Mædica - a Journal of Clinical Medicine

MAEDICA – a Journal of Clinical Medicine

2013; 8(4): 338-342

O RIGINAL PAPERS

Indolent Lymphoma: Diagnosis and

Prognosis in Medical Practice
Anca CIOBANUa; Oana STANCAb; Irina TRIANTAFYLLIDISb; Anca LUPUb
a
Department of Hematology, Coltea Clinical Hospital, Bucharest, Romania
b
“Carol Davila“ University of Medicine and Pharmacy, Bucharest, Romania

ABSTRACT
Introduction: Non-Hodgkin lymphomas represent malignant tumors of lymphoid cells. These chronic
lymphoproliferative disorders stand for malignancies with varied histological aspects, clinical features,
evolution, prognosis and aggressiveness. Follicular lymphomas are the most frequent form of indolent
lymphomas and they represent around 25% of all malignant lymphomas in adults.
Material and method: Between 2011 and 2012, we have retrospectively observed, analyzed and
described a group of 24 patients diagnosed with follicular lymphomas in the Department of Hematology
from Coltea Hospital. The admittance criteria were: age, gender, hemoglobin and LDH levels, number
lymph nodes affected and the Ann Arbor lymphoma staging system. Also used as patient study param-
eters were the following immunohistochemical criteria: CD20, UCHL1, CD79a, expression of Bcl 2 and
Bcl 6, CD10 and the proliferative index (Ki-67).
Results: Multiple studies have shown that prognosis depends far more on clinical and histology pa-
rameters, including age, the presence of extra-node diseases and the performance status. In our study,
regarding the ratio between the two genders, the male patients were more numerous than the female
patients. The impairment of the male patients is associated with an unfavorable prognosis. From the age
perspective, most of the diagnosed patients were part of the age group over 60. The age exceeding 60 is
considered a negative prognosis factor. The serum lactate dehydrogenase (LDH) level is also considered
an unfavorable prognosis factor. In our study, stage III and IV were frequently and this represents a
poor prognosis factor.
Conclusions: Although it was a small number of patients, the results obtained correspond to the
results existing in literature

Keywords: Follicular lymphoma, diagnosis, prognosis

INTRODUCTION cleaved cells) and centroblasts (large noncle-

aved cells). The frequency of follicular lympho-

F
ollicular lymphomas are the most fre- mas is around 20% in Western European coun-
quent indolent non-Hodgkin lympho- tries. In Romania, the frequency is 5-7%, similar
ma, presenting as a painless, slowly to other Eastern European and Asian countries
progressive adenopathy. They are de- (1).
fined as malignant proliferations of Follicular lymphomas include clinical symp-
the follicular centre cells: centrocytes (small toms caused by node damage. They can be

Address for correspondence:

Anca Ciobanu, Coltea Clinical Hospital, Department of Hematology, I.C. Bratianu Avenue, 030171, Bucharest.
E-mail: ancaciobanu05@yahoo.com.

Article received on the 19th of November 2012. Article accepted on the 4th of November 2013.

338 Maedica A Journal of Clinical Medicine, Volume 8 No.4 2013

 INDOLENT LYMPHOMA: DIAGNOSIS AND PROGNOSIS IN MEDICAL PRACTICE

evaluated by morphological and biological cri- Prognostic Index (FLIPI) is used more frequent-
teria. Follicular lymphoma patients most fre- ly for follicular lymphomas.
quently present with a late advanced stage dis- The FLIPI index results in 3 risk groups re-
ease. ported to a 10 year survival rate (low - 71%,
Although many of the cases of follicular intermediate - 51% and high - 36%).
lymphomas (of 1-2 degree) are considered in- The immunohistochemical expression of
dolent lymphomas, their clinical evolution is the bcl 2 anti-apoptotic protein A is also con-
often unpredictable. We have patients who ex- sidered to be a prognostic factor. The overex-
ceed the survival average considerably, by 8-10 pression of this protein is a marker that suggests
years, and patients which turn into aggressive a poor prognosis, while the expression of bcl 6
lymphomas shortly after the diagnosis. This as- or CD10 (germinal center markers) indicate a
pect hinders the diagnosis, especially for follic- favorable prognosis (5).
ular lymphomas with mainly centroblastic cells The relatively recent discovery of the hu-
(2). The follicular lymphomas distinguish them- manized monoclonal antibodies anti-CD20
selves through the clinical evolution with mul- has opened up a new era of treatment for fol-
tiple relapses, disease free survival (DFS) and licular lymphomas. The combination of anthra-
overall survival (OS) varying from one patient cyclines with alkylating agents and the adminis-
to another. tration of interferon or purine analogues, or the
Studies of non-Hodgkin lymphomas at mo- association with the autologous transplant with
lecular and gene levels (through FISH/CISH, hematopoietic cells, treatments previously at-
PCR, RT-PCR techniques, defining the gene tempted for stage II/IV patients could not be
profile with cDNA microarray, etc.) has allowed standardized. The treatment with monoclonal
the identification of new entities, but has also antibodies of Rituximab type has gradually be-
opened up the possibility of new, customized, come more widespread and has the tendency
therapeutic approaches, with higher results of becoming a first-line therapy, with or with-
compared to traditional treatments. out any association with chemotherapy. Anoth-
The translocation t (14;18) has been de- er category of therapeutic agents is represented
scribed as being specific and diagnostic for fol- by radioimmunoconjugates associated or not
licular lymphomas. In this translocation, the with chemotherapy. 
bcl2 gene approaches the Ig heavy chain gene.
The blc 2 gene encodes a protein capable of MATERIAL AND METHOD
inhibiting apoptosis, so that the cancer cells
have a longer life resulting in their local accu-
mulation (3).
Recently, immunephenotypic and genotyp-
S tarting from the existing patient data regard-
ing prognostic factors, a group of 24 patients
was selected from patients admitted in “Col-
ic analysis carried out with the help of mono- tea” Hospital Hematology Clinic in 2011-2012.
clonal antibodies and the new techniques in Some studies have shown that age, sex, num-
molecular biology, have allowed the identifica- ber of extra-nodal determinations, disease B
tion of malignant populations with monoclonal symptoms, and erythrocyte sedimentation rate
proliferations and the recognition of morpho- (ESR) and serum lactate dehydrogenase (LDH)
logical and functional differentiation stages at a levels may be prognostic predictors (6).
cell line level (4). FLIPI index (considered an important indi-
Modern cytogenetic methods demonstrat- cator for prognosis) comprises the following
ed that all lymphomas have chromosomal negative factors: age over 60, AnnArbor stage
changes such as translocations, deletions, rear- III or IV, hemoglobin <12g / dl, >4 lymph
rangements, inversions. Recent research has nodes affected areas, increased serum LDH (7).
identified the factors which activate cell prolif- The following parameters were analyzed for
eration: c-myc 62 phosphoprotein, the prolif- the stratification of patients included in the
eration of cell nuclear antigen (PCNA). Also the study: patient data (sex, age), clinical balance
Ki 67 antigen is increased, also having a prog- (ECOG performance status, disease B signs,
nosis value (4). syndrome tumor, stage of disease at diagnosis),
The prognostic variables in follicular lym- laboratory findings balance (renal and hepatic
phomas may be heterogeneous. function, eg.histopathology of lymph node and
The Follicular Lymphoma International bone biopsy, molecular biology tests in select-

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INDOLENT LYMPHOMA: DIAGNOSIS AND PROGNOSIS IN MEDICAL PRACTICE

Half of the patients in our group have shown

general signs of the disease.
The Ann-Arbor staging system is a necessary
but not sufficient prognostic parameter (7). For
10% of the patients with follicular lymphoma,
the disease was localized upon diagnosis.
Follicular lymphomas of degree 1 and 2 can
be found at onset in stages III-IV, in 80% of the
cases, with bone marrow involvement in 50%
of the cases, but this will not radically impact
FIGURE 1. The distribution of the patients considering the stage of the prognosis.
the disease.
In our study, the distribution of patients by
the stage of the disease at the onset was the
following: in stage II – 4 patients; in stage III – 8
patients, and in stage IV – 12 patients (Figure
1).
The distribution of patients depending on
the histological degree was as follows: Degree I
– 4 patients; degree II – 6 patients; degree IIIA
– 9 patients; degree IIIB – 5 patients (Figure 2).
It was noticed that most of the patients had his-
tology type III, which corresponds to an unfa-
vorable prognosis.
Laboratory findings analysis: the complete
blood count is normal in most of the cases at
FIGURE 2. The distribution of patients considering the histological
degree.
onset or during localized stages. Usually, there
is no pathognomonic data.
The number and leucocyte count may be
ed cases), imaging tests - chest X-ray, ultrasound
normal or sometimes there might be a decrease
and computer tomography. The immunohisto-
in the lymphocyte count. There is a small per-
chemical criteria used in the study of the pa-
centage of cases in which the peripheral dis-
tients were as follows: CD20, UCHL1, CD79a,
charge of lymphoid cells with atypical features
bcl 2, CD10 and the proliferative index (Ki-67).
is similar to the ones found in the lymph nodes
It represents a nuclear antigen present during
(7).
the cell cycle (G, G2, S, M) and absent in the
In our study, 18 patients had normal values
resting cells (6,7). It is identified by monoclonal
of hemoglobin at the disease onset, while 6 pa-
antibody Ki-67 MoAb as a proportion of Ki-67
tients had low values.
+ cells in the total cell. 
In our group, 9 patients showed a normal
RESULTS value of the erythrocyte sedimentation rate at
onset, while 15 patients had increased values.

T he average age in the patient group was 61,

with thresholds between 34 and 83 years of
age. The results showed that the average age at
The serum lactate dehydrogenase (LDH)
level is an absolute bias parameter of overall
survival in follicular lymphomas and is treated
diagnosis of patients suffering from follicular conventionally (5). 16 of our patients had in-
lymphoma is 60. creased values of serum lactate dehydrogenase
Follicular lymphoma is an elderly lympho- (LDH) at onset.
ma, with increasing incidence, thus the group All the cases in the study group have tested
older than 75 will report an increase of 1.8% positive for bcl 2 and CD 10. From an immuno-
per year. histochemical perspective, the reaction for bcl
In our study, the gender ratio was: men/ 2 was intense and diffuse (Figure 3).
women 16/8. In patients with small cell follicular lympho-
Smoking is considered an important factor mas, the proliferative index was variable, both
in the etiology of lymphomas. In the patient for the areas with nodular pattern and for the
group, 14 patients were smokers. ones with diffuse pattern, but a little higher

340 Maedica A Journal of Clinical Medicine, Volume 8 No.4 2013

 INDOLENT LYMPHOMA: DIAGNOSIS AND PROGNOSIS IN MEDICAL PRACTICE

than it is estimated in the existing data; only

Ki67 had a values under 10% (7).
In our group, 10 patients had an increased
Ki-67 >70% (Figure 4, 5).
Generally speaking, the analyzed cases
were positive for L26, the positive nature being
intense and diffuse. Yet in certain cases, L26
was negative, the only B line marker being
CD79a. In all cases, there was also a popula-
tion of small T cells, positive for UCHL1. These
cells will be analyzed in a subsequent stage
with the purpose of identifying the Treg cells
and their receptors. 
DISCUSSIONS

A ccording to the existing data, the age over

60 represents an unfavorable prognosis
factor. In our study, most of the patients were FIGURE 3. Malignant non-Hodgkin Follicular Lymphoma with
nodular patterns, small B cells. Col. IHC for bcl 2 – positive diffuse
over 60.
reaction Ob. 20x.
The specialized literature shows the fact
that the evolution of follicular lymphomas is
more severe in male patients than in female
ones.
The existence of B symptoms at the onset of
the disease represents an unfavorable prognos-
tic factor. Regarding follicular lymphomas, the
existence of the B symptoms is reduced at on-
set, being more frequent in advanced stages
and influencing the survival considerably.
Multiple studies have shown that prognosis
depends far more on clinical and histology pa-
rameters, including age, the presence of extra-
node diseases and the performance status.
Stage III and IV represent a poor prognosis fac-
tor (6).
The histological degree is used for thera-
peutic guidance concerning follicular lympho-
FIGURE 4. Follicular lymphoma with large B cells, degree 3b. Col.
mas and is also correlated with the prognosis.
IHC for Ki67. Positive reaction in approximately 70% of the cells. Ob.
The erythrocyte sedimentation rate repre- 20x.
sents the biological parameter which is best
correlated with the clinical stage of the disease, The following factors have a well-known
while the value of the C reactive protein is cor- importance: the immunohistochemical expres-
related best with the histological degree of ma- sion of the bcl 2 anti-apoptotic protein, usually
lignancy (6). Serum lactate dehydrogenase resulted from t (14,18) with the juxtaposition of
(LDH) represents an indicator of the response the BCL2 oncogene at the locus of the IGH
to treatment, the higher values at onset being heavy chains. The overexpression of this pro-
associated with the low rate of complete and tein is a poor prognosis marker, while the ex-
partial remissions. It plays the role of a specific pression of bcl 6 or CD10 (germinal center
tumor marker. markers) indicates a favorable prognosis (5).
The peripheral cytopenias (leukopenia and The relatively recent discovery of the hu-
thrombocytopenia) are most frequently a sec- manized monoclonal antibodies anti-CD20
ondary effect of the cytostatic therapy; but they has opened up a new treatment era for follicu-
can also be generated by a massive bone mar- lar lymphomas. The treatments previously at-
row infiltration or a hypersplenism (5). tempted in the patients with stage II/IV, such as

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INDOLENT LYMPHOMA: DIAGNOSIS AND PROGNOSIS IN MEDICAL PRACTICE

nosis, presence of extra-node determinations

and their location.
The most common chemotherapy treat-
ment used was R-CHOP followed by R-COP
and R-COEP. Up to 57.7% reduction in tumor
mass was obtained with >50% having a favor-
able prognosis. In the study group, the largest
tumor mass reduction rate, after the initial ther-
apy, was obtained with R-CHOP.
We achieved complete remission (CR) in
42.3% of patients in the study group and partial
remission in 32.4% overall response rate being
74.7%. 

CONCLUSIONS

FIGURE 5. Follicular lymphoma with follicular and diffuse pattern.

Col.IHC for Ki67. Proliferative index 7-8%. Ob. 40x.
A lthough they refer to a small number of pa-
tients, the results obtained correspond to
the results existing in literature. Regarding the
ratio between the two genders, the male pa-
the combination of anthracyclines with alkylat- tients were more numerous than the female
ing agents and the administration of interferon patients. The impairment of the male patients
or purine analogues or the association with the is associated with an unfavorable prognosis.
autologous transplant with hematopoietic cells, From the age perspective, most of the diag-
could not be standardized. The treatment with nosed patients were part of the age group over
monoclonal antibodies such as Rituximab has 60. The age exceeding 60 is considered a nega-
gradually become more widespread and has tive prognosis factor. The serum lactate dehy-
the tendency of becoming a first-line therapy drogenase (LDH) level is also considered an
(8), with or without any association with che- unfavorable prognosis factor. The molecular
motherapy. Another category of therapeutic biology techniques allow not only the increase
agents is represented by the radioimmunocon- in the accuracy of the diagnosis, but also the
jugates associated or not with chemotherapy. monitoring of the therapeutic response by de-
In our study, treatment response was de- tecting the minimal residual disease.
fined as complete remission (CR), partial remis-
sion (PR), non-response (NON-R). Conflict of interests: none declared.
Chemotherapy was chosen according to Financial support: none declared.
age, comorbidity, stage of lymphoma at diag-

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