In B-PLL, in the peripheral blood, >55 % of the lymphocytes are prolymphocytes. They have a small rim of slightly basophilic cytoplasm, round even nuclei with a moderately condensed cytoplasm, and, usually, a single central nucleolus. T-PLL cells are medium-sized lymphocytes with deeply basophilic cytoplasm without granules and oval or irregular nuclei with deep indentations (Pawson et al. 1997). In the bone marrow, the infiltration pattern of both B-PLL and T-PLL may be interstitial, nodular, diffuse, or patchy. In the spleen, the white pulp nodules are enlarged in B-PLL, often producing a multinodular, at times coalescing, architecture. Red pulp sinusoids are variably expanded by prolymphocytes (Galton et al. 1974; Lampert et al. 1980; Ruchlemer et al. 2004). In T-PLL, the infiltration is mainly found in the red pulp (Osuji et al. 2005). Lymph nodes in B-PLL may show – rarely – patchy or vaguely nodular or diffuse infiltrates. In those cases, the picture may be similar to cases of prolymphocyte-rich B-CLL, but pseudofollicles are absent. In contrast, in T-PLL, the infiltration of lymph nodes is frequent, and infiltrates are centered in the interfollicular area, sometimes sparing residual germinal centers. One characteristic feature of T-PLL is the presence of arborizing high-endothelial venules that are transmigrated by lymphoma cells. The liver may show portal and sinusoidal infiltrates in both B-PLL and T-PLL. Skin infiltrations in T-PLL are usually confined to the dermis (Matutes et al. 1991).

For the pathologist, the prolymphocytes in B-PLL, in tissue sections, may be more similar to the paraimmunoblast as defined in the Kiel classification of lymphomas (Lennert 1992), and hence, differentiation from progressed (paraimmunoblast-rich or prolymphocyte-rich) stages of B-CLL may prove difficult. However, in contrast to B-CLL and B-CLL/PL, proliferation centers are absent. Presence of the t(11;14)(q13;q32) chromosomal translocation excludes the diagnosis of B-PLL (Dunphy and Perkins 2001; Ruchlemer et al. 2004; Singleton et al. 1999).

Prolymphocytes in B-PLL express pan-B-cell-associated antigens CD19, CD20, CD22, CD79A, PAX5, and FMC7 and strongly express surface IgM ± IgD. Roughly 50 % of cases will show positivity for CD5, while CD23 is rarely expressed. CyclinD1, CD10, and BCL6 are negative (Campo et al. 2008; Hercher et al. 2001). T-PLL cells express pan-T-cell markers such as CD3, CD2, CD5, and CD7, and most cases are CD4+. However, both CD4- CD8+ and CD4+ CD8+ cases exist. TCRαβ and TCL1 proteins are usually positive, and NK markers are not expressed (Matutes et al. 1991).

Immunoglobulin heavy chain (IGH) genes in B-PLL are clonally rearranged. B-PLL is a lymphoid neoplasia apparently deriving from both mutated and unmutated progenitor cells. Therefore, mutated IGHV genes are encountered in roughly 50 % of cases. Most B-PLL cases have been reported to use members of the VH3 and VH4 gene families, respectively (Davi et al. 1996; Del Giudice et al. 2006a, b). The t(11;14) chromosome translocation had been described in 20 % of cases that were previously thought to represent B-PLL owing to the prolymphocytic appearance of the tumor cells. To date, however, these lymphomas have been recognized as mantle cell lymphomas (MCL) with “prolymphocytic” features (Dunphy and Perkins 2001; Wong et al. 2002). Ninety of T-PLL cases usually demonstrate clonal chromosomal aberrations involving inversions of the TCL1 in 14q32 or MTCP1 in Xq28 loci with the TCRA/D locus in 14q11 (inv14q11q32) (Pekarsky et al. 1999; Stern et al. 1993). T-PLL is among those lymphoid tumors with the highest number of secondary chromosomal aberrations (Nowak et al. 2009), in virtually all sporadic cases also targeting the ATM gene in 11q21-q23 that usually shows biallelic inactivation by missense mutations (Stilgenbauer et al. 1997). Trisomies of chromosome 8 or 8q are also common.

The diagnosis of B-PLL warrants the exclusion of morphologically and clinically related entities, such as B-CLL with increased prolymphocytes, leukemic MCL, splenic marginal zone lymphoma (SMZL), hairy cell leukemia-variant (HCLv), and T-cell prolymphocytic leukemia (Viswanatha et al. 2012). In some cases, the distinction from “paraimmunoblastic” diffuse large B-cell lymphomas may equally prove difficult. While B-CLL, DLBCL, and T-PLL may be readily distinguished by their clinical presentation and/or immunophenotype, splenomegalic and leukemic forms of MCL have to be excluded by CyclinD1 staining and/or FISH for the t(11;14). The unequivocal exclusion of entities like SMZL and HCLv requires attention, because both the clinical presentation and the cytological presentation of the tumor cells may be similar. In general, however, the tumor cells in SMZL are more polymorphic with “villous” lymphocytes apparent, and HCLv is excluded by its distinct antigen expression profile including CD103 (Matutes et al. 2003).

The differentiation of T-PLL from other leukemic T-cell lymphomas may be challenging because of similarities in morphology and immunophenotype to other leukemic lymphomas such as hepatosplenic T-cell lymphoma, Sezary syndrome, or T-LGL. T-PLL, in contrast to the other entities, does show protein expression of TCL1 and CD26. Ultimately, however, the diagnosis must be confirmed by demonstration of the characteristic genetic profile of the disease including rearrangements of TCL1, MTCP1, trisomy 8 or 8q, and ATM inactivation.

B-PLL initially described as a variant of CLL, is now recognized as a distinct clinicopathological entity in the current WHO classification, typically with an aggressive clinical course and a median overall survival of 3–4 years (Swerdlow et al. 2008). Historical series had included a substantial proportion of patients with t(11;14), but these are now classified as leukemic-phase MCL.

In most patients, T-PLL shows an initially aggressive course and often chemo-refractory behavior to conventional cytotoxic agents resulting early relapses within 1 year (Herling et al. 2004; Herling et al. 2008; Matutes 1998; Matutes et al. 1991).

Some anecdotal reports and small series have described apparently initially indolent cases of T-PLL either associated with a complex karyotype (Soma et al. 2002) or a specific immunophenotype with a CD45RO+/CD45RA- phenotype (Garand et al. 1998). Despite this initial indolent phase with a median of 33 months until requiring treatment, most patients then display an aggressive course and an outcome that is nearly as poor as for patients showing a primarily aggressive course (Garand et al. 1998).