Page 1448 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 80

CLINICAL MANIFESTATIONS, STAGING, AND TREATMENT OF

FOLLICULAR LYMPHOMA

John G. Gribben

Non-Hodgkin lymphoma (NHL) refers to all malignancies of the difficult. The complexity of the epidemiology of NHL mirrors the
lymphoid system with the exception of Hodgkin lymphoma. Devel- complexity of the disease and the complexity of the immune system.
opment of the lymphoid system is a highly regulated process, char- Since lymphomas do not constitute a single disease, it should come
acterized by differential expression of a number of cell-surface and as no surprise that there is no single etiologic factor. The influence
intracytoplasmic proteins and antigen receptor gene rearrangements, on immune dysregulation of viruses, chemicals, radiation, diet, and
somatic hypermutation, and class switching. Dysregulation of this aging remains unclear. Immune suppression leads to increased inci-
orderly process can result in humoral deficiency, autoimmunity, or dence of aggressive lymphomas, but not usually indolent lymphomas.
malignancy. The indolent B-cell lymphomas are mature peripheral FL typically presents in middle age and in the older adult, and the
B-cell neoplasms that exclude those diseases associated with an aggres- median age at diagnosis is 60 years. There is a slight female
sive clinical course. Despite differences in cell of origin, molecular preponderance. 2
biology, clinical presentation, and clinical course, the indolent lym-
phomas share common features, including frequent localization to
the principal lymphoid organs, a propensity for bone marrow (BM) PATHOGENESIS
infiltration and leukemic presentation, and generally an indolent
clinical course. The classification of NHLs has been a challenge for FL (Fig. 80.1) is derived from germinal center B cells and maintains
4
pathologists as well as practicing physicians. A number of classifica- the gene expression profile of this stage of differentiation. FL cells
tions have been proposed over the years, leading to considerable express CD19, CD20, CD22, and surface immunoglobulin and 60%
confusion and difficulty in comparison of outcomes of clinical trials express CD10. A hallmark of the disease is the chromosomal trans-
performed using different pathologic classifications. The World location t(14.18) contributing to overexpression of the antiapoptotic
Health Organization (WHO) lymphoma classification lists nearly protein BCL2. Morphologically the disease is composed of a mixture
1
100 different types of lymphoid neoplasm. This classification uses of centrocytes and centroblasts. The WHO third edition pathologic
all available information such as morphology, cytochemistry, immu- classification recommended grading in grades 1–3 according to the
nophenotype, and molecular genetics as well as clinical features. The number of centroblasts (0–5, 6–15, and >15 per high-power field,
WHO classification does not include the terminology indolent lym- respectively). Grade 3 was further subdivided into 3A (centrocytes
phoma. This is a clinical and not a pathologic term and defines those still present) and 3B (sheets of centroblasts). An increased percentage
lymphomas that tend to grow and spread slowly and produce few of centroblasts is predictive of poor outcome. A problem with this
symptoms (http://www.nih.gov). Indolent lymphomas represent classification is that it is poorly reproducible among pathologists. It
35% to 40% of NHLs, and follicular lymphoma (FL) is the most is also clear that there are no major biologic or clinical differences
common of the indolent lymphomas. between grades 1 and 2, whereas grade 3B FL is biologically distinct
from grades 1–3A, with features suggesting a close relationship to
5
diffuse large B-cell lymphoma (DLBCL). These considerations led
EPIDEMIOLOGY to the recommendation to group together FL grade 1–3A as FL and
create a new category called FL3B. However, the gene signature in
6
It is estimated that in 2016 more than 72,500 cases of NHL will be FL3B is closer to FL than to DLBCL. The final classification com-
diagnosed in the United States and more than 20,000 patients will bined FL grades 1 and 2 into one category (FL1–2 of 3) and made
die of their disease, making NHL the seventh most common cancer the distinction between FL3A and FL3B optional rather than manda-
7
and the fifth most common cause of death from cancer (http:// tory. The fourth edition of the WHO classification recognizes some
seer.cancer.gov/statfacts/html/nhl.html). NHL is extremely heteroge- distinctive clinical and genetic subtypes of FL, including primary
neous in its molecular pathophysiology, histology, and clinical course, duodenal FL and the pediatric type of FL that lacks the t(14 : 18) and
and there are major differences in the incidence of subtypes in dif- usually presents with localized disease. Several variants of FL that lack
ferent geographic locations and among different racial and ethnic the t(14;18) have some distinctive features, e.g., predominantly
populations. This difference in geographic distribution is particularly diffuse FL with deletions of 1p36 that presents with localized bulky
striking for FL and in the Western world, FL is the second most disease in the inguinal region. The gene expression profiles of FL cases
common lymphoma, comprising approximately 20% of all NHLs. with and without t(14;18) show some differences, with t(14;18)–
The incidence of FL in the United States is approximately 3.18 cases negative FL resembling activated late-stage germinal center B cells. 8
per 100,000 persons per year and in Europe is approximately 2.18 Although 85% of patients with FL have the t(14;18), the patho-
2
cases per 100,000 persons per year. The incidence of FL and other genesis of FL remains poorly understood. Recent studies have dem-
indolent lymphomas is shown in Table 80.1. The incidence appears onstrated frequent secondary genetic alterations including genomic
stable over time. There is no strong sex preponderance, but the gains, losses, and mutations, particularly inactivating mutations of
9
incidence in whites is approximately twice that of black and Asian the MLL2 gene, which occurred in 89% of FL cases examined, as
populations and the disease appears less common in Central and well as in the EPHA7, TNFRSF14 and EZH2 genes. The major
South America. The incidence increases with age and the median age mutations seen in FL are shown in Table 80.2. A notable feature of
of diagnosis is 65 years. Although most cases are sporadic, there is an these findings is that many of the mutated genes are involved in
increased incidence in family members of affected individuals, with transcriptional regulation. It is likely that posttranscriptional modifi-
3
a relative risk of 2.3 for siblings of patients. Differentiation of cation of histones is of key importance in germinal center B cells and
complex environmental factors from true inherited factors remains that the deregulated histone modification caused by these mutations

1288