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 Table of Contents  
Year : 2014  |  Volume : 5  |  Issue : 1  |  Page : 23-26

Richter syndrome: An unusual case of concurrent small lymphocytic lymphoma, Hodgkin lymphoma, and anaplastic plasmacytoma

Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA

Date of Web Publication2-May-2014

Correspondence Address:
Jingnan Xiao
660 S. Euclid Avenue, Campus Box 8118, St. Louis, MO 63110
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1658-5127.131822

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Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a mature B-cell neoplasm that usually follows an indolent course. In a subset of cases (2-7%), transformation to a higher grade lymphoma occurs (Richter syndrome (RS)). Herein, we report an unusual case of Richter transformation to a composite classical Hodgkin lymphoma (CHL) and anaplastic plasmacytoma in the same left axillary lymph node from a patient who was diagnosed with CLL/SLL seven years prior. The diagnosis of CHL was based on the presence of Reed-Sternberg (R-S) cells and mononuclear variants that showed CD30 and CD15 staining in a membranous and Golgi pattern, weak PAX-5 staining, and negativity for CD20 and CD45. The anaplastic plasmacytoma component comprised of CD138+, CD20 − malignant cells with lambda light chain restriction. Due to the absence of available tissue, clonality studies could not be performed. However, a single clonal origin was highly suggested, as the CLL/SLL component (CD5+, CD19+, CD20+, CD23+, and partial FMC-7+) also demonstrated lambda light chain restriction by flow cytometric analysis. In this article, we describe the clinical and pathological characteristics of this unique case and review the pertinent literature.

Keywords: Chronic lymphocytic leukemia, Hodgkins disease, plasma cells

How to cite this article:
Hussaini M O, Klein J, Xiao J, Kreisel F, Frater J, Hassan A. Richter syndrome: An unusual case of concurrent small lymphocytic lymphoma, Hodgkin lymphoma, and anaplastic plasmacytoma . J Appl Hematol 2014;5:23-6

How to cite this URL:
Hussaini M O, Klein J, Xiao J, Kreisel F, Frater J, Hassan A. Richter syndrome: An unusual case of concurrent small lymphocytic lymphoma, Hodgkin lymphoma, and anaplastic plasmacytoma . J Appl Hematol [serial online] 2014 [cited 2023 Mar 27];5:23-6. Available from: https://www.jahjournal.org/text.asp?2014/5/1/23/131822

  Introduction Top

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an indolent lymphoproliferative neoplasm of B-cell origin that can involve the peripheral blood, bone marrow, spleen, and lymph nodes. [1] It usually follows a prolonged course, but various immunophenotypic and genetic factors such as IgVH mutation status, ZAP-70 and CD38 expression, del 11q22-23, and del 17p are recognized as adverse prognostic factors and have shown increasing importance in the prognostication of patients with CLL. [2],[3] In a subset of cases, CLL/SLL progresses to a higher grade lymphoma, Richter syndrome (RS), which portends a significantly worse prognosis. Though the use of the term RS has expanded since its first description in 1928 to include various B-cell non-Hodgkin lymphomas (HL) and even acute leukemia, RS is typically used to refer to progression of CLL to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma, and less commonly classical HL (CHL). [4],[5] RS can be divided on molecular grounds into those cases in which the transformed lymphoma is clonally related to the original CLL clone (true RS) and those in which the two neoplasms are not clonally related. The cumulative risk for RS is over 10% after 10 years [6] and RS has an overall prevalence of 2-7% in CLL. [7]

When clinically suspected, guidelines require histologic evidence to establish the diagnosis of RS. [4],[8] The classic histology of RS is that of a DLBCL. Transformation to CHL is rare and when it does occur, the morphology and immunophenotype resemble those of de novo HL. Even rarer, however, is transformation to a composite and/or transformation to a lymphoma with plasmacytic differentiation. In 2000, O'Sullivan, et al., reported transformation of CLL treated for 3 years with single agent fludarabine to a composite prolymphocytoid lymphoma and HL. The clinical course was that of a pure prolymphocytoid transformation. [9] In 2010, Foo et al., reported co-occurrence of CHL and plasmablastic lymphoma in a patient with CLL treated with fludarabine. Immunoglobulin gene rearrangement studies and Epstein-Barr virus (EBV)-positivity in the plasmablastic lymphoma suggested an immunodeficiency-related neoplasm rather than a true RS. [10]

In this report, we describe the unique occurrence in a lymph node showing the presence of SLL/CLL, in addition to a concurrent HL and anaplastic plasmacytoma.

  Case report Top

The patient was a 57-year-old woman who initially presented in 2003 with palpable lymphadenopathy. Imaging revealed retroperitoneal, mediastinal, and axillary lymphadenopathy. Right axillary lymph node biopsy performed at an outside institution reported a CD5, CD19, CD20, CD23 positive, lambda light chain restricted low grade B-cell lymphoma consistent with SLL/CLL. She was treated with six cycles of CVP (cytoxan, vincristine, and prednisone) in 2004 with partial response followed by two cycles of rituximab. The patient was stable until 2009 when she developed progressive lymphadenopathy and shortness of breath on exertion. A CT scan revealed significant mediastinal lymphadenopathy, a left pleural effusion, and a pericardial effusion. The pleural effusion was drained and the fluid was sent for flow cytometric analysis, which was consistent with CLL/SLL. The patient was treated with bendamustine for six cycles without rituximab. In October of that year, a positron emission tomography (PET)/CT scan demonstrated mild residual activity and prominent upper neck, hilar, and mediastinal lymph nodes. She was observed without treatment until June 2010 when she complained of a cough without fevers, chills, or night sweats. She also reported a 40 pound weight loss over the previous year. ACT scan did not demonstrate clear evidence of progression. She later developed worsening of the cough and repeat imaging revealed a right pleural effusion and mediastinal lymphadenopathy. Left axillary lymphadenopathy was noted in October 2010. A biopsy of the axillary lymph node was performed at an outside institution. The material was sent to a second institution in consultation and a diagnosis of "high-grade B-cell neoplasm with extensive plasmacytoid differentiation in conjunction with CLL/SLL" was rendered. The patient was treated with R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone) in December 2010. A CT scan performed 3 months later after three cycles of R-CHOP, demonstrated a decrease in the size of the mediastinal lymphadenopathy. She then presented to our institution for consideration of transplant, and pathology material from her most recent lymph node biopsy was reviewed.

Additional immunohistochemistry was performed in-house according to previously reported protocols. [11] Briefly, the stains were performed on representative 4 μm sections cut from formalin-fixed, paraffin-embedded tissue blocks, using respective antibodies on a Ventana Benchmark LT automated immunostainer (Ventana Medical Systems, Tucson AZ, USA) according to standard protocols. Detection involved Ventana's ultraView Universal DAB Detection Kit that utilizes a cocktail of enzyme-labeled secondary antibodies that locate the bound primary antibody. The complex is then visualized with hydrogen peroxide substrate and a 3,3'-diaminobenzidine tetrahydrochloride (DAB) chromogen. No biotin was involved. Antigen retrieval, standard on the machine, utilized the Ventana CC1, ehtylenediaminetetraacetic acid (EDTA)-Tris, pH 8.0 solution.

  Results Top

Hematoxylin and eosin (H and E)-stained sections of the lymph node revealed complete effacement of normal nodal architecture by a diffuse infiltrate with variable morphology. The majority of the infiltrate had a low-power appearance of CLL/SLL with a pseudofollicular pattern [Figure 1]a. High power examination revealed singly scattered and focally clustered intermediate-sized cells with small central nucleoli consistent with paraimmunoblasts [Figure 1]b. Immunohistochemical stains show that both the paraimmunoblasts and the small mature lymphocytes were positive for pan-B-cell markers including CD79a, CD19, and CD20. In addition to the scattered paraimmunoblasts, there were scattered large pleomorphic cells with one to two large nuclei, prominent eosinophilic nucleoli, and abundant pink cytoplasm consistent with Reed-Sternberg (R-S) cells and mononuclear variants [Figure 2]a. Immunohistochemical staining demonstrated these cells to be positive for CD30 and CD15 in a Golgi and membranous pattern, weakly positive for PAX-5 and negative for CD20 and CD45 [Figure 2]b-d. An Epstein-Barr virus-encoded small RNA (EBER) in situ hybridization study was positive in rare, singly scattered cells most consistent with R-S cells and mononuclear variants (data not shown). Additionally, there were focal sheets of large atypical cells with pleomorphic nuclei, vesicular chromatin, one to multiple prominent nucleoli, abundant pink cytoplasm, and a plasmacytoid appearance including rare perinuclear hoffs [Figure 3]a. Few multinucleated cells as well as tingible body macrophages were present in these areas. A brisk mitotic rate was appreciated in these areas, but not in the areas of small lymphocytes mixed with R-S cells. The plasmacytoid cells stained positively for MUM-1 and CD138, were weakly positive for PAX-5, and were negative for CD79a, CD19 and CD20, and CD56 [Figure 3]b and c. Immunohistochemical stains for kappa and lambda light chains revealed lambda light chain restriction in the large plasmacytoid cells, but showed no significant staining in the remainder of the infiltrate [Figure 3]d. ALK-1, cyclin-D1, human herpesvirus 8 (HHV-8), and epithelial membrane antigen (EMA) were negative in all cells.
Figure 1: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) component. (a) Low power image showing classic CLL/SLL architecture in lymph node with diffuse effacement and lighter staining proliferation centers (hematoxylin and eosin (H and E), ×100). (b) High power image showing predominantly small lymphocytes and scattered larger nucleolated paraimmunoblasts (H and E, ×400)

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Figure 2: Classical Hodgkin lymphoma component. (a) High power image showing a Reed-Sternberg (R-S) cell and mononuclear variants (H and E, ×1000). (b) CD30 stain showing membranous and Golgi staining pattern in R-S cells (×1000). (c) CD15 stain showing membranous and Golgi staining pattern in R-S cells (H and E, ×1000). (d) CD20 stain is negative in R-S cell, but positive in surrounding background small lymphocytes (×1000)

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Figure 3: Anaplastic plasmacytoma component. (a) Marked pleomorphism and atypical in anaplastic (H and E, ×400). (b) CD20 is positive in the CLL/SLL component (upper right), but negative in the plasma cell component (lower left) (200 ×). (c) CD138 is positive in the anaplastic plasmacytoma component, but negative in the other small lymphocytes (×200). (d) Cytoplasmic lambda staining in plasma cell component (×400)

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Flow cytometric analysis performed at the referring institution revealed most of the analyzed cells to be small lymphocytes with 7% of events judged as large lymphocytes. Almost half of the small lymphocytes were T-cells with slightly decreased expression of CD3 and a normal CD4:CD8 ratio. Almost 60% of the total lymphocytes were lambda-restricted B-cells expressing CD5, CD19, CD20, CD23, and FMC-7 (partial). The lambda light chain expression was reported as moderate to bright in intensity. The large B-cells showed an identical immunophenotype to the small B-cells although demonstrating brighter CD20 and lambda light chain expression.

  Discussion Top

Richter's transformation is a term reserved for situations when CLL progresses to a higher grade lymphoma. A majority of transformations occur as a diffuse large B-cell lymphoma although rarely, transformation to HL does occur (<1% of CLL). [1],[4] The frequency of EBV positivity in cases of RS with Hodgkin-like features supports the theory that these, in many cases, may be unrelated secondary malignancies or secondary to chemotherapy. [12]

There are rare case reports of composite, high-grade lymphomas occurring in patients with CLL. In 2002, the co-occurrence of CLL/SLL, anaplastic large cell lymphoma (ALCL), and CHL was reported. The anaplastic lymphoma component was negative for ALK and CD20 suggesting a T/0 origin; however, molecular studies showed identical IgH gene rearrangements in all three components. It was postulated that the CLL transformed to ALCL, which then progressed to HL. [13] In 2004, Copur et al., reported a case of composite CLL (90%) and follicular lymphoma (10%) involving the bone marrow in a patient who 5 years later developed HL in the liver. Assay for t (14;18) was positive in the initial follicular lymphoma, but negative in the liver biopsy. [14] Another reported case of composite transformation comprised of a  prolymphocytic lymphoma and HL arising in patient with known CLL treated with single agent fludarabine. [9]

CLL transformation to a plasma cell neoplasm or lymphoma with plasmacytic differentiation has also been described. [13] In 2003, Aktan et al., reported the development of clonally-related, nonsecreting, multiple myeloma in a 73-year-old patient 7 years after the patient was diagnosed with CLL. [15] Furthermore, there is a single case report of CLL/SLL with concurrent HL and plasmablastic lymphoma. In this patient, the plasmablastic lymphoma was considered to be immunodeficiency-associated rather than a true Richter transformation due to diffuse EBV positivity and patient's prior fludarabine therapy. [10]

Herein, we report a case of nodal SLL/CLL with composite HL and anaplastic plasmacytoma. To the best of our knowledge, such a case has never been previously described. Of note, our patient had no reported history of fludarabine therapy and EBV was only positive in scattered single cells that were most consistent with R-S cells; therefore, we do not feel that these concurrent malignancies should be considered immunodeficiency-related neoplasms. Recent studies show that due to prognostic differences, the term Richter's transformation should only be reserved for cases where CLL is proven to be clonally related to the large cell component. [7] Due to lack of material, we were unable to investigate the clonal relationship between the CLL and anaplastic plasmacytoma components by molecular methods such as IgH gene rearrangement analysis, conventional cytogenetics, or fluorescence in situ hybridization (FISH). However, the presence of the anaplastic plasmacytoma in the same lymph node as the CLL/SLL component suggests a common origin; although, admittedly collision tumors are known to occur. In addition, the light chain restriction discovered in the plasma cell component by immunohistochemistry is identical to the light chain detected by flow cytometry in the CLL component as well as the reported light chain specificity in prior biopsies from this patient. This also argues, in the absence of a setting of immunodeficiency, in favor of single clonal origin. One may postulate that as the CLL/SLL clone progressed to classic HL with loss of CD20 and CD45, a subset of these cells may have undergone further differentiation and transformed to the anaplastic plasmacytoma. The possibility of two separate transformation events instead of a linear progression also exists and is favored by the geographic distribution of the three malignancies in this case. The R-S cells seemed to be confined to the CLL/SLL portion of the node, which was sharply demarcated from the anaplastic plasmacytoma component in this case.

The patient was treated with six cycles of salvage R-CHOP chemotherapy. A CT scan performed after three cycles of R-CHOP showed a decrease in the size of mediastinal lymphadenopathy. In September 2011, she received autologous peripheral stem cell transplant. In late October 2011, she was admitted for hypotension, acute renal failure, and an elevated lactate dehydrogenase (LDH) and uric acid. Due to the high likelihood of relapse of lymphoma and little utility of aggressive treatment of her hypotension and renal failure, she was discharged home on hospice care.

  References Top

1.Swerdlow SH. International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. 4 th ed. In: World Health Organization Classification of Tumours. Lyon: International Agency for Research on Cancer; 2008. p. 180-2.  Back to cited text no. 1
2.Greipp PT, Smoley SA, Viswanatha DS, Frederick LS, Rabe KG, Sharma RG, et al. Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis. Br J Haematol 2013;163:326-33.  Back to cited text no. 2
3.Sagatys EM, Zhang L. Clinical and laboratory prognostic indicators in chronic lymphocytic leukemia. Cancer Control 2012;19:18-25.  Back to cited text no. 3
4.Tsimberidou AM, Keating MJ. Richter syndrome: Biology, incidence, and therapeutic strategies. Cancer 2005;103:216-28.  Back to cited text no. 4
5.Richter MN. Generalized reticular cell sarcoma of lymph nodes associated with lymphatic leukemia. Am J Pathol 1928;4:285-92.  Back to cited text no. 5
6.Rossi D, Gaidano G. Richter syndrome: Molecular insights and clinical perspectives. Hematol Oncol 2009;27:1-10.  Back to cited text no. 6
7.Rossi D, Gaidano G. Richter syndrome. Adv Exp Med Biol 2013;792:173-91.  Back to cited text no. 7
8.Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: A report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446-56.  Back to cited text no. 8
9.O'Sullivan MJ, Kaleem Z, Bolger MJ, Swanson PE, Zutter MM. Composite prolymphocytoid and hodgkin transformation of chronic lymphocytic leukemia. Arch Pathol Lab Med 2000;124:907-9.  Back to cited text no. 9
10.Foo WC, Huang Q, Sebastian S, Hutchinson CB, Burchette J, Wang E. Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: A dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus. Hum Pathol 2010;41:1802-8.  Back to cited text no. 10
11.Ma C, Lewis J Jr. Small biopsy specimens reliably indicate p16 expression status of oropharyngeal squamous cell carcinoma. Head Neck Pathol 2012;6:208-15.  Back to cited text no. 11
12.de Leval L, Vivario M, De Prijck B, Zhou Y, Boniver J, Harris NL, et al. Distinct clonal origin in two cases of Hodgkin's lymphoma variant of Richter's syndrome associated With EBV infection. Am J Surg Pathol 2004;28:679-86.  Back to cited text no. 12
13.van den Berg A, Maggio E, Rust R, Kooistra K, Diepstra A, Poppema S. Clonal relation in a case of CLL, ALCL, and Hodgkin composite lymphoma. Blood 2002;100:1425-9.  Back to cited text no. 13
14.Copur MS, Ledakis P, Novinski D, Fu K, Hutchins M, Frankforter S, et al. An unusual case of composite lymphoma involving chronic lymphocytic leukemia follicular lymphoma and Hodgkin disease. Leuk Lymphoma 2004;45:1071-6.  Back to cited text no. 14
15.Aktan M, Akkaya A, Doðan O, Dincol G. Chronic lymphocytic leukemia and multiple myeloma in the same patient: Case report. Leuk Lymphoma 2003;44:1421-4.  Back to cited text no. 15


  [Figure 1], [Figure 2], [Figure 3]

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