Case 3 -
Mantle Cell Lymphoma, Small Cell Variant, with a Very Indolent Clinical Behavior
Elias Campo, M.D.
Hospital Clinic, University of Barcelona
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78 year-old female with a 10-year history of a low grade, leukemic, B-cell neoplasm, initially
diagnosed in 1995 as chronic lymphocytic leukemia [stage A(0)]. In December 2003, a stage I renal cell
adenocarcinoma was resected without complication. At the end of 2004, she developed progressive
lymphocytosis, anemia, and thrombocytopenia and was referred to our hospital for splenectomy. Physical
examination was normal with the exception of the splenomegaly. Laboratory tests demonstrated normal LDH
levels, B2 microglobulin 6.2 mg/L (normal 0-2.3) WBC 123.40 x103/µL (lymphocytes 85%), RBC
2.88 x106/µL, Hgb 8.7 g/dL, HCT 29%, MCV 89.7 fL, platelets 119 x103/µL. Flow
cytometry of the peripheral blood showed a clonal lymphoid proliferation positive for CD19, CD79b, CD20
(bright), CD22, CD23 (66% of all B-lymphocytes), FMC7, IgM/IgD, kappa (bright) and negative for CD5,
CD43, CD10. The general status of the patient improved after the splenectomy, but the lymphocytosis
persisted. She did not receive additional treatment for two years, until July 2007, when because of
progressive lymphocytosis she again received cyclophosphamide for 6 months. The patient is currently
alive with clinically stable disease.
Case 3 - Slide 1
Case 3 - Figure 1
The histological section of the spleen shows an expansion of the white pulp with a diffuse lymphoid infiltrate in the red pulp
Case 3 - Figure 2
Some nodules of the white pulp had a hyalinized aspect. The nodules were not very well demarcated, and the lymphoid cells of merged with the infiltrate of the red pulp.
Case 3 - Figure 3
A small reactive germinal center could be recognized in occasional white pulp nodules.
Case 3 - Figure 4
The tumor cell infiltrate was composed of small lymphoid cells with round nuclei, dense chromatin and scant cytoplasm.
Case 3 - Figure 5
The tumor cells had a monotonous morphology with round nuclei and dense chromatin without prominent nucleoli. No plasmacytoid differentiation could be seen.
Case 3 - Figure 6
The tumor cells were strongly positive for CD20 with a similar intensity in all the areas.
Case 3 - Figure 7
CD3 staining revealed few scattered lymphoid cells, but the tumor cells were negative.
Case 3 - Figure 8
CD5 staining was positive only in few lymphocytes with a similar distribution to that of the CD3 positive cells. Some of these cells tended to be at the periphery of the white pulp nodules. The tumor cells were negative.
Case 3 - Figure 9
CD5 positivity is present in residual lymphoid cells, but tumor cells are negative.
The histological sections of the spleen revealed a nodular expansion of the white pulp with a
monotonous lymphoid proliferation of small lymphocytes with round nuclei, dense chromatin, and scant
cytoplasm. The boundaries of most nodules were not well defined and the tumor cells tended to merge with
the cells in the red pulp. Clear germinal centers were only rarely seen and they were small and well
delineated and preserved. The red pulp was extensively infiltrated in the sinusoids and cords by a
similar population of lymphoid cells with a diffuse pattern. Mitotic figures were very rare.
The immunophenotype of the tumor cells was examined by flow cytometry of splenic cell suspensions and
immunohistochemistry of the histological sections. The flow cytometry confirmed the phenotype observed
in the peripheral blood and also showed that CD25, CD11c, and CD103 were negative. The immunostaining
also demonstrated that the tumor cells were positive for CD20, CD23, IgM, and IgD with kappa restriction
but negative for CD5, CD43, CD10, BCL-6, and IRF4/MUM1. CD23 and CD21 revealed a meshwork of follicular
dendritic cells in the white pulp nodules indicating the existence of lymphoid follicles that were
overrun by the neoplastic cells. Cyclin D1 was strongly positive in the nucleus of virtually all tumor
cells. Ki67 was positive in less than 10% of the cells.
A conventional cytogenetic study of the splenic cell suspension revealed the translocation
t(11;14)(q13;q34) as a single alteration without additional chromosomal aberrations.
Mantle cell lymphoma, small cell variant, with a very indolent clinical behavior
The clinical, morphological and phenotypic features of this lymphoid neoplasm are very uncommon and
the diagnosis not easy to establish. This case raises several questions on the classification of the
tumor and the practical management of the patient. The differential diagnosis includes atypical chronic
lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), lymphoplasmacytic lymphoma, splenic
B-cell lymphoma, unclassifiable, and mantle cell lymphoma (MCL). Although the diagnosis of hairy cell
leukemia may be entertained, it can easily be ruled out because of the distinct phenotype and
The patient had been initially diagnosed as a CLL in a community hospital based on the B-cell
lymphocytosis. After a long indolent clinical course of 10 years, the patient was referred to our center
because of progression of the disease with splenomegaly. The studies in our center showed that the
morphology of the peripheral blood cells was not typical for CLL because some cells showed clear
cytoplasm and 4% had villous prolongations suggesting a splenic marginal zone lymphoma. The flow
cytometry study of the peripheral blood showing negativity for CD5 and strong expression of CD20 and
surface Ig argued also against CLL. CD23, however, was positive. The histological morphology was not
consistent with a CLL diagnosis because the tumor cells were monotonous and no prolymphocytes or
paraimmunoblasts were observed. The diagnosis of lymphoplasmacytic lymphoma might be considered but the
lack of plasmacytoid differentiation and strong immunoglobulin staining help to exclude the diagnosis.
The diagnosis of SMZL was strongly considered. The clinical presentation with a long clinical
history, splenomegaly, and absence of lymphadenopathy, the presence of some villous lymphocytes and the
phenotype were consistent with this diagnosis. However, the histological examination showed a monotonous
proliferation of small B-cells without the typical biphasic morphology of small and large B-cells
surrounding and infiltrating reactive germinal centers. The infiltration of the red pulp was more
diffuse that the typical micronodular pattern observed in SMZL.
We were considering the diagnosis of a splenic B-cell lymphoma, unclassifiable when the cytogenetic
study revealed a t(11;14)(q13;q34) translocation. This result prompted us to perform a cyclin D1
staining that was strongly positive. We confirmed also the presence of the translocation in the tumor
cells by FISH. This finding made us consider the diagnosis of MCL. The CD5 negativity and CD23 positive
phenotype are atypical for this diagnosis, but both aspects have been recognized in around 10% of
otherwise typical MCL.
However, the most unusual aspect was the long indolent clinical
history of the patient. The case was discussed with the clinicians and no additional chemotherapy was
given to the patient after the splenectomy due to the previous indolent evolution. She remained with a
relatively stable lymphocytosis the following 25 months when she was treated with cyclophosphamide for 12
months and later discontinued. She has been asymptomatic with stable disease for the last six months.
The diagnosis of MCL in a patient with such a stable and indolent disease opens several questions: 1)
Does indolent MCL really exist or is this particular case an unusual anecdote? 2) Are those cases real
MCL or do they correspond to other ly mphoid neoplasms with an aberrant genotype? 3) If they are MCL,
what are the differences between this indolent and conventional MCL with more aggressive clinical
Does Indolent MCL Exist?
Mantle cell lymphoma is considered an aggressive lymphoid neoplasm with a median patient survival
between 3-5 years. However, most series have recognized a relatively broad variability in the outcome
with some patients having a rapid course and survival shorter than one year whereas others may have long
survival of more than 7-8 years. This variability has been mainly related to the proliferation rate of
the tumors. Most parameters associated with poor outcome seem to be surrogate markers of high
proliferation such as morphologic variants (blastoid) and several genetic and molecular
This conventional view of MCL was challenged by the study of Orchard et al  that
recognized a subgroup of patients with leukemic disease and absence of peripheral lymphadenopathy that
showed a more heterogeneous clinical behavior. Some of these patients had a clinically aggressive
disease but 24% of them (nine patients) never required treatment for a mean of 58 months (range 8-175
months) and in a further nine, therapy was delayed because of stable disease with a mean of 29 months
(range 10-60 months). The median survival of this group was significantly longer (79 months) than that
of patients presenting with a conventional nodal disease (30 months). These finding strongly support the
idea that some MCL presenting with non-nodal disease may have a very indolent clinical course. Our case
had a clinical presentation and evolution similar to this group of non-nodal MCL patients.
A second strong evidence favoring the existence of MCL with a very indolent clinical course are the
reports of two patients with subclinical peripheral blood and minimal nodal involvement by a lymphoid
neoplasm interpreted as MCL because of the identification of the t(11;14) translocation and the expansion
of the mantle zone of the follicles by a cyclin D1 positive lymphoid neoplasm.
patients had stable and asymptomatic disease for more than 5 and 12 years, respectively. Two other
studies have reported four patients presenting with a similar expansion of the mantle zone area by cyclin
D1 positive lymphocytes.
This limited involvement of the lymph nodes has been named "in
situ" MCL. Unfortunately, the clinical follow up of these patients is scarce but at least one of them
was asymptomatic and with no treatment for four years.  One patient had disseminated
disease at diagnosis and was treated with conventional protocols and an additional patient had
progressive disease one year after the diagnosis. 
We have recently studied 12 patients with a B-cell neoplasm carrying the t(11;14) and cyclin D1
overexpression that had a stable disease without requiring polychemotherapy for more than 24 months
(median 70 months, range 25-121).  Five patients were treated only with splenectomy. One
of them is the patient presented here. Eleven of these patients presented with peripheral blood
involvement but only four had lymphocytosis (> 5x109/L) One patient had a single large
lymph node with no evidence of disease in the blood for more than five years.
These observations clearly indicate that a subset of patients with MCL may follow a very indolent and
stable clinical course without need of chemotherapy for several years. Most of them seem to present
without lymphadenopathy or limited nodal disease. However, two key questions are whether these lymphoid
neoplasms are really MCL or do they correspond to other B-cell neoplasms and how can we distinguish at
diagnosis these indolent MCL variants from more aggressive conventional tumors.
Are Indolent MCL Real MCL?
Early studies had identified the t(11;14) translocation in several B-cell neoplasms in addition to
MCL. Thus some atypical CLL, around 50% of B-PLL and occasional splenic lymphoma with villous
lymphocytes were considered to carry this translocation.
Subsequent reevaluation of
these cases had considered all these tumors as morphological variants of MCL.
Similarly, Orchard et al considered that the non-nodal MCL with indolent clinical behavior had the same
clinical and pathological features as conventional MCL in terms of age, gender, splenomegaly and
gastrointestinal tract involvement, and morphology. None of the indolent cases had typical morphology of
CLL, SMZL, or B-PLL. 
To further answer this question we have performed a microarray expression profile of seven of our
clinically indolent MCL and compared the results with 15 conventional MCL, 15 CLL, 7 FL, 4 SMZL, 3 HCL
and 2 hairy cell leukemia variant (HCLv). Interestingly, an unsupervised hierarchical clustering
analysis showed that the indolent MCL clustered together with conventional MCL whereas CLL, FL and
SMZL/HCL/HCLv clustered in different groups according to the respective diagnosis.  These
findings strongly suggest that indolent MCL belongs to the same entity as conventional MCL.
How Can We Distinguish at Diagnosis the Indolent MCL from Conventional More Aggressive Tumors?
This question is difficult to answer with the current available information. Most patients that have
followed an indolent clinical course have presented with absence of or limited nodal disease and most of
them, but not all, had peripheral blood involvement. Some patients had splenomegaly and leukemic
presentation. However, these clinical aspects may not be sufficient to suggest that the patient may
follow an indolent clinical course since around 20% of patients with a non-nodal disease died in the
first year after the diagnosis. 
Non-nodal MCL have hypermutated (less than 98% homology) IG genes more frequently than conventional
MCL.  Contrary to CLL, the mutational status of the IG genes has not been of prognostic
significance in most studies in MCL.
However, the patients with longer survival in the
Orchard study  had IG genes with somatic hypermutations. The two indolent MCL described by
Nodit et al 
and Espinet et al  also had highly mutated IG genes. In our study
the eight indolent MCL in which the IG status could be examined showed a high level of somatic mutations
(<95% homology) whereas this number of mutations was only seen in three of the 15 conventional MCL.
Conventional MCL has complex chromosomal karyotypes whereas in the non-nodal MCL the t(11;14)
translocation was the only genetic alteration in approximately 50% of the cases. In our study, we have
examined the genomic alterations using the 500K Affymetrix SNP array. Only two of the seven indolent MCL
had one single additional chromosomal aberration that also occurred in regions not commonly involved in
these lymphomas whereas complex karyotypes (more than two aberrations in addition to the t(11;14))
occurred in 12 of the 15 conventional MCL.
Although these observations are still limited they suggest some cases of MCL may have a stable and
indolent clinical course. These patients may present most commonly with absent or limited nodal disease,
carry a high load of IG gene somatic hypermutations and have very simple karyotypes in which the t(11;14)
translocation may be the only chromosomal aberration. More studies are needed to define the
clinicopathological features of this MCL subtype to avoid overtreatment of patients that may not require
aggressive polychemotherapy for a long period of time.
Take Home Points
- Leukemic small B-cell neoplasms encompass a variety of tumors with overlapping morphological and phenotypic features. The differential diagnosis of these entities requires a thorough characterization of the morphology, phenotype, and genetic alterations.
- Although most mantle cell lymphomas have an aggressive clinical evolution with a median survival of 3-5 years, some patients may follow an indolent clinical course with very stable disease without the need of polychemotherapy for many years.
- MCL with an indolent clinical course usually presents with absence of or limited nodal disease, highly hypermutated IG genes and very simple karyotypes in which the t(11;14) translocation is frequently the only alteration.
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