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1190 Part VII Hematologic Malignancies

A A BB CC D EE
Fig. 73.3 MANTLE CELL LYMPHOMA. At low power, mantle cell lymphoma (MCL) can show a diffuse,
vaguely nodular, or mantle zone pattern. In the latter, the neoplastic mantle zones are expanded and can
become confluent leaving “naked” germinal centers (A). At higher power, the lymphoma cells are small or
slightly enlarged (B). They have irregular nuclear contours, especially compared with small lymphocytic
lymphoma, and they have dense chromatin. Typically, cases are positive for cyclin D1 expression (C), which
is related to the t(11;14) involving IgH and CCND1. Some cases can develop a “blastoid” transformation (D),
although some cases can present as a “blastoid” variant. Such cases are characterized by cells with an intermedi-
ate size, a high mitotic rate, and finely dispersed “blastic” chromatin. Sometimes when the “blastoid” cases
develop a leukemic phase, they can be difficult to distinguish morphologically from acute lymphoblastic
leukemia. In such cases, flow immunophenotyping is needed to resolve the differential diagnosis. MCL can
also present with gastrointestinal involvement (E) as in lymphomatoid papulosis.

to MCL, since the majority of in situ cases lacked Sox11 expression. diagnosis, with generalized lymphadenopathy. Staging evaluation will
Also, similar to follicular lymphoma in situ, a distinction should be usually detect bone marrow involvement. Approximately 10% of
made between partial involvement by mantle cell lymphoma with a patients will have circulating malignant cells. However, careful
mantle zone pattern and in situ MCL. The latter refers to a reactive immunophenotypic or molecular analyses may disclose peripheral
lymph node with Cyclin D1 positive cells limited to an otherwise blood involvement in a higher proportion of patients. A more accu-
normal appearing follicle mantle; these cases tend not to progress and rate prognostic index than the international prognostic index (IPI),
should not be labeled as lymphomas. the follicular lymphoma international prognostic index, has been
Another newly identified variant is an indolent form of MCL proposed for FL, and has been widely adopted.
characterized by a leukemic phase without nodal disease, but often The natural history of the disease is associated with histologic
with long standing splenomegaly. These patients have an indolent progression in both pattern and cell type (Fig. 73.4). A heterogeneous
clinical course and do not appear to require aggressive chemotherapy. cytologic composition is one of the hallmarks of FL. Usually, all of
These cases carry t(11;14) with few additional chromosomal abnor- the follicle center cells are represented, but in varying proportions. It
malities and lack expression of Sox11 in contrast to conventional should be stressed that the variation in cytologic grade is a continuum,
MCL. and therefore precise morphologic criteria for subclassification are
MCL occurs in adults (median age 62), with a high male-to- difficult to establish.
female ratio. Most patients present with advanced stage at diagnosis. According to the WHO classification, all low-grade FL are com-
Common sites of involvement include lymph nodes, spleen, bone bined into a single category, Grade 1–2, all containing overall a
marrow, and lymphoid tissue of Waldeyer ring. Gastrointestinal (GI) predominance of centrocytes with fewer than 15 centroblasts/high
tract involvement is frequent and is associated with the picture of power field (hpf). FL grade 3 (with >15 centroblasts/hpf) is further
lymphomatous polyposis. subdivided in 3A and 3B based on the presence or absence of cen-
The hallmark of MCL is a very monotonous cellular composition. trocytes in the background.
In the typical case, the cells are slightly larger than a normal lympho- The vast majority of FL (approximately 85%) are associated with
cyte with finely clumped chromatin, scant cytoplasm, and incon- a t(14;18) involving rearrangement of the BCL2 gene. This transloca-
spicuous nucleoli (Fig. 73.3). The nuclear contour is usually irregular tion appears to result in constitutive expression of BCL2 protein,
or cleaved. Some cytologic variants, blastoid (blastic) and pleomor- which is capable of inhibiting apoptosis in lymphoid cells. The cells
phic, tend to be associated with a more aggressive course, and adverse of FL accumulate and are at risk to acquire secondary mutations,
biologic features, such as tetraploidy or p53 mutation/deletion. The which may be associated with histologic progression. It has been
proliferation rate was previously identified as prognostically impor- postulated that the BCL2/JH translocation occurs during immuno-
tant based on scoring of Ki67-positive cells. More recently gene globulin gene rearrangement in the bone marrow at the pre-B cell
expression profiling (GEP), using genes involved in cell cycle progres- stage of development. This fact might contribute to the difficulty in
sion and DNA synthesis, has identified a proliferation signature that eradicating the neoplastic clone with chemotherapy.
delineates cohorts with varied prognosis. These correlate to some Biologically, the pathogenesis of most cases of FL grade 3B differs
extent with cytologic subtype. For example, the blastoid variant has from that of FL grades 1–2/3A, in lacking the BCL2/IGH, but also
a high proliferation rate, utilizing both KI-67 and GEP. differs from diffuse large B-cell lymphoma, in having a low incidence
11
of BCL6 aberrations. These data provide a biologic explanation for
the greater curability of grade 3B FL with aggressive therapy, although
Follicular Lymphoma some studies have not found support for this hypothesis. Differences
in diagnostic criteria might account for this apparent discrepancy, and
Follicular lymphoma (FL) is the most common subtype of non- the correlation between grade 3A versus 3B, and molecular alterations
Hodgkin lymphoma within the United States and accounts for is imprecise. Other phenotypic variants appear to have prognostic
approximately 45% of all newly diagnosed cases. It has a peak inci- significance, such as FL negative for CD10 but positive for MUM1/
dence in the fifth and sixth decades, and is rare under the age of 20. IRF4. These cases are usually of higher grade and interestingly also
Men and women are equally affected. FL is less common in black lack the BCL2 translocation. Evolution towards a molecularly defined
and Asian populations. Most patients have stage 3 or 4 disease at classification of FL is a possibility for the future.