Lymphoplasmacytic Lymphoma and Waldenström Macroglobulinemia

Peripheral Blood and Bone Marrow

Lymphocytosis may be present, but the absolute lymphocyte count is usually lower than in chronic lymphocytic leukemia (CLL). Circulating neoplastic cells may have plasmacytoid features with clumped chromatin, eccentric nuclei, and moderately abundant basophilic cytoplasm, occasionally with a paranuclear hof ( Fig. 15-1 ). Red cell agglutination and rouleaux formation may be present in patients with serum hyperviscosity due to elevated IgM paraprotein.

Bone marrow aspirate smears demonstrate lymphocytosis with a morphologic spectrum that includes small, round lymphocytes; plasmacytoid lymphocytes; and plasma cells ( Fig. 15-2 ). Varying patterns of bone marrow involvement may be observed in core biopsy specimens, with interstitial and nodular infiltrates most commonly reported. Less frequently, pure paratrabecular or diffuse patterns of marrow involvement may be seen. The lymphoid aggregates are composed mainly of small lymphocytes with variable numbers of plasmacytoid lymphocytes and plasma cells. Plasmacytic differentiation may be reflected by the presence of Russell or Dutcher bodies. Increased mast cells are almost always present in association with the lymphoid aggregates, and their identification may be facilitated by tissue Giemsa stain or CD117 immunohistochemistry; however, this finding is not considered specific for the diagnosis of LPL (see Fig. 15-2, F ).

The pattern of bone marrow involvement may raise the differential diagnosis of other small B-cell neoplasms that more commonly involve the bone marrow, including CLL and follicular lymphoma. Distinction from these entities can be made readily on the basis of the immunophenotype of the neoplastic cells as noted later (see the section on immunophenotype later in the chapter). In addition, although nodular aggregates may extend to paratrabecular locations and infrequent LPL cases with predominant paratrabecular patterns of involvement have been described, these paratrabecular aggregates are generally not associated with linear growth along bony trabeculae or fibrosis, as seen in bone marrow involvement by follicular lymphoma (see Fig. 15-2, C ). Bone marrow involvement by marginal-zone lymphoma presents a more challenging distinction, given its shared immunophenotype with LPL. Interstitial involvement is more commonly seen in LPL compared with marginal-zone lymphoma. In contrast to bone marrow involvement by splenic marginal zone lymphoma (SMZL), intrasinusoidal involvement is rare in LPL. Assessment for the presence of the MYD88 L265P mutation may be helpful in difficult cases. Cases with prominent plasmacytic differentiation may raise the differential diagnosis of plasma cell myeloma, particularly the small lymphocytic variant with lymphoplasmacytic morphology. The latter is distinguishable from LPL on the basis of its CD45-negative, CD19-negative, CD56-positive immunophenotype and frequent cyclin D1 positivity by immunohistochemistry corresponding to an underlying CCND1 rearrangement detectable by FISH.

Lymph Nodes

In the past, two main patterns of nodal involvement have been described. * In the classic pattern, there is subtotal architectural effacement with retention of small primary or enlarged reactive follicles and patent or dilated sinuses ( Fig. 15-3, A ). The interfollicular areas contain a relatively monomorphous infiltrate of small lymphocytes, plasmacytoid lymphocytes, and plasma cells, without prominent follicular colonization (see Fig. 15-3, B ). Only rare large transformed cells are present. Dutcher bodies, increased numbers of mast cells, or hemosiderin deposition may be present. Other cases demonstrate more complete architectural effacement with a vaguely nodular to diffuse polymorphous infiltrate consisting of small lymphocytes, plasmacytoid lymphocytes, and plasma cells, with greater numbers of large transformed cells resembling immunoblasts. The latter may be numerous in some cases, but should not form large aggregates or sheets, in which case a diagnosis of transformation to diffuse large B-cell lymphoma (DLBCL) should be considered. Clusters of epi­thelioid histiocytes may be conspicuous in the so-called polymorphous pattern, sometimes termed polymorphous immunocytoma in previous classification systems. In both the classic and polymorphous patterns, extracellular deposits of immunoglobulin, in the form of amyloid or amorphous Congo red–negative amyloid-like material, may be present, or crystal-storing histiocytes may be identified. Pseudofollicles or proliferation centers, as seen in small-lymphocytic lymphoma (SLL), are not a typical feature.

* References .

More recently, studies of MYD88 L265P mutation analysis in nodal lymphomas initially diagnosed as LPL, nodal marginal zone lymphoma (NMZL), and small B-cell lymphoma with plasmacytic differentiation have helped to refine the morphologic spectrum of nodal LPL. These studies show that some MYD88 L265P–mutated cases demonstrate complete nodal architectural effacement, a vaguely nodular growth pattern, variably prominent follicular colonization, or focal areas containing pale monocytoid or marginal-zone B cells (see Fig. 15-3, C-F ). Cases harboring the MYD88 L265P mutation had significantly more common bone marrow involvement, elevated serum IgM levels, and presence of a serum M component, suggesting that they represent true LPL cases despite the presence of morphologic features previously thought to be more characteristic of NMZL. Conversely, cases initially diagnosed as LPL with a polymorphous pattern of nodal involvement containing prominent histiocytes and occasional immunoblasts were all negative for the MYD88 L265P mutation, suggesting that they may represent a B-cell neoplasm distinct from LPL. Therefore, at this time, it may be best to classify the latter cases as B-cell lymphoma with plasmacytic differentiation until additional studies are undertaken to characterize them further.

Spleen and Other Tissues

Splenic involvement by LPL has not been well described, but older published series and illustrated reviews support the presence of nodular and diffuse infiltrates of lymphoplasmacytic cells involving the red pulp, in a similar distribution to other small B-cell neoplasms with a leukemic pattern of dissemination. The morphologic spectrum of the lymphoma cells, including small lymphocytes, plasma cells, and intermediate forms, is analogous to that seen in bone marrow and lymph node specimens ( Fig. 15-4 ). This cytologic appearance may give rise to the differential diagnosis of SMZL, which may demonstrate plasmacytic differentiation in some cases. Pathologic features favoring a diagnosis of LPL over SMZL include relative sparing of the white pulp with absence of a marginal-zone growth pattern, absence of monocytoid or marginal-zone–type cytology, and conspicuous plasmacytic differentiation that is usually readily apparent by both morphology and on immunohistochemical or in situ hybridization studies of tissue sections (see Fig. 15-4, B-E ). In addition, LPL patients typically have higher IgM paraproteinemia and more extensive disease involving the bone marrow or lymph nodes, with secondary splenic involvement resulting in a milder degree of splenic enlargement compared with SMZL. Other small B-cell lymphoma entities with diffuse red pulp involvement that may enter into this differential diagnosis include hairy cell leukemia (HCL) and splenic diffuse red pulp small B-cell lymphoma (SDRPSBL). Distinction between LPL and HCL is usually straightforward on clinical, morphologic, and immunophenotypic grounds. Although SDRPSBL cases may show subtle plasmacytoid features, they usually lack strong features of plasmacytic differentiation such as cytoplasmic immunoglobulin deposition by immunohistochemistry or in situ hybridization.

Common sites of extramedullary and extranodal disease were described earlier (see the section on clinical features earlier in the chapter). Among the few histologic descriptions in the literature, LPL involving extramedullary sites may show some features that overlap with extranodal marginal-zone lymphoma (EMZL), including the presence of nodular and diffuse infiltrates of lymphoplasmacytoid cells, focal clusters of monocytoid B cells, and presence of Dutcher bodies. However, in gastrointestinal sites such as the stomach and colon, lymphoepithelial lesions and colonization of pre-existing follicles have not been described. Skin biopsies have been reported to show interstitial, nodular, or diffuse dermal infiltration by lymphoplasmacytic cells with perinodal and periadnexal accentuation; focal epidermal ulceration may be present in rare cases. Hepatic involvement, reported in cases with splenic disease, has been reported to show expansion of portal tracts and sinusoids by small plasmacytoid lymphocytes. In cases of CNS involvement (Bing-Neel syndrome), cytologic evaluation of cerebrospinal fluid (CSF) specimens may show a lymphocytic pleocytosis consisting of plasmacytoid lymphocytes and plasma cells, similar to the spectrum of cell populations seen in other tissues ( Fig. 15-5, A-B ). Laboratory evaluation of such specimens via flow cytometry, electrophoresis, immunofixation, and, more recently, MYD88 L265P mutation analysis may help confirm the diagnosis (see Fig. 15-5, C-F ). In some cases, however, the paucity or absence of neoplastic cells in CSF specimens, as in other subtypes of lymphoma involving the CNS, may preclude a definitive diagnosis, requiring brain biopsy.