follicular lymphoma | Advanced In Lymphomas Not Hodgkin Indolent

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Preface......................................................... . 3
Diagnostic Aspects................................ 4
◗ What is the current frequency of lymphoma diagnoses
Follicular?
◗ which presentation to the diagnosis?
◗ What are the necessary criteria for the confi rmation of the diagnosis
Follicular lymphoma to ganglionic biopsy?
Pretherapeutic assessment............................. .12
◗ What are the essential elements
of the pretherapeutic assessment of follicular lymphoma?
◗ How to conclude at the end of the balance sheet?
Support Principles
and follow-up.................................................... 19
◗ in patients with a low tumor mass,
What is the current position of the "armed surveillance" attitude?
◗ what first-line treatment for patients today
Having a strong tumor mass (stages III-IV)?
◗ have the response criteria evolved?
◗ what principles of management in case of progression
or relapse?
◗ the principles of follicular lymphoma management
Are they different in older subjects?
◗ What risk of histological transformation
And with what implications?
◗ What is the pace of monitoring in the long run?
References............... .26
Summary
3
Non-Hodgkin lymphoma (NHL) is a heterogeneous group
of diseases Defi Ned by an abnormal proliferation of lymphoid cells,
Mostly from line B (85% of cases), more rarely from the
Line T (15% of cases) [1]. In 40 to 50% of cases, these are lymphomas
Indolent, characterized by a slightly symptomatic clinical presentation,
A slow evolution and a high risk of recurrence (1).
Follicular lymphoma (LF), still of phenotype B, represents approximately
80% of indolent forms (1). Although considered incurable, he
In recent years of major progress in its
Management, both with regard to the treatment of first
The line of relapses or progression. This progress has
Leads to an elongation signifi proof of the life expectancy of
Patients (2) and diagnose the disease, its balance sheet, the
Choice of therapeutic strategies and long-term surveillance
Important issues.
This first issue of the Lymphormation collection: Advanced in
The objective of non-Hodgkin indolent lymphoma is to share
To clinicians the main achievements and innovations in knowledge
But also the future prospects. Other editions will follow,
Developed on the same lines, on other forms of indolent NHL.
Prof. Thierry Lamy
Department of Clinical Hematology, CHU of Rennes
Preface
The articles published in Onco-hematology correspondences are under the sole responsibility of their authors.
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Follicular
4
Diagnostic Aspects
What is the current frequency of lymphoma diagnoses
 Folli Ordinatespoint?
Follicular lymphoma (LF) constitutes, in order of frequency, the second entity
Among non-Hodgkin lymphomas (NHL), after US diff lymphoma at Large
Cells B (3, 4).
It accounts for 20 to 25% of all lymphoma diagnoses, with an incidence
which has rapidly increased over the last few decades, from
2-3/100 000 inhabitants in the years 1950 up to 5-7/100 000 inhabitants today
(Box 1) [5, 6].
In France, about 3 000 to 4 000 new cases of LF are diagnosed each year,
And the number of patients affected by the disease is between 20 000 and 25 000 (5, 7).
Box 1. LF: One of the 3 main lymphomas explaining the increase
The overall impact of the NHL. In recent decades, the epidemiology of malignant hemic has
Was marked by an exceptional increase in the impact of the NHL (4).
Although the increase seems to have stabilised since the beginning of the years 2000,
NHL have become the most frequent malignant hemopathy (4, 8). In France, according to
The latest estimates available, they are ranked seventh in cancer
Most common in humans (with an incidence of 12.1 *) and the sixth highest
In women (with an incidence of 8.2 *) [1, 4].
The data from the hemic malignant register of Côte-d'or show
That the increase in their incidence was mainly concerned with three types of
Lymphoma: Large B-cell lymphomas, LF and lymphomas
of the marginal zone (FI gure 1) [4].
* Incidence reported to the world population/100 000 inhabitants per year.
5
What presentation to the diagnosis?
The LF is primarily a ganglionic disease, usually revealed by adenopathies
SuperFi Skies, FL uctuante size or progressive increase
Over time (which can affect any ganglionic territory), more rarely
By symptoms related to the presence of deep adenopathies (most often
Sous-diaphragmatic) [9, 10]. In some cases, the disease is manifested by
Abdominal or lumbar pain in relation to a retro-peritoneal mass
which can then be accompanied by edema
Lower limbs or ascites. Extraganglionnaires forms, with impaired
Digestive or cutaneous, in particular, are possible, but are much rarer (9).
4
Standardized incidence rate
To the world's population
3.5
1980-1983 1984-1987 1988-1991 1992-1995 1996-1999 2000-2003
3
2.5
2
1.5
Mantle lymphoma
Burkitt Leukemia/lymphoma
Lymphoma of the marginal zone
Peripheral T-Lymphomas
1
0.5
0
Mycosis Fungoïde/Sezary syndrome
Large-cell diffuse lymphoma B
Follicular lymphoma
Lymphoplasmocytaire lymphoma
Figure 1. Evolution of standardized incidence rates to the world population
of different non-Hodgkin (NHL) Lymphoma entities B and T between 1980 and
2003. Data from the Côte-d'or Hemic Registry (4).
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Patients are most often diagnosed with a disease that is disseminated, with
Medullary (70% of cases), splenic (40% of cases) or hepatic (50% of cases) [10, 11].
The existence of B symptoms (slimming, fi fever, night sweats) does not affect
On the other hand that less than 20% of patients (10).
The median age for diagnosis is 60 years (box 2), with a discreet predominance
Female (10, 12).
Box 2. LF in the elderly: of the specified?
The LF is also frequent after 60 years, at the diff erence of the main other
Types of lymphoma whose incidence in the elderly is more important (3, 13).
As a whole, the NHL of elderly patients have to diagnose the characteristics
Clinical and biological similar to those of young patients, including
Subjects aged over 80 years (13, 14).
What are the necessary criteria for CONFI rmation
From the diagnosis of follicular lymphoma to ganglionic biopsy?

Like the diagnosis of the other NHL, that of LF rests in the majority of cases on
Analysis of peripheral or deep ganglionic biopsy (Box 3) [1, 5, 6, 15].
For morphological examination, tumor proliferation, derived from mature B cells,
Typically reproduces the architecture and cytology of normal germ centers:
It is organized in neoplastic follicles, subtended by a network of cells
Dendritic Follicularis, and containing a mixture of centrocytes and centroblasts
(FI gure 2a, p. 8) [10, 11, 16]. The Who histological grade, prognostic element
Important, is challenged by the number of centroblasts evaluated by counting on
10 microscopic fields at high magnification. When the average account is
Maximum of 5 centroblasts per field, this is a grade 1; Tumors containing
of 6 to 15 centroblasts per field are Grade 2, and those containing more than
of 15 centroblasts per field are Grade 3. According to the WHO classification 2008,
Grades 1 and 2 are grouped together within the same entity (who ranks 1-2).
Grade 3 LF is categorized as 3a and 3b depending on whether a contingent of
Centrocytes (3a) or that the tumor is exclusively composed of centroblasts
(3b) [fi gure 2b, p. 8]. The grade 3a is usually of indolent form, while the 7
Grade 3b is considered an aggressive form, assimilated to a lymphoma diff us
Large B cells (9-11, 17, 18).
Immunohistochemical analysis is an integral part of the histological analysis (19).
It is systematically carried out for the positive diagnosis of LF and for its
Diff erential Diagnosis with other NHL small cell phenotype B.
LF cells are carriers of the surface antigens classically associated with the
Line B (CD19, CD20) and express almost constant the markers of diff érenciation
B cells of the germ centres (CD10, BCL-6). They are also
Often positive for surface immunoglobulins (5, 10, 11, 20). On the other hand,
They do not express the CD5 antigen (diff erential Diagnosis with the lymphoma of the
Box 3. Ganglionic biopsy: An indispensable gesture for diagnosis.
The diagnosis of LF requires a biopsy analysis
Lymph nodes (5). A cytoponction is not sufficient because it does not allow
To evaluate the architecture of proliferation and the proportion of centrocytes and
Centroblasts (determinant to distinguish grades 3a from grades 3b, these
The latter under a diff erent support), nor to assess the possibility of a
Histological Transformation (5, 6). Isolated analysis of a medullary ltration
is not appropriate as there may be a discrepancy between the grade of the
Histological observed in the bone marrow and ganglion (5, 11).
As for the analysis of Extraganglionnaires localization, it is only justified in
Exceptional cases where these locations are the only manifestation of the
Disease (5).
Like the other NHL, the LF is corticosensible, so any corticotherapy
Can change the anatomopathologic aspect. In front of a lymphadenopathy of origin
Emergency, it is therefore recommended not to have any other
Prescribing corticosteroids prior to biopsy (1).
The biopsy must be of sufficient size and quickly taken care of, the
Levy to be addressed fresh and non-fi xed to the pathologist for
Allow the analyses necessary for the diagnosis (19, 22).
The conclusion of the Anatomopathologic report should refer to the classification
Who 2008 Malignant hemic (1, 15). According to the recommendations
Of the INCa, a second reading must be carried by a pathologist
Specialized in lymphomas (1). For this, a national reference network
Anatomopathologic, LYMPHOPATH, was set up by the INCa and the DGOS (1).
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Figure 2a. Ganglionic histology: Normal ganglion (left) and LF ganglion
(right). [Thanks to Patrick Tas, laboratory of pathological anatomy, CHU
of Rennes.]
Normal Ganglion (magnification × 4).
The physiological follicles are aligned in
The cortex under the capsule, with a clear center and
A polarized peripheral mantle area
to the capsule.
Follicular lymphoma (magnification × 20).
There is a development of nodules on any
Ganglionic area (cortical and medullary areas).
There are clear pseudo-centres
Without mantle area and made up of
of Centrocytes and Centroblasts.
Follicular lymphoma of grade 1-2 (magnification
× 40). There are less than 15 centroblasts
By field. All other cells are
Centrocytes.
Follicular lymphoma Grade 3b (magnification
× 40). The tumor nodule is made up
Exclusively from Centroblasts.
Figure 2b. Ganglionic histology: LF of grade 1-2 (left) and LF of grade
3b (right). [Thanks to Patrick Tas, laboratory of pathological anatomy,
CHU of Rennes.]
9
Coat), nor CD23 antigen (diff erential Diagnosis with lymphocytic lymphoma)
[5, 20]. Finally, in the majority of cases, the immunostaining is positive for
BCL-2 (FI gure 3), secondarily to the existence of a translocation t (14; 18), which may
Have an interest in diff erential diagnosis with certain follicular hyperplasia
(which are BCL-2 negative) [10, 11, 16].
Cytogenetic analysis, optional for diagnosis (as well as analyses
Identified in 85% of cases a translocation T (14; 18) [Fi gure 4] (5, 10).
This translocation has a diagnostic value but has no prognostic value
(21).
Non-rearranged profile of BCL-2. Presence of
2 Two-color copies per core.
Rearranged of BCL-2. Separation of Signals
Red (5 ' BCL-2) and Green (3 ' bcl-2).
Figure 3. Ganglionic FISH (in situ hybridization in FL uorescence) for BCL-2: tissue
Normal (left) versus tumor tissue during the LF (right). [Acknowledgements
To Catherine Henry, cytogenetics Laboratory, CHU of Rennes.]
Figure 4. Translocation (14; 18) of LF cells.
18 18
T (14; 18)
14 14
IgH IgH
BCL-2 BCL-2
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Immunity
Antitumor
Defective
B lymphocyte
Normal
Pre-FL T (14-18) Lymphomateuse cell
LF (del 1p, Del 6q,
Del 17p, + 7, + 12q),
Deregulation of Myc
BCL-6 translocation
Microenvironment cells
TCD8
Tph
Tam
Tam
Mrc
Frc
Msc
Fdc
Treg
Nk
Tγ5
Figure 5. Factors involved in tumor development during the LF (from
K. Tarte, U917 University of Rennes 1).
PerspectiveSurgical biopsy replaced by guided biopsy (23)?
For the diagnosis of lymphoma, the reference method with regard to the biopsy
is based on a surgical gesture by resection of an entire ganglion, in order to ensure that all
Techniques necessary for diagnosis (Anatomopathologic, immunohistochemical,
Cytogenetics, possibility of freezing) be feasible. This invasive procedure can
Be accompanied by scars, seromas or infections, which currently justifies
The increasingly frequent realization of imaging-guided biopsies (ultrasound
or CT scan). Several studies have shown that guided biopsies
Allow a reliable diagnosis in 95% of cases, both at the level of the lymph nodes
Deep as the SuperFi ganglia, since the number and size of the samples
are sufficient and their quality adequate. As with surgical biopsies, a
Cooperation between all the actors involved in the diagnosis (clinician, radiologist,
Pathologist) is indispensable.
FRC: Fibroblastic Reticular Cell; MRC: Mesenchymal Reticular Cell; MSC: Mesenchymal Stem Cell; Tam:
Tumor Associated Macrophage.
11
Perspective
The pathophysiology of the LF better apprehended.
The LF results from the malignant transformation of B cells from the germ center.
The major genetic anomaly encountered in the LF is the translocation T (14; 18),
Present in 85 to 90% of patients and responsible for an overexpression of the protein
Anti-apoptotic BCL-2 (24).
This translocation occurs at an early stage of the diff érenciation lymphocyte B
Within the bone marrow, even though contact with the antigen has not yet
occurred.
However, this event is not alone enough to lead to the process of
Malignant (25). Secondary mechanisms will be involved in the entry of cell B,
Known as pre-LF, in the germ center. First, this cell B is going to be the object
of additional genetic anomalies. Thus, the sequencing of the LF genome showed
That it existed in 88.5% of the cases (n = 31/35) of the mutations of the MLL2 gene involved
In histone methylation, and in 13.4% of cases (n = 35/261), mutations in the
MEF2B gene involved in their acetylation (24). In addition, many of these anomalies
are not oncogenic in themselves, but they allow for a stronger contact
With cells from the tumor microenvironment. This is the case of BCR mutations
That promote continuous stimulation in the absence of Antigen (26). These interactions
Complexes involve, within entangled tumor nodules, stromal cells
Like dendritic follicular cells (FDC), Specifi c subpopulations
(t follicularis helpers [TFH] and T regulators), follicular cells helpers and
cells, and establish close contacts with tumor cells
(Cytokine secretion like IL-15, antigenic presentation), facilitating growth
And the survival of these (fi gure 5) [27]. The new prognostic markers proposed
In the LF refl ect the composition of the microenvironment (number of
Macrophages CD68 +, number of TFH PD-1 +, etc.) [28]. One study highlighted
The number of CD8 + T lymphocytes and CD68 + macrophages present in the
Ganglion tumor microenvironment was meant cantly less important
When there was a medullary flooding that if it did not, this result
Suggesting that the extraganglionnaire extension of the LF could depend on the ProFi le of
Immune cells associated with tumor cells within the lymph nodes (29).
All these elements will help guide the therapeutic perspectives
Based on associations of molecules that jointly target the cells
Tumors and microenvironment cells.
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Pretherapeutic Assessment
What are the essential elements
The préthéra balance of follicular lymphoma?
The purpose of the pretherapeutic assessment of a LF is to assess:
◗ the stage of the disease (localized or disseminated);
◗ the importance of tumor mass (weak or strong);◗ the impact on the general condition and possible comorbidities.
All the information determines the prognosis and the therapeutic decision.
They also provide reference data for patient monitoring.
The balance sheet is first clinical (1, 5, 6, 19, 30, 31):
◗ interrogation with, in particular, search for general signs (symptoms B:
Fi fever, weight loss, night sweats), personal or family history
Hemic, exposure to specific substances (for example,
Dioxins, agricultural pesticides) or a risk of infection;
◗ careful examination of the areas ganglion SuperFi ciels and the oral cavity,
In particular the ring of Waldeyer, accompanied by a summary diagram
Details of the areas affected;
◗ search for a hepatomegaly and a splenomegaly;
◗ evaluation of the functional index (ECOG/WHO scale).
Table I presents the main recommended explorations in addition to the
Of the clinical balance sheet (1, 5, 6, 12, 30, 31).
The Cervico-thoraco-abdominal-pelvic scanner must be carried out with intravenous injection
Contrast product (in the absence of contra-indication) to allow the
Érencier the ganglion structures of the blood vessels and to increase the
Sensitivity of detection of hepatic or splenic impairment. For the abdominal exam,
A digestive Opacifi is recommended in order to érencier any possible
Abdominal masses of intestinal inlets.
Spinal biopsy is essential because of the high frequency of injury
Medullary diagnosis; If it is negative, some authors propose the realization
Contralateral biopsy to display the absence of medullary
This is, in practice, rarely eff conducted.
13
Table I. Recommended additional explorations in the pretherapeutic balance sheet
of the LF (1, 5, 6, 30, 31).
Objective Review
Ct
Cervico-Thoraco-Abdominopelvic
Evaluation of a ganglionic and visceral extension for the
Determination of the stage and the therapeutic decision
Reference examination for estimating the response to treatment
One-sided medullary biopsy for medullary intrusion for determination
of the stadium
Biological balance
• CBC with review
Morphological smears
Blood
Anemia (prognosis)
Search for neutropenia and/or thrombocytopenia
(Prognosis and adaptation of treatment if chemotherapy is
contemplated) and circulating lymphoma cells (prognosis)
• Urea, creatinine, Uricémie
• LDH and β2-Microglobulin
Serum
Markers whose value is useful for determining the
Prognosis
• HIV serology, hepatitis B and C taking into account therapeutic consequences (e.g.,
Reactivation of HBV, or even HCV, under Immunochimiothérapie)
• Protein electrophoresis
Serum
Searching for a monoclonal peak or hypogammaglobulinemia
Perspective
A place for the toe during the initial extension balance?

Several studies have shown that pet * could play an important role in the balance sheet
Initial extension of the LF, providing additional information in relation to the
CT * * For the evaluation of ganglion, splenic or hepatic locations
(Fig. 6, p. 14). In addition, this review can confi RM the existence of a location
and thus be complementary to the medullary biopsy (32). The pet allows
To evaluate the intensity of the fixation (SUV) and thus provide an argument of
Weight in favour of the existence of a transformation of LF into aggressive lymphoma. A
Biopsy directed at the site where the SUV appears very frankly high compared to the
Other binding sites can then be discussed (32). The still limited character of
Data explains that in 2012, pet does not yet constitute, apart from clinical trials,
A recommended review for initial staging and evaluation of the response
Treatment (6, 30, 31, 33, 34). According to the recommendations of the NCCN * * *, the review may
Nevertheless be useful to confi RM localized stadiums (eliminating the existence
"Occult" sites, not detected by conventional examinations, or in the
Patients for whom there is a suspicion of histological transformation (30).
* Pet: Positron emission tomography; * * CT: CT scan; NCCN: National
Comprehensive Cancer Network.
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How to conclude the outcome of the balance sheet?
At the end of the pretherapeutic balance sheet, the LF extension balance must be specified according to
The classification of Ann Arbor (table II), and its evolutionary profi le in the prognostic index
Flipi-1 (Table III; box 4, p. 16) and the criteria for high tumor mass defi ned
By the GELF (box 5, p. 17) [5, 6, 30, 35]. For the determination of FLIPI-1 and
Tumor mass, the calculation of the number of ganglion areas affected is based on the
Defi Nition of the areas presented in FI gure 7, p. 17.
Table II. ANN Arbor Classification (6).
Stadiums Description
Stage I (IE
) Attaining a single ganglionic area or unique Extraganglionnaire hit
Localized (IE.