Hematopathology Case 01
Final Diagnosis & Discussions:
FINAL DIAGNOSIS: Composite Follicular Lymphoma and Chronic Lymphocytic Lymphoma
DISCUSSION
Composite lymphoma is a rare occurrence that is characterized by presence of two non-Hodgkin lymphomas or in more rare instances of Hodgkin and non-Hodgkin lymphoma at the same anatomical site. Composite lymphoma in its true sense should be restricted to any two different types of lymphomas whether they are clonally related or not and should be used as descriptive nomenclature [4]. The pathogenesis behind composite lymphoma is poorly understood and varies depending upon the type of lymphoma involved. Several theories have been postulated including clonal selection, genomic instability or common precursor cell [5]. Common precursor cell theory or clonal evolution may explain composite lymphoma. Studies using morphology, flow cytometric, and molecular techniques have tried to investigate the clonal origin of the two components.
CLL/SLL is a neoplasm composed of monomorphic, clonal, small, round to slightly irregular B lymphocytes, admixed with prolymphocytes and paraimmunoblasts forming proliferation centers. In the lymph nodes, a pseudofollicular pattern of pale areas corresponding to proliferation centers containing larger cells in a dark background of small cells is seen. The CLL/SLL cells express dim surface IgM/IgD, CD5, CD19, CD20, CD22, CD23 and CD79a, with restricted light chains. CD10, FMC7 and cyclin D1 are generally negative. The most common cytogenetic abnormalities in CLL include del 13q14.3 and trisomy 12 in 50% and 20% patients respectively. Less common genetic abnormalities include deletions of 11 q22-23, 17p13 and 6q21. Follicular neoplasm is a neoplasm of germinal/follicle center B-cells with a predominant or partial follicular pattern. The lymph node architecture is effaced by closely-packed follicles with an attenuated or absent mantle zones. Tingible body macrophages are absent in the follicles. Follicular lymphomas stain with CD19, CD20, CD22, CD79a, BCL2, BCL6, CD10 and show surface light chain restriction. The cells stain negative for CD5, CD43, IRF4/MUM1, and other T-cell antigens. Staining for CD21/CD23 may be required to distinguish between large follicles and diffuse areas. The common cytogenetic abnormalities detected in follicular lymphoma include t(14;18)(q32;q21) and BCL2/IGH@ rearrangement; the former being the most common. Other less common abnormalities reported include +7, +18, BCL6 rearrangement, BCL6 5' mutations.
Cases of composite lymphoma comprised of CLL/SLL and FL have been described in the English language literature previously [8,12,13]. Molecular studies are not available from two other cases. The case described by Copur et al [12] was unusual as the patient developed Hodgkin disease after 5 years of follow-up and intermittent treatment of the composite lymphoma. Unfortunately, due to the lack of tissue due to multiple attempted FISH studies, we could not perform any other molecular studies.
Previous reports suggest that composite lymphoma has the similar prognosis as that of the more aggressive component. Linck et al [14] showed successful treatment of composite lymphoma comprising of Hodgkin disease (treated with chemotherapy) and follicular lymphoma (treated with rituximab). As CLL/SLL is an indolent disease, treatment is not necessary in early stage disease. Similarly, the follicular lymphoma in this case was low grade and required no treatment. However, a more aggressive component of composite lymphoma may co-exist such as Hodgkin lymphoma as described by Copur et al [12]. In addition progression to higher-grade follicular lymphoma, diffuse large cell lymphoma or Richter's transformation may develop in such case. Thus clinical follow-up with biopsy of new or progressive nodes is recommended in these cases for proper documentation of progression and initiation of appropriate therapy.
In summary, composite lymphomas can have histological overlap and can pose diagnostic dilemmas. Although, molecular/FISH analysis might require to delineate composite lymphoma, in our case an expanded panel of immunohistochemical stains including CD5, CD10, BCL-2, BCL-6, MIB1 and cyclin D1 was sufficient for this differentiation and to render a definitive diagnosis.
References
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- Fend F, Quintanilla-Martinez L, Kumar S, et al. Composite low grade B-cell lymphomas with two immunophenotypically distinct cell populations are true biclonal lymphomas. A molecular analysis using laser capture microdissection. Am J Pathol 1999;154(6):1857-66.
- Copur MS, Ledakis P, Novinski D, er al. An unusual case of composite lymphoma involving chronic lymphocytic leukemia follicular lymphoma and Hodgkin disease. Leuk Lymphoma 2004 May;45(5):071-6.
- Kang SJ, Schmack I, Wojno TH, Grossniklaus HE. Composite lymphoma of the orbit treated with rituximab.Ophthal Plast Reconstr Surg 2007;23(2):143-4.
- Linck D, Lentini G, Tiemann M, et al. Sequential application of chemotherapy and monoclonal CD20 antibody: successful treatment of advanced composite lymphoma. Leuk Lymphoma 2005;46:285-8.