| Abstract|| |
Introduction: Mantle cell lymphoma (MCL) is a type of B-cell non-Hodgkin lymphoma (NHL) with distinctive morphologic, immunophenotypic and a characteristic cytogenetic abnormality, the t(11;14)(q13;q32) and overexpression of cyclin D1. The common histologic features include effaced lymphoid architecture by a monomorphic lymphoid population with a vaguely nodular, diffuse or mantle zone growth pattern. The classic cytomorphologic features include small to medium sized lymphoid cells with irregular nuclear contours and scanty cytoplasm, closely resembling centrocytes. Materials and Methods: This retrospective study comprises 13 cases of MCL over a period of 5½ years in our department, comprising 4% of all nodal NHL diagnosed. All cases were diagnosed on lymph node biopsy. Results: The mean age of the presentation was 57 years. There was a male preponderance (M:F = 2.25:1). The disease was nodal in all cases. Most patients (84.5%) had generalized lymphadenopathy and/or hepatosplenomegaly. Bone marrow involvement was seen in 81.8% of cases. Three cases showed a nodular pattern on lymph node biopsy while remaining ten had a diffuse pattern. Immunophenotyping showed positivity for CD20, CD5 and cyclin D1 and CD23 negativity. Conclusion: Despite certain morphological similarity to other low-grade/intermediate-grade lymphomas, MCL has a characteristic appearance of its own. Since it is more aggressive than other low-grade lymphomas it needs to be accurately diagnosed.
Keywords: Cyclin D1, mantle cell lymphoma, non-Hodgkin lymphoma
|How to cite this article:|
Roy A, Kar R, Basu D. Nodal mantle cell lymphoma: A descriptive study from a tertiary care center in South India. Indian J Pathol Microbiol 2013;56:94-7
|How to cite this URL:|
Roy A, Kar R, Basu D. Nodal mantle cell lymphoma: A descriptive study from a tertiary care center in South India. Indian J Pathol Microbiol [serial online] 2013 [cited 2020 Feb 26];56:94-7. Available from: http://www.ijpmonline.org/text.asp?2013/56/2/94/118680
| Introduction|| |
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma (NHL) derived from a subset of naïve pregerminal center cell or the mantle zone of secondary follicles. , It comprises approximately 2-10% of NHL. , Lymph nodes are the most commonly involved site. Spleen, bone marrow, gastrointestinal tract and Waldeyer's ring are the other common sites of involvement. The clinical course is relatively aggressive, with poor response to conventional therapy. MCL generally expresses B-cell antigens (CD19 and CD20) as well as CD5 and is CD10- and CD23- with, t(11;14)(q13; q32), resulting in overexpression of the cyclin D1/bcl-1 oncoprotein. The histological appearance of MCL has been well-described, but the diagnosis can be problematic due to morphological overlap with other low-grade lymphomas. The present study describes the clinico-pathological features of 13 cases of nodal MCL in our center and highlights the problems encountered in the morphological diagnosis.
| Materials and methods|| |
This retrospective study comprises 13 cases of MCL diagnosed over a period of 5 1 / 2 years (January 2007 to June 2012) in our institute. Cases with extranodal presentation were excluded from this study. All cases were documented by biopsy of involved lymph nodes. Detailed clinical information was recorded from the case sheets. This included age and sex of the patients, duration of illness, site of biopsy, distribution of disease, presence or absence of B symptoms, complete blood counts and bone marrow aspiration and trephine biopsy findings.
Hematoxylin and eosin stained sections were studied and the following histological features evaluated:
Subsequently, immunohistochemistry (IHC) was done. The following antibodies were used according to histomorphological features - CD3, CD5, CD10, CD20, CD23, cyclin D1, bcl2, Tdt and Ki67. IHC was performed by Avidin Biotin peroxidase method with pre-treatment by microwave heating.
- Pattern of growth (diffuse, nodular and mantle)
- Morphology of the cells and their relative preponderance (conventional lymphocytic and blastic)
- Number of mitotic figures per 10 random high power field (HPF)
- Pink histiocyte
- Hyalinized capillaries
- Capsular and extracapsular involvement
- Presence or absence of residual reactive follicles
Strict histologic and recently updated criteria were applied and patients with a confirmed diagnosis of MCL were included in the study. Tumor cell with classical morphological features in a CD20 positive NHL, expressing cyclin D1 and/or CD5 while negative for CD23 and CD10 were a requirement for diagnosis of MCL. Cases with a nodular pattern of growth showing residual germinal center were considered to have a MCL with a mantle zone growth pattern. Cases were labeled nodular or mantle zone pattern if 10% or more of the tumor had such a pattern. Cases were labeled blastic if 20% or more cells were transformed.
| Results|| |
Between January 2007 to June 2012, 324 cases of nodal NHL were diagnosed in our institute. The 13 cases of nodal MCL, thus accounted for 4% of all NHL in this period. The clinical characteristics of the 13 cases are summarized in [Table 1]. The mean age of the presentation was 57 years. There was a male preponderance (M:F = 2.25:1). Most patients had generalized lymphadenopathy (84.6%) and/or hepatosplenomegaly (53.8%). Bone marrow involvement was seen in 81.8% cases with peripheral blood spill-over in six cases. Systemic B symptoms were seen in 46.15% of cases. Lymphadenopathy was generalized in 84.6% of cases; epitrochlear and intra-abdominal lymph node involvement was seen in 23% and 30.7% of cases respectively. Hepatomegaly, splenomegaly and pleural involvement were seen in 46.15%, 53.8% and 15.4% of cases respectively.
|Table 1: Clinicopathological features of thirteen cases of mantle cell lymphoma|
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At low power, the affected lymph nodes showed complete effacement of normal architecture. Three cases showed a vaguely nodular pattern, which was appreciated at a low magnification with the condenser kept low. In one of these cases, residual reactive follicles were seen focally. The remaining ten cases had a diffuse pattern.
On higher magnification, the neoplastic population was seen to be monomorphic and composed of small lymphocytes with scanty cytoplasm. The nuclei were irregular and cleaved [Figure 1]. Nucleoli were inconspicuous in most. Mitotic figures ranged from 5 to 20 per 10 HPF. In two cases (case number 2 and 6), there was a mixture of large cells with vesicular nuclei and prominent nucleolus resembling blasts. Both these cases showed a diffuse pattern. Remaining eleven cases had conventional morphology. Capsular involvement was noted in six cases.
|Figure 1: Lymph node biopsy with diffuse pattern of infiltration by monomorphic small lymphoid cells with scanty cytoplasm, the nuclei were irregular and cleaved with inset highlighting pink histi ocytes (H and E, ×400)|
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Scattered histiocytes with granular eosinophilic cytoplasm were commonly seen. Prolymphocytes and proliferation center were not seen. Almost all cases showed prominent hyalinized blood vessels. The differential diagnoses that were considered included small lymphocytic lymphoma in two cases, follicular lymphoma in three, large cell lymphoma in two and lymphoblastic lymphoma in two. In four cases diffuse small-cleaved lymphoma of intermediate grade was considered, a possibility of mantle cell lymphoma being kept in mind. IHC was done in all cases.
All cases were positive for CD20, CD5 and cyclin D1 [Figure 2]a-c and negative for CD3, CD23 [Figure 2]d and e. One case (case number 5) showed aberrant expression of CD10 and all other cases were consistently negative for CD10 expression [Figure 2]f.
|Figure 2: Immunohistochemical panel showing positive expression of (a) CD20 membranous, (b) CD5 cytoplasmic and membranous, (c) cyclin D1 nuclear and negative expression of (d) CD3, (e) CD23 and (f) CD10 (immunohistochemistry, ×400)|
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Peripheral blood findings
Complete blood counts were available in all cases. Four cases showed absolute lymphocytosis and six cases had circulating lymphoma cells. The cells were polymorphous, small to medium sized with slightly irregular, eccentric nucleus and fine chromatin [Figure 3]a. Some cells showed a single nucleolus. A thin rim of gray blue cytoplasm was seen.
|Figure 3: (a) Peripheral smear showing small to medium sized lymphoma cells with slightly irregular nucleus and fine chromatin (Leishman, ×1000). (b) Bone marrow section shows diffuse infiltration by lymphoma cells (H and E, ×100)|
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Bone marrow aspiration and biopsy findings
Bone marrow aspiration was performed in all cases. Trephine biopsy was done in eleven cases. Bone marrow involvement was noted in nine cases. In three cases, the peripheral blood did not show leukemia. Lymphoma cells constituted 12% to 95% of the marrow cells. Three cases had nodular, four cases had diffuse [Figure 3]b, one case had interstitial and one case had paratrabecular and nodular infiltration. The details of the peripheral and bone marrow findings are given in [Table 2].
|Table 2: Hematological parameters in eleven pati ents with peripheral blood and bone marrow involvement|
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Treatment and outcome
Follow-up was available in 8 out of 13 cases. One case (case number 12) had expired before the start of chemotherapy. Median duration of follow-up was 13.5 months (1-33 months). Treatment with curative intent was offered in seven patients. Different treatment regimen offered were cyclophosphamide, hydroxyurea, daunorubicin, oncovin, prednisolone, cyclophosphamide, vincristine, prednisolone, cyclophosphamide, etoposide, oncovin, prednisolone and bendamustine, with or without rituximab, depending upon the feasibility. Five patients are on follow-up -till date and two have been lost to follow-up after few months.
| Discussion|| |
Mantle cell lymphoma is a type of B-cell NHL with distinctive morphologic and immunophenotypic features and a characteristic cytogenetic abnormality, the t(11;14)(q13;q32), involving the BCL-1 locus on chromosome 11q13 and the immunoglobulin heavy chain gene complex on chromosome 14q32.  MCL is relatively uncommon, comprising of 2-8% of NHL in the United states.  In a study by Naresh et al. on the regional distribution of various lymphoid malignancies in India, the incidence of MCL ranged from 0% to 4.6%.  In the present study, MCL comprised -4% of all NHL diagnosed in 5 1 / 2 years.
MCL is more common in males and tends to affect older individuals, the mean age of diagnosis being 60 years.  In our cases, mean age of diagnosis was 57 years. A point of interest in our study was that the mean age in females was 46 years, much less than in males in whom it was 62 years. Most patient with MCL present with disseminated disease and generalized lymphadenopathy. ,,, In our study, there was generalized lymphadenopathy in 84.6% of cases. The spleen is involved in half of the cases and may be the only site of the disease. Involvement of Waldeyer's ring is reported in 10-15% cases.  The involvement of the gastrointestinal tract in the form of lymphomatous polyposis is also known. We did not encounter any such case though intra-abdominal nodes were present in 30.7% cases. In a previous study carried out by our institute showed generalized lymphadenopathy, hepatomegaly and splenomegaly in 77%, 23% and 38.5% of cases respectively. 
Patients with MCL have frequent bone marrow involvement.  In the present study, 81.8% had a bone marrow infiltration with peripheral spill-over in 6 (66.67%) cases. Leukemic involvement in MCL is a common finding and the reported incidence in literature varies from 53% to 93%. , However, de novo leukemic involvement is also well-documented. , The leukemic phase may infrequently present without lymphadenopathy, in which case it becomes difficult to differentiate from chronic lymphocytic leukemia (CLL) and other low-grade lymphoma infiltration. Recognition of the leukemic phase is also important because it indicates a poor prognosis.  Wong et al. described four cell types in mantle cell leukemia: (1) Mixture of small to medium-sized cells, (2) predominantly medium-sized cells, (3) predominantly large cells and (4) giant cells.  The distinguishing features from CLL and prolymphocytic leukemia are the heterogeneous population of cells, pronounced nuclear irregularity, less clumped chromatin and scant rim of cytoplasm.  In two of our patients with leukemic phase a mistaken diagnosis of CLL was made prior to the tissue diagnosis of MCL. In our study, 77% showed diffuse and 23% nodular pattern. Mantle zone pattern was not seen in any case though one case showed focal preservation of residual follicles.
In classical MCL, the neoplastic cells are monotonous.  Nuclei are small to medium-sized, have nuclear membrane indentations and have inconspicuous nucleoli. Some cells with round nuclei are noted. Cytoplasm is sparse. When evaluating a lymphoma with a nodular pattern, a mixture of large noncleaved lymphocytes and smaller angulated cells favor a diagnosis of follicular lymphoma. Nuclear irregularities and absence of large prolymphocytes, paraimmunoblast and proliferation center distinguish MCL from a small lymphocytic lymphoma. The cellular monotony is an important feature of most cases of MCL.  Pink histiocytes and sclerosed blood vessels are commonly present and are important to the diagnosis. In general, the neoplastic cells are CD5, CD20 and bcl2 positive with strong surface IgM and IgD, but are negative for CD23, CD10, CD11c and CD25. The overexpression of cyclinD1 is highly characteristic and is observed in 100% of cases in our study.
Transformation to a high-grade blastic form of MCL has been described. , Two of our cases had blastoid cytomorphology. Mitosis was also high in these areas. When this transformation occurs focally, the area of the large cells can mimic, at low magnification, proliferation center of small lymphocytic lymphoma. Close attention to the nuclear irregularity and absence of prolymphocytes and immunoblasts are helpful in making the distinction. Blastic form is associated with a more aggressive course. ,
MCL is generally more aggressive than other small B cell lymphomas. Argatoff et al. reported an overall survival of 43 months.  It is important to carefully look for and appreciate the morphological features that separate MCL from other NHL since morphology remains the gold standard for most diagnostic pathologists. This is especially true in a developing country like ours where facilities for IHC and cytogenetics may not be routinely available.
| References|| |
|1.||Hankin RC, Hunter SV. Mantle cell lymphoma. Arch Pathol Lab Med 1999;123:1182-8. |
|2.||Weisenburger DD, Chan WC. Lymphomas of follicles. Mantle cell and follicle center cell lymphomas. Am J Clin Pathol 1993;99:409-20. |
|3.||Swerdlow SH, Campo E, Seto M, Hermelink HK. Mantle cell lymphoma. In: WHO Classification of Hematopoietic and Lymphoid Tissue. Lyon, France: WHO Blue Book Published; 2008. p. 229-37. |
|4.||Gujral S, Agarwal A, Gota V, Nair R, Gupta S, Pai SK, et al. A clinicopathologic study of mantle cell lymphoma in a single center study in India. Indian J Pathol Microbiol 2008;51:315-22. |
|5.||Yatabe Y, Suzuki R, Tobinai K, Matsuno Y, Ichinohasama R, Okamoto M, et al. Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: A clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma. Blood 2000;95:2253-61. |
|6.||Kauh J, Baidas SM, Ozdemirli M, Cheson BD. Mantle cell lymphoma: Clinicopathologic features and treatments. Oncology (Williston Park) 2003;17:879-91, 896. |
|7.||Naresh KN, Agarwal B, Sangal BC, Basu DD, Kothari AS, Soman CS. Regional variation in the distribution of subtypes of lymphoid neoplasms in India. Leuk Lymphoma 2002;43:1939-43. |
|8.||Argatoff LH, Connors JM, Klasa RJ, Horsman DE, Gascoyne RD. Mantle cell lymphoma: A clinicopathologic study of 80 cases. Blood 1997;89:2067-78. |
|9.||Swerdlow SH, Williams ME. From centrocytic to mantle cell lymphoma: A clinicopathologic and molecular review of 3 decades. Hum Pathol 2002;33:7-20. |
|10.||Basu D, Yaranal PJ, Kalyan K, Soundararaghavan J. Mantle cell lymphoma - A clinicopathological study of 13 cases. Malays J Pathol 2005;27:17-22. |
|11.||Wong KF, So CC, Chan JK. Nucleolated variant of mantle cell lymphoma with leukemic manifestations mimicking prolymphocytic leukemia. Am J Clin Pathol 2002;117:246-51. |
|12.||Rahman K, Subramanian PG, Kadam PA, Gadage V, Galani K, Mittal N, et al. Morphological spectrum of leukemic mantle cell lymphoma. Indian J Pathol Microbiol 2012;55:66-71. |
|13.||Wong KF, Chan JK, So JC, Yu PH. Mantle cell lymphoma in leukemic phase: Characterization of its broad cytologic spectrum with emphasis on the importance of distinction from other chronic lymphoproliferative disorders. Cancer 1999;86:850-7. |
|14.||Weisenburger DD, Vose JM, Greiner TC, Lynch JC, Chan WC, Bierman PJ, et al. Mantle cell lymphoma. A clinicopathologic study of 68 cases from the Nebraska lymphoma study group. Am J Hematol 2000;64:190-6. |
|15.||Kaleem Z, Wakoff AR, Smith RP, Hess JL. Blastic transformation of mantle cell lymphoma. Arch Pathol Lab Med 1996;120:577-80. |
Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry - 605 006
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]