Clinical History
The patient was a 61-year-old male with generalized lymphadenopathy who was otherwise
asymptomatic. He underwent a right inguinal lymph node biopsy and subsequent staging evaluation. A bone
marrow core biopsy was positive for lymphoma and he was considered to have stage IV disease. He was
treated with CHOP chemotherapy and had a good clinical response, but eventually died of disease at 88
months after the diagnosis.
Case 3 - Figure 1 - Low power of lymph node showing a vaguely nodular pattern.
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Case 3 - Figure 2 - Medium power of lymph node showing a burnt-out germinal center that is surrounded and infiltrated by atypical lymphoid cells (mantle zone pattern).
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Case 3 - Figure 3 - Atypical lymphoid cells with irregular nuclei and scant cytoplasm, with a few histiocytes admixed.
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Histologic Findings
The lymph node architecture is effaced, and the pericapsular tissues are infiltrated by
atypical small lymphoid cells with irregular nuclei, moderately-coarse chromatin, inconspicuous nucleoli,
and scant cytoplasm. The growth pattern is vaguely nodular at low power, and scattered atrophic and
hyalinized germinal centers are surrounded by concentric mantles of atypical small lymphoid cells. The
interfollicular areas are heavily infiltrated, and scattered benign histiocytes with pink cytoplasm
containing nuclear debris are scattered among the neoplastic lymphoid cells. The mitotic rate is low,
and transformed large cells and plasma cells are lacking. Immunostains revealed the following phenotype:
CD3-, CD5+, CD10-, CD20+, CD23-, CD43-, and cyclin D1-. FISH for the t(11;14)(q13;q32) was negative.
Differential Diagnosis
The differential diagnosis of a CD5+ small B-cell lymphoma includes mantle cell lymphoma
and small lymphocytic lymphoma (B-CLL), and rarely other subtypes.
Phenotypes of the various B-lymphocytic lymphomas
| Subtype | cIg | CD5 | CD10 | CD23 | CD43 | FDC | Cyclin D1 |
| Mantle cell lymphoma | - | + | - | - | + | + | + |
| Follicular lymphoma | - | - | + | +/- | - | + | - |
| Small lymphocytic lymphoma | -/+ | + | - | + | + | - | - |
| Nodal marginal zone lymphoma | -/+ | - | - | -/+ | - | - | - |
| Mucosa-associated lymphoma | -/+ | - | - | - | -/+ | - | - |
| Lymphoplasmacytic lymphoma | + | - | - | - | - | - | - |
| Splenic marginal zone lymphoma | -/+ | - | - | - | - | - | - |
Abbreviations:
| FDC | follicular dendritic cell network |
| CLL | chronic lymphocytic leukemia |
| + | > 80% positive |
| +/- | >50% positive |
| -/+ | <50% positive |
| - | <20% positive |
In this case, no pseudofollicular proliferation centers, prolymphocytes or
paraimmunoblasts are present, thus ruling out a diagnosis of small lymphocytic lymphoma (B-CLL).
Although the histologic features are typical for mantle cell lymphoma, the lack of staining for cyclin D1
and the absence of the t(11;14) make the diagnosis questionable. However, cDNA microarray analysis of
the gene expression profile of the tumor cells in this case revealed the distinctive gene expression
signature of mantle cell lymphoma, with lack of expression of cyclin D1 but with the expression of cyclin
D3. Subsequent immunostains revealed strong nuclear staining for cyclin D3 in the neoplastic cells.
Diagnosis
Nodular mantle cell lymphoma with a mantle-zone pattern, cyclin D1-, cyclin D3+.
Discussion
Mantle cell lymphoma (MCL) is a distinctive B-cell lymphoma with various growth patterns
(nodular, mantle-zone, diffuse) and a broad range of cytological features [1]. Most cases of MCL exhibit
a characteristic phenotype and have the t(11;14)(q13;q32) with overexpression of the involved CCND1
(cyclin D1) gene. The existence of cyclin D1-negative MCL has been controversial, with most cases
attributed to false negative cytogenetics, suboptimal immunostaining, or misdiagnosis. However, a recent
study [2] of MCL using cDNA microarray technology revealed that 6% of cases failed to express cyclin D1
mRNA, but still showed the characteristic gene expression signature of MCL. A followup study, presented
at this meeting [3], has confirmed the existence of cyclin D1-negative MCL as a bone fide entity. Such cases have the typical histologic features of MCL,
although some cases may have an aberrant phenotype (CD5-, CD43-). Immunstains for cyclin D1 are
negative, with positive internal control cells, and the t(11;14) is absent. However, the characteristic
gene expression signature of MCL is present in such cases. Immunostains for cyclin D2 or cyclin D3 are
positive in about 50% of the cases, indicating a substitutive role for these cyclins in MCL, whereas the
remainder of the cases have no characteristic molecular features as of yet. The clinical features and
survival of patients with cyclin D1-negative MCL are similar to those with cyclin D1-positive MCL.
The diagnosis of cyclin D1-negative MCL may be challenging for the practicing pathologist,
especially if the histologic features are atypical or the phenotype is aberrant. Immunostains for cyclin
D2 or cyclin D3 may be confirmatory, but a presumptive diagnosis can still be made if these stains are
negative or cannot be performed. In the near future, gene expression profiling will provide confirmation
of this diagnosis. In the meantime, pathologists should be aware of the range of histologic, phenotypic,
and genetic features in MCL, and recognize the existence of cyclin D1-negative MCL as a variant within
the spectrum of MCL.
References
- Weisenburger DD, Armitage JO. Mantle cell lymphoma- an entity comes of age. Blood 87:4483-94, 1996.
- Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 3:185-97, 2003.
- Fu K, Weisenburger DD, Greiner TC, et al. Cyclin D1-negative mantle cell lymphoma: a study of nine cases. United States and Canadian Academy of Pathology Meeting, 2004.
