—  SPECIALTY CONFERENCE  —

Cytopathology

Case 1 - CLL/SLL with Hodgkin's Transformation

Nour Sneige
University of Texas
M.D. Anderson Cancer Center
Houston, TX





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Clinical History:
A 73-year-old man underwent FNA of a 4-cm right cervical node. Two months previously, he was diagnosed as having melanoma of the left cheek with a parotid sentinel lymph node positive for a microscopic metastatic melanoma and concurrent right-sided cervical chronic lymphocytic lymphoma. Bilateral bone marrow biopsy findings confirmed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The patient also had a history of prostate cancer, for which he had undergone radiation therapy.


Case 1 - Figure 1
Diff-Quik, low power
Case 1 - Figure 2
Diff-Quik, high power

Case 1 - Figure 3
Papanicolaou stain, high power
Case 1 - Figure 4
Papanicolaou stain, high power


Cytologic Findings:
The FNA smears demonstrated many eosinophils and Reed-Sternberg-like cells dispersed in a background that consisted primarily of mature-appearing small lymphocytes. No metastatic melanoma was identified.

Flow cytometry demonstrated a B-cell population expressing CD5 (dim), CD19, CD20 (dim), CD23, and CD38 (dim) with k light chain restriction, consistent with the patient's history of CLL/SLL.

In situ hybridization, performed on a cell block section with appropriate controls, showed the large atypical cells to be positive for Epstein-Barr virus (EBV)–encoded RNA (EBER). A diagnosis of Hodgkin's transformation of CLL/SLL was favored.

Histologic and Clinical Follow-up:
Surgical excision of the cervical node revealed classic Hodgkin's disease associated with CLL/SLL (composite lymphoma). The patient had CLL/SLL involving bone marrow; thus, the Hodgkin's disease component could be interpreted as the Hodgkin's variant of Richter's syndrome.

The patient was treated for Hodgkin's disease with six cycles of R-ABVD chemotherapy, and all of the enlargement in his lymph nodes seemed to resolve.

Discussion:
CLL/SLL is rarely complicated by the development of neoplasms that morphologically and immunophenotypically resemble Hodgkin's lymphoma. Although the term "Hodgkin's variant of Richter's transformation" has been used, the term "Hodgkin's transformation of CLL/SLL" describes this disease more accurately. The large cells of Hodgkin's transformation of CLL/SLL are characterized by the morphologic and immunophenotypic features of Hodgkin's and Reed-Sternberg (H-RS) cells of typical Hodgkin's lymphoma and express CD15 and CD30. In vitro studies have shown that these cells are derived from mature B cells that undergo transformation, and this transformation is accompanied by a change in the cellular milieu, with numerous T cells and histiocytes, a cellular background that is typical of Hodgkin's lymphoma.

Two types of Hodgkin's transformation of CLL/SLL have been described. Type 1 transformation is characterized by H-RS cells scattered in a background of CLL cells. In type 2 transformation, H-RS cells are present in a typical polymorphous inflammatory background, separate from the CLL cells. Histologic and immunophenotypic findings suggest that H-RS cells in patients with type 1 transformation represent a histologic progression of the underlying CLL cells, especially when the H-RS cells express B-cell markers. In type 2 transformation, although two different disease types are considered to be present, the two lesions may be related. A clonal relationship between CLL and H-RS cells was demonstrated in three of four patients who had Hodgkin's transformation of CLL/SLL by using single-cell PCR analysis and DNA sequencing.

Although Hodgkin's lymphoma has been reported to be one of the most common secondary cancers in patients with CLL/SLL, it was observed in our series and in other studies that other cancers, such as basal cell or squamous cell skin carcinoma, breast cancer, prostate cancer, and large cell lymphoma, occur more frequently. Among 4,121 patients with CLL/SLL (in the M. D. Anderson Cancer Center series), 18 (0.4%) developed Hodgkin's transformation.

EBV plays an important role in the pathogenesis of Hodgkin's transformation of CLL/SLL. In a previous study, in situ hybridization showed that 12 of 13 patients with CLL/SLL and possible Hodgkin's transformation of CLL/SLL tested positive for EBER. EBV DNA was detected by PCR analysis of lymph nodes from two patients with the Hodgkin's variant of CLL. In another study, ABV latent membrane protein (LMP-1) was identified in four patients in whom there was an absence of expression of the EBV lytic cycle switch protein ZEBRA, suggesting that the EBV genome is integrated in the absence of active viral replication in these patients.

The outcome of patients with de novo Hodgkin's lymphoma is generally favorable. With the use of combined-modality treatment and multiagent chemotherapy, ≥80% of patients with de novo Hodgkin's lymphoma and ≥90% of patients with limited-stage Hodgkin's lymphoma (stage 1A or 2A) can be cured. In a meta-analysis, the clinical outcomes of patients with Hodgkin's transformation of CLL/SLL were inferior to the outcomes of patients with de novo Hodgkin's lymphoma but were superior to the outcomes of patients with Richter's syndrome. Only 34%–47% of patients with Richter's syndrome respond to multiagent chemotherapy, and the median overall survival of these patients was only 8 months in the M. D. Anderson series.

References:
  1. Tsimberidou A-M, Keating MJ. Richter syndrome. Cancer 2005;103:216-28.

  2. Tsimberidou A-M, O'Brien S, Kantarjian HM, Koller C, Hagemeister FB, Fayad L, Lerner S, Bueso-Ramos CE, Keating MJ. Hodgkin transformation of chronic lymphocytic leukemia. Cancer 2006;107:1294-302.