Page 887 - Hematology_ Basic Principles and Practice ( PDFDrive )

770 Part VII Hematologic Malignancies

MBL has been diagnosed more frequently than previously and progressive transformation of germinal center-like changes.
reported; this is thought to be related to high sensitivity of flow Presentation with isolated cervical lymphadenopathy is common in
cytometric analyses. MBL is defined as the presence of a circulating pediatric nodal MZL. The WHO classification also recognizes two
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monoclonal B-cell population below 5 × 10 /L, persisting for at least rare Epstein-Barr virus (EBV)–associated T-cell diseases: systemic
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3 months, in otherwise asymptomatic individuals. Based on clonal EBV T-cell lymphoproliferative disease of childhood and hydroa
B-cell counts and clinical significance, MBL is now subdivided into vacciniforme-like lymphoma. These diseases occur almost entirely in
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high-count MBL (0.5–5.0 × 10 /L) and low-count MBL (less than children, primarily in those of Asian origin.
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0.5 × 10 /L). High-count MBL progresses to CLL at an annual On the opposite spectrum of age-related lymphoproliferative dis-
rate of 1% to 2%, with the clonal B-cell count at presentation being orders is EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL)
the greatest risk factor. The presence of palpable lymphadenopathy, of the older adult, which is among the newly included provisional
organomegaly, and/or infiltration of lymphocytes within the BM entities in the 2008 WHO classification. The underlying immuno-
(greater than 30% of nucleated cells) fulfills the International Work- logic deficit in this setting is believed to be immunosenescence, which
shop on Chronic Lymphocytic Leukemia (IWCLL) criteria for CLL, is defined as the natural decay of the immune system as a consequence
even in the absence of clonal lymphocytosis, while the WHO diagnosis of aging. This entity also is defined histologically as malignant B-cell
of CLL/SLL is based upon the presence of extramedullary involve- lymphoproliferation in people older than 50 years of age, without
ment. Current recommendations for management of CLL-like MBL any known immunodeficiency or prior lymphoma diagnosis, and is
include yearly monitoring with therapeutic intervention if clinically associated with an aggressive clinical behavior pattern. Initial studies
indicated. Low-count MBL, based on current data, is unlikely to reported some overlap with classic Hodgkin lymphoma encountered
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progress to CLL and does not warrant clinical monitoring. MBL with in the older adult. At present, there is a broader understanding
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an atypical CLL-like phenotype (CD5 , bright CD20, CD23 ) could than previously appreciated of the wide clinicopathologic spectrum
represent an early leukemic manifestation of MCL, and a thorough of age-related EBV-positive lymphoproliferative disorder (LPD).
staging workup including fluorescence in situ hybridization (FISH) This spectrum includes reactive lymphoid hyperplasia, polymorphic
testing for t(11;14) translocation is recommended. extranodal LPD (76% have EBV mucocutaneous ulcer), polymor-
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FL in situ was initially described as the localization of atypical B phic nodal LPD and EBV+ DLBCL. Both polymorphic nodal
cells that have t(14;18)(IgH-B-cell lymphoma [BCL2]) translocation lesions and EBV+ DLBCL are characterized by poor survival. In
in the germinal centers of reactive-appearing lymph nodes with strong this clinicopathologic spectrum, histologic types are highly predictive
expression of CD10 and BCL-2. The lymph node architecture is of outcome; and small-volume disease, particularly in mucosal sites
generally intact. The majority of cases of FL in situ do not progress to and skin (EBV mucocutaneous ulcer), which are associated with a
overt lymphoma, thus the alternate term “follicular lymphoma-like B good prognosis. It is important to keep in mind that although these
cells of undetermined significance” was recently proposed. In the 2016 lymphomas tend to cluster in the very young or the older adult age
WHO classification revision, alternative term of in situ FL neoplasia groups, they are not age restricted. Similarly, EBV+ DLBCL of the
is used in order to reflect the uncertain clinical significance of this older adult can occur in a younger population. 33
entity. In situ FL neoplasia must be differentiated from partial involve-
ment by low-grade FL, which usually shows partially effaced nodal
architecture with enlarged, crowded follicles, and attenuated mantle Aggressive B-Cell Lymphoma, Borderline Entities and
zones. This distinction is clinically relevant, as partial involvement by Site-Specific Categories
low-grade FL is more likely to be associated with or progress towards
overt FL. The 2008 WHO classification identified several subtypes of DLBCLs
Analogous to in situ FL neoplasia, incidental diagnosis of coloni- (Table 55.9). However, many DLBCLs lack pathologic, clinical, or
zation of the mantle cuffs of reactive follicles by cyclin D1-positive other defining features that can be used to stratify them. Thus, these
B cells has been termed in situ mantle cell neoplasia (MCLIS). In are designated DLBCL, NOS in the WHO classification. Stratifica-
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these cases, cyclinD1 highlighted a small subset of B cells within tion according to gene expression profiling as germinal center B-cell
the mantle zone, indicating low-level involvement by lymphoma. (GCB) versus activated B-cell (ABC) types has proven to have
This peculiar pattern of cyclinD1 positivity encircling follicles is prognostic value. The GCB and ABC subtypes are now formally
characteristic of an early or in situ MCL. The in situ variant of MCL recognized in the 2016 WHO classification, despite the absence of a
is rare and exhibits cyclinD1 positivity within the innermost mantle reproducible routine diagnostic test and the imperfect correlation of
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zone B lymphocytes, and often is reserved for only partial encircling immunohistochemical surrogate markers with genomic studies.
of follicles by MCL cells. In contrast, it has been proposed that full Digital multiplexed gene expression utilizing formalin-fixed paraffin-
encircling of follicles by cyclinD1-positive cells should be interpreted embedded–derived RNA at a reasonable cost and turnaround time
as an early sign of involvement by MCL. This distinction is important to classify B-cell lymphomas according to cell of origin is currently
as partial MCL is more likely than MCLIS to progress or coexist with being validated as a routine clinical assay. 35,36 The clinical need and
advanced disease. Current management recommendations for MCLIS utility of this designation is rising, with more studies suggesting that
include whole-body imaging and unilateral BM biopsy (if indicated) ABC versus GCB lymphomas exhibit differential sensitivity to certain
to rule out a concomitant overt lymphoma. In the absence of overt drugs and therapeutic modalities. 34
disease, no treatment is required and careful follow-up is advised. In addition to the designation of DLBCL to ABC or GCB sub-
types, next-generation sequencing technologies have unveiled the
remarkable complexity of DLBCL. More important, it has become
Age as a Disease-Defining Feature increasingly clear that these complexities represent lymphoma sub-
types which are driven by very different intracellular oncologic signal-
The 2008 WHO classification introduced the concept of age as ing pathways and which can be differentially exploited for therapeutic
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a defining feature in several disease categories. The entities of FL benefit. Recent studies have demonstrated the high frequency of
and nodal marginal zone lymphomas (MZLs) that present in the abnormalities (i.e., noted in greater than 50% of DLBCLs) affecting
pediatric age group differ from their adult counterparts clinically histone/chromatin-modification enzymes, such as CREBBP, EP300,
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and biologically. The pediatric variant of FL usually presents with MLL2, and EZH2. The role of therapeutic agents that target the
localized disease and is of high histologic grade. These lymphomas epigenome has been suggested in DLBCL subgroups due to the
lack translocations t(14;18) and do not express BCL2 and have variability in DNA methylation and its association with outcome. 39,40
good prognosis, although the optimal management remains to be Currently, the role of MYC and BCL2 proteins in DLBCL is an
determined. Nodal MZLs in children also appear to have a low risk area of an active investigation. It is proposed that cases of DLBCL
of progression. Pediatric nodal MZLs are clonal diseases characterized be evaluated for concurrent MYC and BCL2 dysregulation at diag-
by marginal zone expansion with fragmentation of germinal centers nosis, in order to determine the presence of translocation/protein