Page 1104 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1068 ParT EIGhT Immunology of Neoplasia

The proliferation rate based on Ki67-positivity has been Surface Ig is positive, most commonly with IgM expression, but
considered of prognostic relevance. More recently, GEP using IgG or IgA can also be seen in many cases. CD10 and BCL6 are
genes involved in cell cycle progression and DNA synthesis has positive, but CD5 is usually negative.
identified a proliferation signature—defining different prognostic The 2008 WHO classification had recognized variants of
groups and showing correlation with cytological subtype to some FL, namely, pediatric FL, GI tract FL, and other extranodal FL.
extent. For example, a high proliferation rate has been shown Pediatric-type FL (now a definite entity in the 2016 classification)
in the blastoid variant. is more common in males and presents as localized nodal disease.
The treatment approach for newly diagnosed patients with It typically has an expansile serpiginous pattern, with relatively
MCL depends on their eligibility for stem cell transplantation monotonous, medium-sized, blastoid cellular composition. BCL2,
(SCT). However, purging of the neoplastic cells is difficult to BCL6, and MYC rearrangements are lacking. Complete remissions
achieve because of frequent bone marrow involvement, and may be obtained with either surgical excision or local radiation
autologous SCT has not proven be curative. The incorporation therapy. Some studies have raised the possibility that pediatric-
of rituximab into chemotherapeutic regimens has become an type FL might be a “benign clonal proliferation with low malignant
evidence-based standard of care. Of the current drugs used for potential.” 11,12
MCL, the application of the BTK inhibitor ibrutinib might change The WHO classification recognizes “FL in situ” (now termed
treatment paradigms by obviating the need for transplantation in-situ follicular neoplasia [ISFN]) as a distinctive lesion. It should
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in younger patients and chemotherapy in older patients. The be distinguished from partial involvement of FL. ISFN shows
patients with the nonnodal variant as described above do not involvement of germinal centers by CD10 and BCL2-positive
appear to require aggressive chemotherapy. 9 cells carrying t(14;18) in an otherwise reactive lymph node, which
is typically an incidental finding. Patients have a very low risk
Follicular Lymphoma of progression, but ISFN may be detected in association with
Follicular lymphoma (FL) is the most common subtype of other forms of B-cell lymphoma, necessitating additional clinical
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non-Hodgkin lymphoma (non-HL) in the United States and assessment. Fewer chromosomal abnormalities are noted in
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accounts for approximately 45% of all newly diagnosed cases. IFSN in comparison with partial or overt FL. Patients lacking
It has a peak incidence in the fifth and sixth decades and is rare evidence of FL at staging have a low risk of developing the disease;
under the age of 20 years. Both sexes are equally affected. Most this phenomenon appears to represent the tissue counterpart of
patients have stage 3 or 4 disease at diagnosis, with generalized circulating clonal B-cells carrying t(14;18) as detected in healthy
lymphadenopathy and bone marrow involvement. Approximately individuals. A higher level of circulating t(14;18) positive lym-
–4
10% of patients have circulating malignant cells; appropriate phocytes (>10 of total cells) indicates a higher risk for FL.
immunophenotypic or molecular analyses may reveal involvement The new 2016 classification addresses GI tract FL as duodenal-
of peripheral blood in a higher proportion of patients. type FL, as these can also be seen elsewhere in the GI tract and
FL is composed of varying proportions of follicle center–type have features overlapping with ISFN and extranodal mucosa-
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cells, centrocytes, and centroblasts, with centroblasts representing associated lymphoreticular tissue (MALT) lymphoma. These
the proliferative component. According to the WHO classification, present as small mucosal polyps or nodules, and most cases
all low-grade FL are combined into a single category, grade are discovered incidentally on endoscopy. The lesions are
1/2—with an overall predominance of centrocytes and fewer usually low-grade and have an indolent clinical course, and most
than 15 centroblasts per high-power field (hpf). Grade 3 (with patients have been managed without therapy. Local recurrences
>15 centroblasts/hpf) is further subdivided into 3A and 3B, based in the intestine may occur, but spread beyond the small intestine
on the presence or absence of background centrocytes. FL is rare.
represents the neoplastic counterpart of the reactive germinal- Primary cutaneous follicle center lymphoma frequently lacks
center cells; intraclonal heterogeneity with high numbers of the BCL2 translocation and BCL2 expression. However, when
somatic and ongoing Ig mutations can be detected in the neo- BCL2 expression is detected, the possibility that this may represent
plastic cells, as in the normal counterparts. Biologically, grade a secondary site of involvement should be considered. These
3B is more closely related to diffuse large B-cell lymphoma lesions are generally managed locally with conservative approaches
(DLBCL) compared with FL. and have a low risk of spread beyond the skin. The scalp is a
The vast majority of FL (approximately 90%) is associated common site of presentation.
with a t(14; 18) involving rearrangement of the BCL2 gene. This Two recent variants or subtypes of FL have been described;
translocation appears to result in constitutive expression of BCL2 one subtype described by Karube et al. occurring in older
−
+
protein, which is capable of inhibiting apoptosis in lymphoid individuals showed a CD10 /MUM1 immunophenotype that
cells. The cells of FL accumulate and are at risk for secondary tends to show grade 3 morphology, usually lacks BCL2 transloca-
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mutations, which may be associated with histological progression. tions, and often shows BCL6 abnormalities. This is in contrast
It is thought that the BCL2 translocation occurs at a very early to another recently described distinct new provisional entity of
stage of B-cell development, during immunoglobulin gene a low-stage large B-cell lymphoma with IRF4 rearrangement
rearrangement. Mutations in BCL2 can lead to loss of BCL2 common in children or young adults, typically involving the
protein in the presence of the translocation; fluorescence in situ Waldeyer ring and/or the cervical lymph nodes. These cases show
hybridization (FISH) studies for t(14; 18) in these cases are strong IRF4/MUM1 expression, usually with BCL6 and a high
informative. Of note, t(14; 18) is not specific to FL and can be proliferative fraction, and are considered more aggressive than
seen in CLL and other low-grade B-cell lymphomas as well. other pediatric-type FL; however, when treated, they show good
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Grade 3B FL is less commonly associated with BCL2 translocation response. Another distinctive subtype described by Katzenberger
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and carries genetic aberrations more commonly seen in DLBCL. et al. is characterized by t(14;18)–negative nodal grade 1/2 FL
The neoplastic cells in FL have a mature B-cell phenotype with with a high proliferation rate that predominantly shows diffuse
expression of the B-cell antigens (CD19, CD20, and CD22). growth pattern and deletions in the chromosomal region 1p36.