HISTORY AND PHYSICAL EXAMINATION
In February 2004, a 71-year-old man presented with a 1-year history of progressive knee pain with swelling and was treated with nonsteroidal antiinflammatory medicines. He had no antecedent trauma and no constitutional symptoms, such as weight loss or fever. His past medical history included chronic lymphocytic leukemia diagnosed in 1980 treated by splenectomy in 1981. He also had a remote history of melanoma.
On physical examination, the patient appeared healthy with stable vital signs. There was mild swelling around the left knee with no overlying skin changes. He had full painless range of motion of the knee with fullness over the infrapatellar region. His ligamentous examination was normal, and there was no significant pain or tenderness to palpation in the medial or lateral joint lines. There was mild-to-moderate tenderness to palpation around the inferior pole of the patella and in the retropatellar fat pad. There was no diffuse lymphadenopathy or abdominal organomegaly.
On laboratory examination the patient's white cell count was 10.34 × 103 μL, which is in normal limits, he had a hematocrit of 44%, and a platelet count of 277,000 μL. Serum chemistry values were normal.
Radiographic studies included anteroposterior (AP) and lateral radiographs and magnetic resonance images (MRI) of the knee (Figs 1-3). Based on the history, physical examination, laboratory findings, and imagining studies, what is the differential diagnosis
The lateral knee radiograph (Fig 1) shows a lytic lesion involving the inferior half of the patella with suggestion of cortical destruction inferiorly. There is no matrix production apparent.
An oblique sagittal proton density spin-echo MR image of the patella (Figs 2, 3) shows extensive replacement of the normal marrow, with the mass extending into the infrapatellar fat. The mass is hyperintense to skeletal muscle on proton density and T2 weighted images and replaces the lower half of the patella extending into the soft tissues inferiorly and invading Hoffa's fat pad and the posterior margin of the proximal infrapatellar tendon. A second mass with similar image characteristics is noted in the prepatellar bursa. The distal femur is normal.
Metastatic neoplasm (melanoma or carcinoma)
Extramedullary myeloid tumor (Granulocytic sarcoma/ Chloroma)
Lymphoma (Richter transformation of chronic lymphocytic leukemia)
A Temno™ needle (Cardinal Health, Dublin, OH) biopsy on the soft tissue component was done (Fig 4). Based on the history, physical examination findings, laboratory studies, imaging studies and histologic picture, what is the diagnosis and how should the patient be treated?
The needle biopsy shows dense and somewhat reactive connective tissue infiltrated with a mixture of large cells and lymphocytes (Fig 4A). The large cells have an enlarged, variably shaped vesicular nucleus with a centrally located nucleolus and a slight amount of amphophilic cytoplasm. The immunohistochemical stain for leukocyte common antigen (LCA or CD45) is diffusely positive (Fig 4B), which indicates that the lesion is a lymphoma. The immunohistochemical stain for CD20 (B-cells) is diffusely positive (Fig 4C), and the stain for CD3 (T-cells) shows only focally positive cells (Fig 4D). The immunohistochemical stains for myeloperoxidase and muramidase (granulocyte stains) were negative. These immunohistochemical stains confirm the presence of a malignant large B-cell type lymphoma and exclude a granulocytic sarcoma (chloroma). We did not immunophenotype the lymphoma by flow cytometry.
Malignant lymphoma, large B-cell type consistent with a Richter's transformation of chronic lymphocytic leukemia.
DISCUSSION AND TREATMENT
Histologically, the tumor has the appearance of a lymphoma, but the clinical and radiographic differential diagnosis included a metastatic neoplasm and an extramedullary myeloid tumor. In view of the patient's history, a metastatic neoplasm includes a melanoma, an adenocarcinoma and a squamous cell carcinoma. A melanoma would be composed of sheets of large cells with abundant amphophilic cytoplasm. The nuclei would be large and have prominent nucleoli. The cells would stain immunohistochemically for S-100, HMB 45 and Melan-A. An adenocarcinoma would be composed of larger than normal epithelial cells with enlarged hyperchromatic nuclei. The cells would form glands with no intervening stroma. A squamous cell carcinoma would form tongues and sheets of malignant squamous cells that could be producing squamous pearls. Both carcinomas would stain immunohistochemically for keratin.
An extramedullary myeloid sarcoma is composed of myeloblasts or myeloblasts with more mature granulocytes. These tumors were initially called chloromas, because the cells usually contained myeloperoxidase and upon exposure to air the freshly cut surface soon turned green. Tumors can be composed of a uniform population of immature cells and may be misdiagnosed as a lymphoma. Occasionally, the lesion contains immature eosinophils and maturing neutrophils. This lesion may be differentiated from lymphomas by positive immunostains for myeloperoxidase, muramidase, and CD117 (C-kit).
In our patient, the malignant cells stained immunohistochemically for leukocyte common antigen (CD45), an antigen found on lymphoid cells, and CD20, an antigen found on B-cells, indicating the lesion is a B-cell lymphoma. The immunohistochemical stains for myeloperoxidase and muramidase were negative, which excludes an extramedullary myeloid tumor.
In 1928, Richter described a patient with chronic lymphocytic leukemia who developed a reticular cell sarcoma, which would probably be classified using current terminology as malignant lymphoma, large cell type.8 In 1964, Lortholary et al6 applied the term Richter's syndrome to four patients with chronic lymphocytic leukemia who developed a terminal disease that included fever, weight loss, and dysproteinemia. At autopsy, these patients were found to have reticulum cell sarcomas. Subsequently, other reports of large cell lymphoma complicating chronic lymphocytic leukemia appeared in the medical literature, which reiterated the findings of these earlier reports.1,4 In 1993, Robertson et al11 reported 39 patients with Richter's syndrome. The syndrome included a history of chronic lymphocytic leukemia and a subsequent development of biopsy-proven large cell lymphoma. They also found the following other features associated with the syndrome: systemic symptoms, such as fever, night sweats and weight loss (59%); progressive lymphadenopathy (64%), extranodal involvement (41%), elevation of lactate dehydrogenase (LDH, 82%), a monoclonal gammopathy (44%), and a median survival of 5 months from the time of diagnosis. The reported incidence of large cell lymphoma complicating the course of chronic lymphocytic leukemia is estimated at 3%, but has been reported to be as high as 10%.7
The lymphomas in Richter's syndrome may arise from a clone of the chronic lymphocytic lymphoma or de novo.7 In early studies, the clonality was based on the membrane and/or cytoplasmic immunoglobulin light chains. When the cells of the lymphoma and the chronic lymphocytic leukemia contained the same light chains, it was assumed that the lymphoma arose from the leukemia. In contrast, when the neoplastic cells had different light chains, the lymphomas were considered to arise de novo. In some cases the light chains were identical, in others they were not. Since those early studies, molecular techniques, such as Southern blotting and nucleotide sequencing, have been used to determine clonality. These tests suggest that about ½ of the large cell lymphomas in Richter's syndrome originate from the B-cell chronic lymphocytic leukemia clone and the other ⅓ arise de novo. One report summarized 37 reported cases of Richter's syndrome where an attempt was made to identify the clonal origin of the lymphoma. The report found that 28 cases (76%) were from the same B-cell clone as the leukemia whereas the other nine cases (24%) were from a different clone of B-cells.2 Other reports estimate that the majority of the large cell lymphomas, up to 80%, originate from the same clone of cells as the chronic lymphocytic leukemia.9,14 The treatment of Richter's syndrome is problematic with no effective regimen for Richter's syndrome having been found.8,11,12,15
Two previous cases of Richter's syndrome with the lymphoma originating in the bone have been described. The patients did not have systemic symptoms, lymphadenopathy, or hepatomegaly at the time of presentation. The first case was a 66-year-old man with large B-cell lymphoma presenting as a pathologic fracture of the femur.10 In January of 1999, he underwent therapy with six courses of cladribine for chronic lymphocytic leukemia and achieved a complete response by August 1999. In August of 2000, he developed a fracture of the femur, which was biopsy-proven to be a lymphoma. A bone scan with technetium-99m showed no other site of bony involvement and a computerized tomography scan of the chest and abdomen showed no enlarged lymph nodes. The patient was treated with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) and radiotherapy with a complete resolution of the lymphoma in the femur. Additional testing showed that the large cell lymphoma was not from the same clone of lymphocytes as the chronic lymphocytic leukemia.
The second patient was a 69-year-old woman who was diagnosed with chronic lymphocytic leukemia in 1992.5 She underwent various chemotherapy regimens over the years. In November 2001, she developed pain in her right tibia with an overlying palpable mass. Imaging studies showed an osteolytic lesion in the tibia. A biopsy showed a Grade 1 follicular lymphoma with transformation into a diffuse large B-cell lymphoma. She had no systemic symptoms and physical examination revealed no lymphadenopathy. A bone scan with technetium-99m showed no other site of bony involvement and a computerized tomography scan of the chest and abdomen showed no enlarged lymph nodes. Additional testing showed that the large cell lymphoma was not from the same clone of lymphocytes as the chronic lymphocytic leukemia. She received three courses of CHOP followed by radiotherapy and was in remission 8 months later.
Our patient has Richter's syndrome considering the history of chronic lymphocytic leukemia and the subsequent diagnosis of a large cell lymphoma. The patient did not have any of the secondary features that usually accompany Richter's syndrome. After the knee biopsy, the patient was evaluated with imaging studies and a bone marrow examination. The lymphoma did not appear to be present at any other sites and the marrow examination showed no evidence of CD20 positive large cell lymphoma. No studies were done to determine if the lymphoma was from the same clone of cells as the lymphoma. The lymphoma appeared isolated to the patella.
An oncologist examined the patient and recommended three to four cycles of CHOP and Rituxan™ (Genentech, South San Francisco, CA). The patient declined the CHOP, but received Rituxan™ and radiotherapy of the primary site. He continues to receive Rituxan™ every 2 months. Meanwhile, the MRI of his knee has returned to normal and he appears to be free of disease 15 months after his diagnosis and treatment.
The patient described in this report had a lesion arising in an extranodal site over the left knee with a protracted clinical course. Extranodal disease was found in 16 of 39 patients (41%) with Richter's syndrome as reported by Giles et al3 with the most common extranodal site being the central nervous system (12%) and the next most common site the pleura (10%). Trump et al13 described three cases of Richter's syndrome with bone involvement, but the patients also had disease in other sites.
We present a case of Richter's syndrome where the large cell lymphoma arose in an extranodal site involving the patella and the soft tissues of the knee with a more indolent than expected clinical course. The patient received Rituxan™ and radiotherapy and appears to be disease free at 15 months. Richter's syndrome arises in about 3% of patients with chronic lymphocytic leukemia. At presentation, these patients generally have systemic symptoms with a rapidly progressive lymphadenopathy and organomegaly. Clinical features include an elevated LDH, and the patients may also have dysproteinemia and hyper-calcemia. The prognosis of these patients is generally poor with a median survival of 5 months. An effective chemo-therapeutic regimen does not currently exist for these patients.
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