B-CELL NEOPLASMS
Precursor B cell lymphoblastic leukemia/lymphoma
Are discussed with the acute leukemias
Peripheral B cell Neoplasms
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL)
In the WHO classification, B-CLL/SLL includes a variant with monoclonal gammopathy / plasmacytoid
differentiation)
Lymphoplasmacytic lymphoma (LPC)
B-cell prolymphocytic leukemia (B-PLL)
Morphologically, B-CLL/SLL often shows lymphoid infiltrates composed of monotonous looking mature
lymphocytes. The infiltrate can be diffuse or multifocal, nodular (but not paratrabecular) or interstitial.
The latter, when limited, can be difficult to recognize morphologically. B-CLL/SLL cells usually show
positivity for CD20, CD5, CD23, and often for CD43. CD23 expression is usually maintained during large cell
transformation of B-CLL/SLL (Richter's syndrome) while CD5 expression may be lost. CD10 and cyclin-D1 are
negative. The B-CLL/SLL plasmacytoid subtype can be CD5/CD23 negative. This subtypes overlaps with LPC
lymphoma.
Lymphoplasmacytic lymphoma (LPC) is typically seen in patients with Waldenstrom macroglobulinemia. LPC
lymphoma is usually CD5/CD23 negative. Clinical and laboratory data (e.g. serum paraprotein type and level
in WD) are necessary to reach a correct interpretation in those cases.
B-PLL can be recognized by its characteristic cytologic features, better appreciated in marrow /peripheral
blood aspirate smears; immunophenotypically, B-PLL is usually CD5 negative.
Mantle Cell Lymphoma (MCL)
MCL infiltrates the marrow in a pattern similar to that observed in B-CLL/SLL. Although MCL cells have less
regular nuclear outlines than the one in B-CLL/SLL these two types cannot be reliably separated without
immunophenotyping. MCL and B-CLL/SLL are both positive for CD20, CD5, and CD43. However, only MCL
expresses cyclin D1. In addition, CD23 is negative. The blastoid variant can be difficult to distinguish
from ALL/LBL in bone marrow biopsies. However the coexpression in the former of CD5/20 associated with the
negativity with TdT and CD99 allows for an objective separation. Cyclin-D1, positivity, can be misleading
however, since it is also expressed in cases of ALL.
Follicular Lymphoma (FL)
FL can be distinguished morphologically by its multinodular paratrabecular localization in the bone marrow
biopsy. In most cases a mixture of small cleaved and large noncleaved cells with a preponderance of the
former cell type is observed. The lack of CD5 and CD43 is useful in distinguish FL from MCL (cyclin-D1 is
also negative) and B-CLL/SLL (CD23 can be positive in FL) . The frequent positivity with CD10 helps to
distinguishes FL from marginal zone cell lymphoma (see below). BCL-2 reactivity has been shown to be useful
in bone marrow biopsies to separate reactive follicular hyperplasia from FL. It is positive in the latter.
It is not uncommon to find numerous CD3 positive reactive T lymphocytes intermingled with the follicular
lymphoma cells. The presence of a "mixed" B and T cell infiltrate in these cases may trick the unaware
observer into a false negative interpretation of reactive lymphoid hyperplasia.
Marginal Zone B-cell Lymphoma (MZBCL) nodal (+/-monocytoid B-cell), extranodal, Splenic Marginal Zone Cell
Lymphoma (SMZCL) (+/- villous lymphocytes)
With the exception of the splenic subtype, marginal zone B-cell lymphoma is only rarely detected in bone
marrow specimens. In cases of SMZCL with villous lymphocytes the "lymphomatous" pattern of involvement
distinguishes this disease from hairy cell leukemia (see below). Bone marrow infiltration in SMZCL is
usually multinodular. Cytologically, MZBCL cells appear more heterogeneous than those observed in B-CLL/SLL
with most cases displaying a characteristic dimorphic population (small and large lymphoid cells). The
small cell component can present a "monocytoid" morphology. A peculiar intrasinusoidal pattern has also
been observed (Franco et al, 1996). In these cases, immunostaining with CD20 can help in detecting the
intravascular lymphoma cells.
Immunophenotypically, MZBCL is still largely a diagnosis of exclusion. The cells are CD20 positive, but
CD5, CD23, and CD10 negative. The presence of a t(11;14) translocation in some cases of SMZCL with
circulating villous lymphocytes suggests the possibility of cyclin D1 reactivity in some of these cases.
DBA.44, a B-cell antigen characteristically expressed in hairy cell leukemia has also been reported to stain
lymphoma cells in cases of nodal monocytoid MZCL but is not usually expressed in SMZCL.
Hairy Cell Leukemia
Hairy cell leukemia shows a characteristic interstitial pattern of involvement as well as cytologic
appearance in bone marrow biopsies. In most cases a final diagnosis is obtained by correlating the biopsy
findings with the presence of tartrate resistant acid phosphatase (TRAP) positive hairy cells in the
peripheral blood in the presence of pancytopenia and splenomegaly. However, morphologic variants have been
reported which can cause considerable diagnostic difficulties. In addition, residual hairy cells can be
difficult to document in post treatment bone marrow biopsies of patients treated with alpha-interferon,
deoxycophormycin, or clorodeoxyadenosine. In those cases, immunohistochemistry can be helpful in providing
a more objective identification of the residual malignant cells by outlining their characteristic
interstitial distribution.
In our experience with HCL, we find useful a panel of three antibodies which includes, in increasing order
of specificity, CD20, DAB.44, and a recently available monoclonal antibody to TRAP. CD20 is the most
sensitive, with more than 90% of the hairy cells being stained in a given case. DAB.44 is less sensitive.
It stains 50-60% of the hairy cells. It is only slightly more specific than CD20, being also positive in
various types of B-cell lymphoma including monocytoid B-cell lymphoma. It is, however, negative in the
majority of cases of splenic marginal zone cell lymphoma. TRAP staining is the least sensitive but the most
specific for HCL. However, one needs to keep in mind that TRAP positivity in lymphomas other than HCL can
also rarely be observed.
Large B-cell Lymphomas include the following variants: Diffuse Large Cell (DLC) Immunoblastic (IBL),
Burkitt-like, T-cell/histiocyte-rich, Anaplastic large B-cell, Mediastinal (thymic) large B-cell lymphoma,
Intravascular large B-cell lymphoma
Burkitt lymphoma (BL)
Lymphoblastic lymphoma (LBL)
Subclassifying large B-cell lymphomas in bone marrow sections is impractical and should not be attempted in
most cases. However, fairly characteristic findings can be observed in several subtypes.
Immunohistochemistry is very useful to confirm the B-cell origin of the neoplastic cells in these cases.
Large B cell lymphoma can be CD20 negative in 15-20% of cases. In these cases, we find CD79a particularly
useful in confirming the B-cell derivation of the malignant cells. Cases of immunoblastic lymphoma,
plasmacytoid in the bone marrow can be difficult to separate from cases of plasmacytoma with an
anaplastic/plasmablastic morphology. However, CD20 is characteristically absent in plasmacytoma cells while
usually present in ordinary IBL cases. In cases of B-cell lymphomas in immunodeficient patients,
immunohistochemistry of the bone marrow biopsy can be used to demonstrate the presence of EBV infection by
staining the section with an antibody reactive with the EBV coded latent membrane protein or by using an in
situ technique to detect the presence of EBV-RNA (EBER). B-cell lymphoma-associated hemophagocytic syndrome
(B-LAHS) is extremely rare in Western countries but has recently been increasingly reported in Asian
countries, especially Japan. In these cases, CD68 stain can be used to confirm the presence of an increased
number of histiocytes within the marrow cavities.
T-cell-rich B-cell lymphoma (TCRBCL) and the related entity known as histiocyte-rich B-cell lymphoma show a
high incidence (60%) of bone marrow involvement. The histologic appearance of this lymphoma subtype is not
pathognomonic, with the differential diagnosis including Hodgkin's disease, lymphoid predominance (LP-HD) in
particular, and peripheral T-cell lymphoma. The infiltrates typically have a pale low-power appearance due
to histiocytic infiltration and relative hypocellularity that, in conjunction with the presence of a
polymorphous infiltrate of scattered large atypical cells amid a mixed infiltrate of small lymphocytes and
histiocytes, may be suggestive of Hodgkin's disease. Immunohistochemistry shows CD20 positivity in the
large atypical cells with the absence of CD15 and CD30 reactivity, supporting the diagnosis of TCRBCL. The
absence of CD57 "rosetting" cells is helpful to separate TCRBCL from LP-HD. A prominent small CD3 positive
T-cell infiltrate accompanying the large atypical cells is observed in all positive BM biopsy specimens. In
histiocyte-rich cases, a large number of CD68 positive histiocytes can be found in the bona marrow. Rarely,
a true hematophagocytic syndrome picture may observed.
Typical cases of Burkitt lymphoma can usually be morphologically separated from other lymphoma subtypes.
Difficulties may arise, however with Burkitt-like and lymphoblastic lymphomas. Burkitt-like lymphoma, as
seen in the adult population are for the most part not related to Burkitt lymphoma. In children, lymphomas
with Burkitt-like features should be lumped together with the classical Burkitt's tumor since they appear to
behave similarly and share the same genetic abnormalities. Immunohistochemical staining with CD10, a marker
usually expressed in Burkitt lymphoma cells but negative in Burkitt-like, cases can be helpful in separating
the two lymphoma subtypes.
Intravascular large B-cell lymphoma (IVBL) can be documented in bone marrow sections by staining the
intravascular large B-cells with CD20. CD34 and FVIII stains can help in confirming its intravascular
localization. The expression of CD5 by the neoplastic cells in some cases of IVBL has recently been
documented. In other cases of IVBL, the neoplastic B-cells are accompanied by numerous hemophagocytic
histiocytes which can be demonstrated in the marrow sections by their intense CD68 reactivity.
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