Aggressive Cyclin D1 Negative Blastoid Variant Mantle Cell Lymphoma—A Case Report

Introduction

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm, representing <10% of all non-Hodgkin lymphoma subtypes. ¹ This tumor has an unpredictable behavior that ranges from indolent to a very aggressive clinical course.

Approximately 90% of MCL exhibit the classical morphology of vague nodular or diffuse proliferation of monotonous small to intermediate lymphoid cells with nuclei showing irregular membranes, having dark clumpy chromatin, inconspicuous nucleoli, and scant cytoplasm. However, 10% are variants that include small cell variants, monocytoid-like variants, and the aggressive ones such as pleomorphic variants, blastoid variants, and the challenging cyclin D1-negative MCL.

The current World Health Organization guidelines for the diagnosis of MCL rely on morphologic examination and immunophenotyping with a demonstration of cyclin D1 protein overexpression and/or the t(11;14) (q13;q32) for confirmation.

MCL is characterized by the specific translocation t(11;14) (q13;q32) (that juxtaposes cyclin D1 gene [CCND1] gene to the immunoglobulin heavy locus [IGH] gene) leading to overexpression of cyclin D1. ² This translocation is thought to represent the primary genetic event. ³ However, ∼10% of MCL lack this specific translocation and do not express cyclin D1. These cases are referred to as “cyclin D1 negative MCL.”

SOX11, a neural transcription factor is expressed in 93% to 95% cases of MCL, its expression is independent of cyclin D1 expression and CCND1 translocation. Hence, it becomes a very useful marker for the identification of cyclin D1 negative MCL.

Case Report

A 68-year-old male presented with penile swelling and abdominal pain of 3 to 4 months duration.

Position emission tomography scan showed extensive lymphadenopathy involving bilateral neck nodes, mediastinal nodes, hilar nodes, axillary and retroperitoneal nodes with metabolically active masses in both lungs, right atrium, greater curvature of stomach, pancreas, and soft tissue thickening in the penis.

An excision biopsy of the right axillary lymph node was performed and it was sent for histopathological evaluation.

A microscopic examination revealed total effacement of lymph node architecture and replacement by diffuse proliferation of intermediate-sized cells having round nuclei, finely dispersed chromatin, and small indistinct nucleoli. A high mitotic count of 25 to 30 per 10 high power fields was recorded (Figure 1).

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Figure 1.

(a) Hematoxylin and eosin (H&E) 4×, lymph node tissue showing diffusely proliferating atypical lymphoid cells. (b) H&E 10×, infiltration into the perinodal adipose tissue. (c) H&E 40×, intermediate-sized cells having finely dispersed chromatin and small indistinct nucleoli. A high mitotic count of 25 to 30 per 10 high power fields was recorded. (d) H&E 100×, showing blastoid morphology of tumor cells.

Considering the cell morphology and high-grade nature of this tumor, a broad panel of immunohistochemical (IHC) was performed, which included CD20, CD3, CD10, B-cell lymphoma 2 (Bcl2), B-cell lymphoma 6 (Bcl6), terminal deoxynucleotidyl transferase (TdT), and Ki67 along with CD5 and cyclin D1.

The tumor cells expressed CD20, CD5, CD10, Bcl2, and Bcl6. They were negative for CD3, cyclin D1, and TdT. The MIB1 proliferation index was 95% (Figure 2).

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Figure 2.

(a) CD20 expression in atypical lymphoid cells. (b) CD5 expression in atypical lymphoid cells. (c) Cyclin D1 is negative in atypical lymphoid cells. (d) CD10 expression in atypical lymphoid cells. (e) Bcl6 expression in atypical lymphoid cells. (f) Bcl2 expression in atypical lymphoid cells. (g) SOX11 expression in atypical lymphoid cells. (h) Ki67 expression in atypical lymphoid cells (95%). (i) FISH with a dual fusion IGH/CCND1 probe showed no evidence of IGH/CCND1: t(11;14). (j) CMYC expression is seen in 30-40% of all atypical lymphoid cells. (k) P53 is negative in atypical lymphoid cells.

Looking at CD5 positivity, SOX11 was done later, which proved to be positive (Figure 2).

Based on histomorphology along with the expression of CD5 and SOX11 and cyclin D1 negativity, this tumor was diagnosed as aggressive cyclin D1-negative blastoid variant of MCL.

Fluorescence in situ hybridization (FISH) analysis was performed by using an Abbott Mol LSI IGH/CCND1 Dual fusion probe and showed no evidence of IGH/CCND1: t(11;14) thereby, confirming our diagnosis of aggressive cyclin D1-negative blastoid variant of MCL (Figure 2).

In view of the high clinical stage and blastoid morphology, P53 and CMYC IHC stains were performed. The tumor was negative for P53 and CMYC expression was seen in around 30% to 40% of the cells (Figure 2).

However, MYC gene rearrangement and P53 mutation studies were not performed because of the nonavailability of the tissue.

The patient was started on a standard R-CHOP chemotherapy regime, however, he did not respond after 4 cycles of therapy and was categorized as R-CHOP refractory lymphoma. He was then started on lenalidomide and showed partial response after 1 month. Unfortunately, the patient succumbed to his disease a year and a half later.

Discussion

The term “MCL” reflects the fact that most of these tumors arise from the mantle zone of a secondary lymphoid follicle.

MCL represents just 3% to 10% of all non-Hodgkin lymphomas. ³ It is mainly seen in adults with a median age of 60 years. Men are affected more frequently than women. Most of the patients present with the late-stage disease with extensive lymphadenopathy and organ involvement.

Clinically, this tumor has an unpredictable behavior that ranges from indolent to a very aggressive course having frequent relapses and a shorter median survival. Bernard et al, ¹ in their study of 154 MCL, highlighted the median survival of 2 to 3 years with a complete response rate in <30% patients.

Immunohistochemically, classical MCL expresses B cell markers, namely, CD20, CD19, paired box 5, and CD79a. The expression of CD5, cyclin D1, and SOX11 is considered to be diagnostic of MCL in the majority of cases. However, a subset of cases may lack expression of either CD5 or cyclin D1. Other markers such as CD10, CD23, and Bcl6 are also mostly negative in some classical cases.

SOX11 is a neural transcription factor, normally expressed in an embryonic central nervous system. The expression of SOX11 is very specific in MCL because its expression is independent of cyclin D1 expression and CCND1 translocation. ²

Narurkar et al ⁴ identified SOX11 expression in 93% cases of MCL and in 100% cases of cyclin D1 negative MCL, highlighting the sensitivity and importance of SOX11 in MCL, especially in cyclin D1 negative cases. High specificity implies that other lymphomas in the differential diagnosis of MCL (eg, chronic lymphocytic leukemia, marginal zone lymphoma, diffuse large B cell lymphoma, etc) generally and consistently test negative for SOX11. However, exceptions to this are certain lymphomas such as B and T lymphoblastic leukemia/lymphoma and Burkitt's lymphoma. SOX11 is also expressed in certain nonhematolymphoid tumors such as ovarian carcinoma, medulloblastoma, and malignant glioma. ²

Most of the MCLs are of classical types, however, there are several variants described in the literature. These include monocytoid-like MCL, MCL with plasmacytic differentiation, small cell variant, etc.

The aggressive variants are discussed below:

Blastoid variant. This is a rare, very aggressive variant of MCL with an extremely poor prognosis. It accounts for 10% to 20% of all MCLs. ⁵ Histologically the cells are medium sized with round nuclei, finely dispersed chromatin, and small indistinct nucleoli, resembling a lymphoblast. A mitotic rate is high with more than 20 to 30 mitoses per 10 high power field. ⁵

Most of these cases have classic MCL IHC expressions (CD5 and cyclin D1). However, in some cases, there can be loss of CD5 as well cyclin D1, instead, they express CD10 and Bcl6 and are easily misdiagnosed as Blastic lymphoma/Burkitt lymphoma or as high-grade B-cell lymphoma, not otherwise specified type. SOX11 is the most important IHC marker in diagnosing such cases.

Cyclin D1-negative MCL. This particular subset is rare and is characterized by lack of cyclin D1 expression and/or the t(11;14)(q13;q32)/IGH–CCND1 rearrangement.

The pathogenetic mechanism involved in development of cyclin D1-negative MCL is currently unknown.

Fu et al ⁶ studied cyclins D1, D2, and D3, which are involved in cell cycle control especially in the G1 to S phase transition. In his study, overexpression of either cyclin D2 or D3 was seen in all 6 cases of cyclin D1-negative MCL, indicating the important substitute role of these cyclins (cyclin D2 and cyclin D3) in this subtype. However, the study was not able to identify the mechanism for upregulation of cyclin D2 or D3 in these cases, and also there was no chromosomal translocation or gene amplification involving cyclin D2 or D3 gene loci by FISH analysis, suggesting an epigenetic mechanism involved in deregulation of cyclin D2 or D3. ⁶

Fratoni ⁵ in his article on unusual variants of MCL mentioned that more than half of the cyclin D1 negative MCL carried CCND2 rearrangements with immunoglobulin genes. These cases had high levels of cyclin D2 messenger RNA detected by reverse transcription-polymerase chain reaction. ⁵

The routine use of IHC detection for cyclin D2 or D3 is not practical as they are frequently expressed in other small B-cell lymphomas.

MYC gene rearrangement in MCL is very rare and is associated with disease progression and poor prognosis. Similar to MYC, additional genetic errors and TP53 mutations likely induce the cells to a high proliferation state. ⁷ Unfortunately, we were not able to perform these mutation studies to look for the association.

To conclude, the present case report highlights the salient features and diagnostic approach to this rare variant of MCL.

A blastoid variant of MCL should be kept as a differential diagnosis in all the high-grade non-Hodgkin lymphoma having small to intermediate cell morphology. CD5 and cyclin D1 should always be included in the IHC panel of such cases.

SOX11 expression being independent of cyclin D1 should be performed in cases with CD5+ and cyclin D1 negative cases for the diagnosis.