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Teaching Case 10Clinical Summary52 year old man who was diagnosed four years ago with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, Rai II, Binet B). He was treated with Fludarabine and Cyclophosphamide with partial response and reportedly did well until approximately six months prior to presentation, when his general condition deteriorated. His subsequent course was characterized by ongoing weight loss and fatigue. In the 6 weeks prior to presentation, a persistent fever was noted. On exam, he had enlarging lymph nodes and hepatomegaly, as well as an elevated LDH. He had no significant clinical response to standard treatment. Transformation of his low-grade lymphoma (i.e. Richter's syndrome) was suspected. An enlarged 3 x 3 cm inguinal lymph node was excised. A bone marrow biopsy performed at the time of his inguinal lymph node biopsy showed involvement by CLL/SLL. Summary of Histologic ExaminationThe lymph node is largely effaced by an atypical lymphoid proliferation, which is remarkable for two distinct components which are often intermixed. The first component is comprised of small-medium sized atypical lymphoid cells, which are monotonous and on high power, have somewhat round nuclei with coarsely clumped chromatin. Growth centers are not prominent. The second component includes scattered large atypical lymphoid cells with classical Reed-Sternberg (RS) and RS variant morphology, often in a slightly depleted background, containing scattered small lymphocytes, histiocytes, and eosinophils. Focal areas of necrosis are also noted and in areas, the RS cells begin to sheet out. Interestingly, there are areas of transition between these two components in which RS variants can be seen scattered amongst neoplastic CLL/SLL cells. In some of these transitional areas, the RS variant cells became quite numerous and began to sheet out. H&E Images
Results of Immunohistochemistry StudiesImmunohistochemical Findings of CLL/SLL ComponentThese atypical CLL/SLL cells are dim CD20+ and coexpress CD43, CD5, focal CD23 but not CD30, CD15, cyclin D1 or p53.
Immunohistochemical Findings of Classical Hodgkin's ComponentThe RS cells are CD30+ and coexpress variable CD15, CD20, but not CD5, CD43, or cyclin D1. p53 is overexpressed in the RS cell (>10% positive). The vast majority of the RS cells are EBER-1+ by in situ hybridization. Overall, the proliferative rate as measured by MIB-1 immunoreactivity is low in the CLL/SLL component and roughly 70-80% in the Hodgkin's component, often highlighting RS cells.
Summary of Immunohistochemical Findings:
Final DiagnosisHodgkin's Transformation of CLL/SLL DiscussionThe present findings are diagnostic of malignant lymphoma. In the light of the patient's clinical history of CLL/SLL and treatment with Fludarabine, a chemotherapeutic agent that often results in prolonged severe T-cell immunosuppression, and the morphologic and immunophenotypic findings which clearly demonstrate two distinct components, this lymphoproliferative process likely represent Hodgkin's transformation of CLL/SLL. Another diagnostic consideration is a collision lymphoma (i.e. de novo classical Hodgkin's lymphoma arising in a patient with CLL/SLL), which is difficult to entirely exclude without additional microdissection studies to confirm the clonal relatedness of these two phenotypically distinct components. Overall, this possibility was not favored. Large cell transformation has been documented in many low-grade B-cell lymphomas, occurring in up to 5% of CLL/SLL, 20-30% of marginal zone B-cell lymphoma (MZBCL) and up to 30% of follicular lymphoma (FL).1-3 In these lymphomas, the high-grade large cell component is typically a diffuse large cell lymphoma and often associated with clinical acceleration of disease and shortened overall survival. In many of these cases, the large cell component can be demonstrated to be clonally related to the underlying low-grade lymphoma, a process thought to represent 'blastic transformation' of the underlying low-grade component. 2,4-9 Recent description of RS-like cells in B-NHLs has drawn attention to the association between classical HL and non-Hodgkin's lymphomas.10-13 This phenomenon has been well documented in CLL/SLL where rare cases show a high-grade component that resembles classical HL.10,12-14 The transformed cells in these cases resemble RS cells morphologically and typically express a classical RS immunophenotype: CD30+, CD15+, CD45-, and CD20+/-. Expression of EBV in many of these cases suggests that EBV infection likely plays a role in the transformation process.12,14 Furthermore, using microdissection techniques, the RS cells have been demonstrated to be clonally related to the low-grade CLL/SLL component.15 Similar to CLL/SLL, Hodgkin-like transformation has also been reported in other lymphomas, including MZBCLs and in this case, have been recently demonstrated to be clonally related to the underlying low grade component.11,16 Clinically, Hodgkin's transformation of CLL/SLL often portends a poor overall prognosis, which is worse than that seen in de novo classical HL, but better than that typically seen in patient with classical Richter's transformation.10,17-19 At presentation, CLL/SLL patients showing Hodgkin's tranformation, typically present with systemic symptoms (60%), lymphadenopathy (50-75%), splenomegaly (10-20%) and autoimmune hemolytic anemia (10%). Since EBV has been demonstrated to play a role in Hodgkin's transformation of CLL/SLL, it is likely that the use of chemotherapeutic drugs, such as Fludarabine, which result in prolonged T-cell suppression may permit opportunistic reactivation of EBV and subsequent infection of neoplastic CLL/SLL cells, ultimately resulting in Hodgkin's transformation. References
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