Final Diagnosis -- Malignant Lymphoma


FINAL DIAGNOSIS:

Comment:
The morphology of the atypical lymphoid cells in the peripheral blood and bone marrow, together with the flow cytometric immunophenotypic, immunohistochemical and cytogenetic studies, support the diagnosis of a mantle cell lymphoma, pleomorphic variant. Although a number of lymphoid cells in the peripheral blood are small to intermediate in size, the marrow shows a greater number of larger, more pleomorphic lymphoid cells. The cytogenetic findings demonstrate a t (11;14) as well as near tetraploidy, both of which are associated with the blastoid as well as pleomorphic variants of mantle cell lymphoma.

DISCUSSION:

The morphologic, flow cytometric immunophenotypic studies and cytogenetic findings in this 72 year-old male are diagnostic of mantle cell lymphoma.

Clinical Features:
Mantle cell lymphoma (MCL) is a prefollicular B-cell lymphoma characterized by distinctive histopathologic, immunologic and cytogenetic features. Recent studies suggest that MCL comprises approximately 7% of all non-Hodgkin's lymphomas (NHL) and generally tends to have an aggressive clinical course with a reported median survival of only 3-4 years [1]. Males predominate and commonly present at a median age of 60-64 years with advanced (stage III/IV) disease. Generalized lymphadenopathy, hepatosplenomegaly and bone marrow involvement are commonly seen. The gastrointestinal tract and Waldeyer's ring are frequently involved. Mild anemia and, less commonly, thrombocytopenia are seen at presentation. Up to 40 % of the cases have a peripheral blood lymphocytosis of >4,000/mL [2].

Microscopic findings:
Cytology - MCL is usually composed of a predominantly monotonous population of atypical, small- to intermediate-sized lymphoid cells. The nuclei are irregular with indentations of the nuclear membrane, moderately coarse chromatin, inconspicuous nucleoli and scant cytoplasm. Some neoplastic cells display prominent nuclear clefts or grooves. Rarely, the predominant cell may show very little nuclear irregularity, or, at the other end of the spectrum, be markedly angulated, cleaved or even cerebriform. The tumor is not always composed of small- to medium-sized cells exclusively. The existence of a large-cell or blastic variant of MCL has been described in different series suggesting that in up to 20 % of cases of MCL, the predominant neoplastic cell is larger than usual, with dispersed chromatin and multiple small nucleoli [3,4]. The term pleomorphic variant has been ascribed to cases that demonstrate a mixture of small neoplastic cells and larger blastic cells. The blastic and pleomorphic variants tend to have a higher mitotic rate and a corresponding higher proliferative fraction, and are thought to represent histologic transformation to a more aggressive stage of disease [5,6].

Lymph Nodes -The lymph nodes show complete or partial architectural effacement by a monotonous, diffuse, vaguely nodular or mantle zone proliferation of neoplastic lymphoid cells. Prominent hyalinized vessels are commonly seen. Plasma cells are inconspicuous, and an important histologic feature is the absence of large transformed cells with vesicular nuclei and prominent nucleoli [7], although Norton et al did note the histologic transformation to blastic cytology upon re-biopsy in 17 % of their cases of MCL, and found blastic cytology in 70 % of their cases at autopsy [8].

Peripheral blood and bone marrow - The incidence of bone marrow involvement at the time of diagnosis varies widely for different types of NHL. The primary diagnosis of NHL is usually established outside of the bone marrow; bone marrow examination is often performed for staging purposes only. The peripheral blood and marrow aspirate smears generally reflect the lymphoid population present in the lymph nodes, although histologic discordance between the two has been noted in 15-40 % of cases, with a more aggressive subtype usually being found in the lymph node [7]. In MCL, the marrow is involved at diagnosis in approximately 65 % of cases [13]. An absolute lymphocyte count of greater than 4,000/mL is seen in 20-40% of cases and has been interpreted as a leukemic phase of the disease. Absolute peripheral blood lymphocytosis of > 20,000/mL, as seen in this patient, is unusual. The leukemic phase is an adverse prognostic factor, being associated with poor response to therapy and aggressive disease[2, 9]. The neoplastic cells in the blood and bone marrow of a given patient may be quite heterogeneous in appearance. The pattern of involvement in bone marrow sections is usually randomly focal or interstitial and in some cases paratrabecular or diffuse. A diagnosis of MCL is not made based on the examination of PB or BM alone because of lack of precise morphologic criteria for such a diagnosis. Supplementary immunophenotypic, cytogenetic and molecular studies can help resolve such cases.

Immunologic features:
MCLs are prefollicular monoclonal B-cell proliferations. The neoplastic cells correspond to normal na´ve B lymphocytes that home to and reside in primary lymphoid follicles and the mantle zones of secondary follicles. MCLs are usually CD5 +, CD10 -, CD23 -, CD43 +, often FMC7 + and express at least moderate amounts of IgM +/- IgD surface immunoglobulin. They also stain for a variety of pan-B-cell antigens (CD19, 20, 22 and 24) and HLA-DR antigen. MCL blastic variants are less likely to express sIgD, CD5 and CD43, and may express CD10 [2]. The phenotype is remarkably similar to chronic lymphocytic leukemia, except for bright sIg and CD20 staining and lack of CD23 expression in MCL. Although CD23 is generally negative in MCL, some anomalous cases have been reported in the literature.

Cytogenetic and molecular genetic features:
The chromosomal translocation t(11;14)(q13;q32), resulting in the rearrangement and over expression of the PRAD1/CCND1 gene, has been shown to be highly characteristic of MCL and is seen in the majority of cases [2,10,11]. This translocation does however occur infrequently in other types of NHL, chronic lymphocytic leukemia and multiple myeloma. The putative oncogene brought into proximity of the enhancer region of the Ig heavy chain gene and consequently deregulated by the translocation, has been identified as encoding the cyclin D1 protein. Cyclin D1 plays a key role in cell-cycle regulation by binding to and activating cyclin-dependent kinases, propelling cells through the G1 checkpoint into the S phase of the cell cycle.

Cyclin D1 is over expressed in nearly all cases of MCL, whereas it is expressed only rarely in other forms of hematopoietic malignancies. Immunohistochemical stains for cyclin D1 expression are commonly used to confirm a morphologic diagnosis of MCL. The break points in the bcl-1 (11q13) locus are not tightly clustered, although 30-40 % of MCL cases have breaks in the major translocation cluster (MTC) region. PCR assays have been designed to detect most of the breaks in the MTC region. Using multiple probes including those for a number of minor breakpoint regions, clonal rearrangements have been detected in up to 70 % of MCL cases [12]. Molecular assays may fail to detect the translocation if they occur at sites outside of those detected by the available probes. 'Fiber FISH' analysis is a more sensitive technique and should document almost all translocations.

Secondary chromosome aberrations reported in MCL include deletions in the long arm of chromosome 6, translocations or deletions involving various bands in 1p, and trisomies for chromosomes 3, 7 and 18. The most striking and consistent alteration is the detection of tetraploid chromosome clones, especially in association with the blastic and pleomorphic variants [6]. Unlike peripheral T-cell lymphomas, where polyploidization is a frequent finding, the finding of tetraploidizations in NHL of B-cell lineage is a rare phenomenon. Other secondary genotypic abnormalities include p53 gene mutations in more aggressive variants of MCL[5].

REFERENCES:

  1. Weisenburger, D.D.; Vose, J.M.; Greiner,T.C.; Lynch, J.C.; Chan, W.C.; Bierman, P.J.; Dave, B.J.; Sanger, W.G.; Armitage, J.O. Mantle cell lymphoma. A clinicopathologic study of 68 cases from the Nebraska Lymphoma Study Group. American Journal of Hematology. 64(3): 190-6, 2000.
  2. Weisenburger, D.D.; Armitage, J.O. Mantle cell lymphoma- an entity comes of age. Blood. 87(11): 4483-94, 1996
  3. Ott, G.; Kalla, J; Hanke, A; Muller, J.G.; Rosenwald, A; Katzenberger, T.; Kretschmar, R; Keipe, H; Ott, M .M.; Muller-Hermelink, H.K. The cytomorphological spectrum of mantle cell lymphoma is reflected by distinct biological features. Leukemia and Lymphoma, 32(1-2), 55-63, 1998.
  4. Lardelli, P; Bookman, M.A.; Sundeen, J.; Longo, D.L.; Jaffe, E.S. Lymphocytic lymphoma of intermediate differentiation. Morphologic and immunologic spectrum and clinical correlations. American Journal of Surgical Pathology. 14, 752, 1990.
  5. Zoldan, M.C. et al. Large-cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome. British Journal of Hematology, 93, 475-486, 1996.
  6. Ott, G.; Kalla, J; Ott, M .M.; Schryen, B.; Katzenberger, T.; Muller, J.G.; Muller- Hermelink, H.K. Blastoid variants of mantle cell lymphomas: Frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones. Blood, 89(4), 1421-1429, 1997.
  7. Swerdlow, S.H. et al. Lymph Nodes. In: Sternberg, S.S., ed. Diagnostic Surgical Pathology, Third Edition, Vol I, Lippincott Williams and Wilkins 1999
  8. Norton, A.J. et al. Mantle cell lymphoma; Natural history defined in a serially biopsied population over a 20-year period. Ann Oncol, 49, 1995.
  9. Vadlamudi, G. et al. Leukemic phase of mantle cell lymphoma, two case reports and review of literature. Arch Pathol Lab Med, 120,35-40, 1996.
  10. Swerdlow, S.H.; Zukerberg, L.R.; Yang, W.; Harris, N.L.; Williams, M.E. The morphologic spectrum of non-Hodgkin's lymphomas with BCL 1/Cyclin D1 gene rearrangements. American Journal of Surgical Pathology. 20(5): 627-640,1996.
  11. Swedlow, S.H. et al. Expression of cyclin D1 protein in centrocytic/mantle cell lymphomas with and without rearrangement of the bcl1/cyclin D1 gene. Human Pathology, 26(9), 999-1004, 1995.
  12. deBoer, C.J.; et al. Multiple breakpoints within the bcl-1 locus in B- cell lymphoma. Rearrangements of the cyclin D1 gene. Cancer Research, 53, 4148,1993.
  13. Weisenburger, D.D.; Duggen, M.J.; Perry, D.A.; Sanger, W.B., Armitage, J.O.Non-Hodgkin's lymphomas of mantle zone origin. Pathol Annu, 26, 138-158, 1991.

Contributed by Ashok Nambiar, MD, Ander Pindzola, MD and Lydia Contis, MD




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