Transformation of Indolent Mantle Cell Lymphoma to Pleomorphic Mantle Cell Lymphoma: Case Report and Review of Clinical and Morphologic Variants

The patient is a 54-year-old man who presented with massive splenomegaly and lymphadenopathy. A femoral lymph node biopsy was performed revealing residual germinal centers with expanded mantle zones composed of relatively small lymphocytes with inconspicuous nucleoli and round nuclear contours (see Figures 1A and 2A). The peripheral blood showed small cells with abundant cytoplasm and occasional cells with polar villous projections (see Figure 3A). Flow cytometry revealed a clonal population of dim κ immunoglobulin light-chain–restricted, CD20-positive B lymphocytes without coexpression of CD5 or CD10. Cyclin D1 immunohistochemical staining was performed and was negative. The initial diagnosis was B-cell non-Hodgkin lymphoma of small cells. The patient was followed with a presumptive diagnosis of marginal zone lymphoma.

The patient was observed and was asymptomatic for 8 years until he presented with abdominal fullness. Splenectomy was performed and revealed a spleen weighing 4.6 kg. Morphologic review of the spleen demonstrated an atypical lymphoid proliferation surrounding germinal centers in the white pulp composed of a mixture of small lymphocytes and larger pleomorphic cells with irregular nuclear contours (see Figures 1B and 2B). Ki-67 showed a very high proliferative fraction of greater than 90%. Cyclin D1 immunohistochemical staining was positive (see Figure 4B), as were cytogenetic fluorescence in situ hybridization studies for t(11;14)(q13;q32). Flow cytometry revealed dim κ light-chain expression, as was previously seen. However, the clonal cells now demonstrated variable CD5 expression, whereas results of the study 8 years prior were negative (see Figure 5A and B). The cells were also positive for FMC-7, with a subset expressing CD23. Repeat cyclin D1 immunohistochemical staining on the femoral lymph node biopsy was also positive, indicating an inadequate initial study (see Figure 4A). Moreover, immunoglobulin heavy-chain gene rearrangement studies confirmed the presence of identical clones in both biopsies (see Figure 6A and B). SOX11 performed on the spleen resection was negative (performed by the panel of reviewers for the European Association of Hematopathology Workshop, Uppsala, Sweden). The patient developed lymphocytosis and the peripheral blood contained circulating large lymphoma cells with prominent nucleoli (see Figure 3B). Flow cytometry performed on the peripheral blood revealed moderate CD5 expression (see Figure 5C). A revised diagnosis of indolent mantle cell lymphoma with progression to pleomorphic mantle cell lymphoma was made. Clinically, the patient experienced increasing lymphadenopathy and central nervous system involvement, as well as tumor lysis syndrome. He died 9 months after splenectomy.

Based on the morphologic features alone, differential diagnostic considerations in this case includes small B-cell non-Hodgkin lymphomas including chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal zone lymphoma, and mantle cell lymphoma. The morphologic, immunophenotypic, and clinical features of each of these entities are briefly discussed below, with a focus on the clinical and morphologic variants of mantle cell lymphoma.

Morphologically, chronic lymphocytic leukemia/small lymphocytic lymphoma is characterized by a monomorphic proliferation of small to medium-sized B lymphocytes with round nuclear contours that frequently form proliferation/growth centers. The neoplastic cells express CD5. CD20 and light-chain expression are typically dim by flow cytometric analysis. Clinically, the disease usually involves peripheral blood and bone marrow and, in the absence of transformation to diffuse large B-cell lymphoma, typically has an indolent course with prolonged overall survival. The case described above had dim light-chain expression with involvement of the peripheral blood. However, at the time of diagnosis the neoplastic cells were CD5 negative. In addition, the absence of proliferation centers and the distribution of neoplastic cells in the mantle zones surrounding germinal centers made this diagnosis highly unlikely.

Nodal and splenic marginal zone lymphomas are neoplasms of small B cells that show an expansion of cells around mantle zones. Peripheralized lymphocytes are usually characterized by the presence of short polar villi as was noted on initial presentation; however, this finding is not entirely specific to marginal zone lymphoma and may be associated with normal surface immunoglobulin expression on physiological lymphocytes,⁴  or may be a nonspecific finding in other chronic B-cell lymphoproliferative disorders. Marginal zone lymphoma cells are usually negative for CD5, CD10, and CD23, but cases with dim CD5 expression have been reported. Clinically, marginal zone lymphomas are typically indolent. Given the finding of occasional circulating villous lymphocytes, the histologic pattern, the lack of CD5 expression, and the erroneously negative cyclin D1 study, this diagnosis was considered, leading to the initial decision to monitor without treatment.

Cellular proliferations of mantle cell lymphoma typically are most evident in the perifollicular area surrounding residual germinal centers in the mantle zone pattern or may diffusely efface the lymph node architecture. Cells of a typical infiltrate are small to intermediate-sized with angulated nuclear contours, inconspicuous nucleoli, and scant cytoplasm. Epithelioid histiocytes and hyalinized blood vessels are commonly seen. Cytogenetically, nearly all mantle cell lymphomas harbor the t(11;14) translocation.⁵  Immunophenotypically, cells are usually CD5 positive and nearly all cases are positive for cyclin D1 overexpression⁶ ; however, immunophenotypic variants are not uncommon in mantle cell lymphomas.⁷  Occasional atypical cases of mantle cell lymphoma may be CD10 positive (8%), CD5 negative (12%), CD23 positive (21%), and/or rarely negative for cyclin D1 expression,^8,9  but there appears to be no definite correlation between immunophenotypic variation and mantle cell lymphoma morphologic variants.⁷  The cyclin D1–negative cases are usually positive for cyclin D2 or cyclin D3, which are occasionally expressed in other B-cell lymphomas, limiting the diagnostic usefulness of these studies.¹  Gene expression profiling of these atypical cases has established their identity as mantle cell lymphoma¹⁰  and uncovered interesting genes potentially involved in mantle cell pathogenesis, including the neuronal transcriptional regulator SOX11, which may act as a tumor suppressor when aberrantly expressed in mantle cell lymphoma.^10,11  Mantle cell lymphomas, including those negative for cyclin D1, are positive for SOX11 in 78% to 93% of cases, whereas SOX11 is uniformly negative in chronic lymphocytic leukemia/small lymphocytic lymphoma.

Cells comprising blastoid mantle cell lymphoma tend to look immature with more dispersed chromatin. Typically these cells have a higher mitotic rate and a high proliferative fraction using Ki-67 immunohistochemical staining. This variant has a poor prognosis.¹²  The pleomorphic variant of mantle cell lymphoma is composed of numerous large cells with irregular nuclear contours and prominent nucleoli, as was seen in the spleen. The morphologic appearance is similar to that of diffuse large B-cell lymphoma. Pleomorphic mantle cell lymphoma also represents an aggressive form of the disease. In addition to the more clinically aggressive course, these variants are frequently correlated with more complex cytogenetic findings.¹³  SOX11 has been found to be variably expressed in the blastoid variants of mantle cell lymphoma.^14,15  Very few pleomorphic variants have been studied; thus, the negative result in the current case is of interest.

The typical clinical course of mantle cell lymphoma is aggressive. Patients often present with widespread disease and usually survive fewer than 5 years after diagnosis with chemotherapy.¹  However, cases have recently been described, including the above-described case, with an indolent clinical course,¹⁶  many having come to light because of initial misclassification. CD5 expression is variable in indolent cases and CD23 is more often positive. Interestingly, in contrast to typical mantle cell lymphoma, which shows a predominance of λ light-chain restriction, κ light chain is more often expressed by indolent mantle cell lymphomas.¹⁶  Importantly, whereas typical mantle cell lymphoma cells usually express SOX11 protein, cells of indolent mantle cell lymphomas may lack expression of SOX11, suggesting that this marker may be useful in predicting clinical behavior.¹⁶  However, a recent study showed that many indolent mantle cell lymphomas express SOX11; therefore, a positive result does not rule out indolent disease.¹⁷  Clinically, indolent cases have been shown to have leukemic involvement and splenomegaly and, in contrast to our patient, typically lack prominent lymphadenopathy.¹⁰  Patients with indolent mantle cell lymphoma show much longer survival even when left untreated. Although further investigation is warranted, it is possible that such cases represent a diagnostic entity distinct from the typical mantle cell lymphoma. Our case is very unusual as it initially presented with an indolent course and then progressed to a more aggressive morphologic variant.

Typical mantle cell lymphoma is an aggressive disease originating from peripheral B lymphocytes of the inner mantle zone of secondary follicles possessing the canonical t(11;14) translocation of CCDN1 and IGH genes. This results in cyclin D1 overexpression. The morphologic types of mantle cell lymphoma, including blastoid variants, are characterized by a high mitotic rate with cells resembling myeloid or lymphoid blasts. Pleomorphic variants are characterized by cellular heterogeneity with numerous larger cells with irregular nuclear contours. Atypical cases include those with CD5-negative immunophenotypes or alternate cyclin D2/D3 overexpression. Finally, although the usual course of mantle cell lymphoma is aggressive, indolent cases of have come to light, including the case described here. These cases of indolent mantle cell lymphoma frequently lack CD5 and SOX11 expression, which may or may not prove to be useful diagnostic predictors of clinical behavior. Further study is needed to determine the clinical course of indolent mantle cell lymphoma and determine the frequency of transformation to a more aggressive disease.

We would like to acknowledge Mihaela Sipa, MD, for her work on this case.