of bone marrow and spleen histology, and immunophenotyping. Our
experience provides further support in considering this enigmatic lymphoma as a distinct
entity within the WHO classification of lymphoid neoplasms.
INTRODUCTION
Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is an extremely uncommon lymphoma
(incidence <1% of non-Hodgkin lymphoma) that is currently classified as a provisional
entity under the Splenic B-cell Lymphoma/Leukemia Unclassifiable Category in the 2008
WHO edition, and in the recently published 2016 update of WHO Lymphoid neoplasms [1
2]. A leukemic presentation with splenomegaly, bone marrow dissemination, and hairy
cells in the peripheral blood is the ‘sine qua non’ for SDRPL, however these features
are far from being specific. There is a considerable amount of morphological overlap
with other lymphomas that primarily afflict the spleen and also display villous lymphocytes,
such as splenic marginal zone lymphoma (SMZL), hairy-cell leukemia (HCL) and, rarely,
the hairy-cell leukemia-variant (HCL-V) [3
4
5]. Although these similarities may pose difficulties in diagnosis, recent literature
has shown convincing differences in histological, immunophenotypical, molecular, and
clinical characteristics of this rare lymphoma [5
6
7]. Characteristic spleen histology, together with a combination of immunohistochemistry
(IHC) and immunophenotyping, are essential for diagnosis. Although studies show SDRPL
to be an indolent malignancy, differentiation is crucial for devising therapeutic
strategies for the patient [3
5
8]. SDRPL is an unfamiliar entity and we present a rare case report of a 45-year-old
male who was clinically diagnosed with a splenic lymphoma.
Case Presentation
A 45-year-old male presented with abdominal swelling and generalized weakness. Co-morbidities
included diabetes mellitus and alcoholic chronic liver disease. An abdominal ultrasonogram
showed massive splenomegaly and mild hepatomegaly without any significant intra-abdominal
lymphadenopathy. Routine blood investigations showed a total leukocyte count (TLC)
count of 300×109/L, and a subsequent peripheral smear examination showed atypical
lymphocytes with copious finger-like projections (Fig. 1). A bone marrow (BM) aspirate
revealed atypical lymphoid cells (79%) with an inconspicuous nucleoli and circumferential
hairy-like projections, and the TRAP (tartrate-resistant acid phosphatase) stain was
negative. Flow cytometric analysis demonstrated negativity for CD103, CD123 and Annexin-A1.
The BM trephine biopsy confirmed an intrasinusoidal and interstitial infiltrate of
atypical lymphoid cells highlighted by CD20 and DBA-44, and non-reactive for CD5,
CD23 and Annexin-A1 immunostaining (Fig. 2). A splenectomy was undertaken and the
specimen measured 30×20×17 cm, with a weight of 4.1 kilograms. The cut surface was
homogenous and beefy-red, displaying wedge-shaped sub-capsular infarcts, devoid of
any gray-white nodules (Fig. 3). Histological examination showed a tumor growing diffusely
in the red pulp sinuses and cords with extensive obliteration of the splenic white
pulp. Tumor cells were monotonous, small and round with smooth nuclear contours, inconspicuous
nucleoli, and scant cytoplasm. Mitotic activity was also inconspicuous. IHC showed
diffuse positivity for CD20, PAX-5, CD79a and DBA-44 with a low MIB-1 proliferation
index of 2% to 4% (Fig. 4). The tumor cells were negative for CD3, CD25, Cyclin-D1,
CD123 and Annexin-A1. Cytogenetic analysis also did not reveal any of the known mutations
associated with SMZL, HCL and HCL-V.
In view of the clinical features, splenic and BM trephine histology, immunoprofile
and the cytogenetic work-up, the diagnosis was consistent with SDRPL. Following splenectomy,
our patient was started on rituximab to which he was intolerant, therefore the CHOP
(cyclophosphamide, Adriamycin, vincristine and prednisolone) protocol was initiated.
After completing 6 cycles of chemotherapy and 22 months of regular follow-up, our
patient is in remission and disease-free state with normal blood counts and bone marrow
examination results.
DISCUSSION
Lymphoma is the most common malignancy of the spleen and, in the clear majority of
cases, it is secondarily involved. Primary splenic lymphomas are rare, comprising
approximately 1% of all lymphomas, and are usually of B-cell origin [9]. Neoplastic
villous lymphocytes can be seen in a variety of chronic lymphoproliferative disorders;
however, the most common splenomegalic lymphoma with villous processes is SMZL, followed
by HCL and its rare variant, HCL-V.
SDRPL is the newest addition to this growing list in the latest 2008 edition of WHO
classifications, as well as in the recently published 2016 WHO update of lymphoid
neoplasms [2]. It is extremely rare, with an estimated incidence of less than 1% of
all non-Hodgkin lymphomas, and is discussed in the published literature in the form
of occasional case reports that describe its clinicopathological features [3
4
5
8
10]. SDRPL mimics SMZL, HCL, and HCL-V, clinically and morphologically, with considerable
overlap immunophenotypically.
Nonetheless, emerging data and studies show clear delineating features among these
neoplasms (Table 1).
Patients are typically older than 40 years of age, and there is a slightly higher
representation of males than females [8]. The leukemic presentation is typical, with
massive splenomegaly and a varying magnitude of cytopenias, but B-symptoms are not
encountered. Peripheral smears show the characteristic villous morphology mimicking
HCL and SMZL, however, nucleoli are inconspicuous [8]. Bone marrow involvement has
been seen in all reported cases to date, with an intrasinusoidal and interstitial
growth pattern [4
8
10]. Unlike SMZL, HCL and HCL-V, which can be diagnosed on peripheral blood/BM trephine
biopsy, SDRPL requires splenectomy for confirmation of the diagnosis [4]. Spleen histology
shows diffuse infiltration of the red pulp due to small monotonous lymphocytes causing
virtual obliteration of the white pulp [4
8
10], a feature in contrast to SMZL which involves only the white pulp.
SDRPL accounts for approximately 10% of lymphomas diagnosed solely on splenectomy
[1
9], necessitating the use of ancillary tests for correlation and confirmation. The
immunoprofile involves characteristic tumor cells being consistently positive for
CD20, DBA-44, and IgG. SDRPL is negative for CD3, CD5, CD10, CD11c, CD23, CD25, CD103,
CD123, Cyclin-D1, and Annexin-A1 [3
4
6
7
8
10].
No specific genetic mutation or chromosomal abnormality has been identified, based
on the studies so far, although occasional cases have shown del 7q, del 17p(TP53)
and trisomy 18 [8
10]. Mutations seen in HCL, such as BRAF-V600E (>90% of cases) and the VH1.2 gene,
or Chromosome 7q loss as seen in SMZL, have never been observed [11].
SDRPL follows a clinically benign course with a favorable long-term survival rate.
The diagnosis of SDRPL should be made based on a constellation of clinical features,
peripheral smear morphology, marrow and spleen histology, immunophenotyping, and cytogenetics.
Differentiation is essential as SDRPL has a good prognosis and is resistant to conventional
chemotherapy that is usually effective for the treatment of HCL, HCL-V and SMZL. This
is an indolent but incurable disease with a good response after splenectomy.
Conclusion
SDRPL is an extremely rare, recently recognized WHO entity with emerging distinct
clinical, biological, morphological, immunohistochemical, and cytogenetic features
that differ from those of other splenic lymphomas.