—  SPECIALTY CONFERENCE  —

Cytopathology

Case 3 - Mantle Cell Lymphoma

Ann T. Moriarty
Ameripath Indiana
Indianapolis, Indiana


Click on each slide thumbnail image for an enlarged view
Clinical History:
A 73-year-old woman was noted at the time of cardiac catheterization to have bilateral inguinal adenopathy. The adenopathy had been present for several months. The patient denied symptoms of fever or night sweats, but had reported a 15 lb. weight loss over the past several months. A fine needle biopsy was performed of the left 4 x 3 x 3 cm inguinal lymph node. (Images 3A-3C)


Figure 3A - Highly cellular smear demonstrating a small sized lymphocytic population. There are "lymphoglandular bodies" in the background, and the lymphocyte nuclei are smaller than the nucleus of the histiocyte. The population is relatively monotonous. There is only mild variation in cell size. (Romanowsky stain, medium magnification)
Figure 3B - Details of the small lymphocytic population. There is coarse chromatin and nuclear irregularity. Nucleoli are inconspicuous. Although the chromatin is coarse, it is not "clumped" as in the nucleus of the small central lymphocyte. (Romanowsky stain, high power)
Figure 3C - The Papanicolaou stained preparation emphasized the monotony of cell size. The cells appear smaller in the alcohol fixed preparations; the nuclei are smaller than the histiocyte nuclei. The chromatin is course and the nuclear irregularities are not as obvious. (Papanicolaou stain, high magnification.)

Cytologic findings:
There is a monotonous population of small lymphocytes characterized by cells with nuclei smaller than the nuclei of histiocytes (Image 3A). The chromatin is coarse, but is not "clotted" or coarsely clumped. (Image 3B, 3C).

Discussion: Mantle Cell Lymphoma.
The single cell population and the monotony of the lymphocyte population should suggest lymphoma. The differential diagnosis of this lymph node aspirate includes lymphomas characterized by "small sized" lymphocytes. The morphologic differential diagnosis includes small lymphocytic lymphoma, mantle cell lymphoma, nodal marginal zone lymphoma, lymphoplasmacytic lymphoma and follicular lymphoma, cytologic grade I.

Flow cytometric analysis was performed on the needle rinses. Using forward scatter versus side scatter, and CD45 (LCA) versus side scatter, a population of cells was identified that were homogeneous in size and brightly expressed CD45. This population corresponds to the small cells that were seen cytologically. Gating upon this population of cells, the cells brightly expressed both CD19 and CD5. They were negative for the antigen CD23, and there was bright lambda light chain intensity and CD 20 intensity. CD10 was absent and kappa fluorescence was negative.

Flow Cytometric Findings:

Differential Diagnosis:
Small cells with coarse, clumped chromatin characterize the peripheral B cell lymphoma, small lymphocytic lymphoma. This pattern of chromatin clumping has been described by French investigators as "cellules grumlées" or clotted chromatin.1 The cells of small lymphocytic lymphoma are the same cells involved in chronic lymphocytic leukemia. They usually co-express the B cell antigen CD19 and

Differential Diagnosis:
Small cells with coarse, clumped chromatin characterize the peripheral B cell lymphoma, small lymphocytic lymphoma. This pattern of chromatin clumping has been described by French investigators as "cellules grumlées" or clotted chromatin.1 The cells of small lymphocytic lymphoma are the same cells involved in chronic lymphocytic leukemia. They usually co-express the B cell antigen CD19 and CD5 (which usually marks T cells). The cells typically express CD20 weakly, and have dim light chain fluorescent intensity. Additionally, CD23 is usually found on the surfaces of small lymphocytic lymphoma.2

Marginal zone lymphoma is another "small size" lymphoma. The cells may have a variable appearance, ranging in size from "small cleaved' type cells to monocytoid cells with more abundant cytoplasm. Marginal zone lymphoma will express CD19, does not express CD5 or CD10 and is usually negative for CD23. Light chain expression is usually strongly positive.3

Follicular lymphoma, grade I (previously, nodular lymphoma, small cleaved cell) demonstrates small cells with slightly more variable nuclear size and shape. The chromatin is less coarse than small lymphocytic lymphoma.4 Slightly more cytoplasm is seen in air-dried smears than Papanicolaou stained preparations. Immunologically, Follicular lymphoma, grade I is characterized by bright CD19 and CD20. CD10 is usually positive, and there is usually intense light chain fluorescence. Cells do not stain for CD5 in follicular lymphomas. BCL-2 reactivity is usually seen in tissue sections, but is less frequently used on cytologic preparations.

Lymphoplasmacytic lymphomas are often associated with the syndrome of Waldenström's Macroglobulinemia. (Hyperviscosity, monoclonal serum IgM and a variety of hyperviscosity related symptoms.) The malignant cells are usually found in the bone marrow. The cells are small with eccentric cytoplasm and nuclear features which may closely resemble plasma cells. Immunologic findings are variable. While lymphoplasmacytic lymphomas usually express CD19, they do not express CD10 or CD5. They may have cytoplasmic immunoglobulin levels detectable by flow cytometric analysis or immunocytochemically.5

Summary of Immunophenotyping for small sized B cell lymphomas:
Lymphoma CD19 CD5 CD23 CD10 CD20 Light chain
Small Lymphocytic + + + - weak weak
Mantle Cell + + - - bright bright
Marginal Zone + - - - + +
Lymphoplasmacytic + - - - + cytoplasmic/surface
Follicular, Grade I + - +/- + bright bright

The immunologic differential diagnosis for a monoclonal B cell lymphoma with coexpression of CD5 and CD19 includes the entities small lymphocytic lymphoma and mantle cell lymphoma. The absence of CD23, the bright intensity of CD20 and light chain expression favor mantle cell lymphoma in this case. The delicate chromatin pattern and monotony of the population, without the "clotted" chromatin of small lymphocytic lymphoma allows proper classification of this lymphoma.

Mantle cell lymphoma is a mature B cell neoplasm that arises from the normal counterpart of B cells that rim the germinal centers.6 Originally, mantle cell lymphomas were named "intermediate lymphocytic lymphoma" and "lymphocytic lymphoma of intermediate differentiation " describing their morphologic features as intermediate between small lymphocytic lymphoma and small cleaved lymphocytic lymphoma. Mantle cell lymphoma is rare and accounts for approximately 6% of all lymphomas. Mantle cell lymphoma occurs in older patients, with a male predominance. It usually presents with widespread lymphadenopathy, is associated with splenomegaly, bone marrow involvement and, like small lymphocytic lymphoma, may have a leukemic pattern. Mantle cell lymphoma is not a low grade lymphoma. Median survival is 3-5 years; therapy is more aggressive than the lymphomas in the morphologic differential. The characteristic immunophenotype and morphology has lent consistency to the diagnosis and allows accurate classification. As in this case, the malignant cells express both CD19 and CD5without CD23 expression. They express bright light chain fluorescent intensity as well as bright CD20 positivity. Mantle cell lymphoma also has a characteristic chromosomal translocation t(11;14) which results in the expression of Cyclin D1. Cyclin D1 can be detected by immunostain and used as a diagnostic aid.

References:

  1. Seidel TA, Garbes AS. Cellules grumelees: old terminology revisited. regarding the cytologic diagnosis of chronic lymphocytic leukemia and well-differentiated lymphocytic lymphoma in pleural effusions. Acta Cytol 1985;29:775-80.
  2. Kilo MN, Dorfman DM. The utility of flow cytometric immunophenotypeic analysis in the distinction of small lymphocytic lymphoma/chronic lymphocytic leukemia from mantle cell lymphoma. Am J Clin Pathol 1996;105:451-7.
  3. Isaacson PG, Nathwani BN, Piris MA, Berger F, Harris N, Müller-Hermelink HK, Swerdlow S. "Nodal marginal zone B-cell lymphoma." In Jaffe ES, Harris NL, Stein H, Vardiman JW (eds.) Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer (IARC) Press
  4. Lyon, 2001.
  5. Young NA, Al-Saleem T. Diagnosis of lymphoma by fine-needle aspiration cytology using the Revised European-American classification of lymphoid neoplasms. Cancer(Cytopathol) 1999;87:325-45.
  6. Tworek JA, Singleton TP, Schnitzer B, His ED, Ross CW. Flow cytometric and immunohistochemical analysis of small lymphocytic lymphoma, mantle cell lymphoma, and plasmacytoid small lymphocytic lymphoma. Am J Clin Pathol 1998
  7. 110:582-9.
  8. Swerdlow S, Berger F Isaacson PI, Müller-Hermelink HK, Nathwani BN, Piris MA, Harris NL. "Mantle cell lymphoma." In Jaffe ES, Harris NL, Stein H, Vardiman JW (eds.) Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer (IARC) Press; Lyon, 2001.