Journal of Clinical Oncology, Vol 21, Issue 1
(January), 2003: 170-172
© 2003 American Society for Clinical Oncology
Uncommon Syndromes and Treatment Manifestations of Malignancy
Case 3. Richter’s Syndrome Heralded by Refractory Hypercalcemia
Nancy J. Freeman,
Debra Holik
Hematology/Oncology Section, Brown University School of Medicine, Providence VA Medical Center, Providence, RI
In June of 1998, a 71-year-old man with well-differentiated stage IIIA lymphocytic lymphoma had no response to chlorambucil and prednisone when he presented with intra-abdominal adenopathy and urinary obstruction requiring a stent. He subsequently improved after six cycles of cyclophosphamide, vincristine, and prednisone (CVP), completed in June 1999. In October 1999, biopsy of a new 1.5-cm right groin mass confirmed the same lymphoma. In March 2001, the node increased to 6 cm and computed tomography (CT) showed right iliac and groin adenopathy with hydronephrosis; lactic dehydrogenase (LDH) was normal. In August 2001, the patient had an excellent partial remission after six cycles of CVP, and the node decreased to approximately 2.5 cm. Within 2 weeks, he was admitted in another state with a CVA, cardiac arrest, renal failure, hypokalemia, hypomagnesiumemia, stable adenopathy, and refractory hypercalcemia unresponsive to pamidronate and mithramycin. He improved temporarily and was discharged in October 2001, on calcitonin and prednisone. Our evaluation noted at that time that the right groin node was 7 to 8 cm and a new left inguinal node was 2 cm. CBC and calcium were unremarkable, LDH 450 U/L (90 to 270 U/L), parathyroid hormone (PTH) intact less than 1.0 pg/mL (12 to 72 pg/mL), PTH-rp 2.4 pmol/L ( 1.3 pmol/L), PTH c-terminal 136 pg/mL (70 to 270 pg/mL), vitamin D (25-hydroxy) 23 mg/mL (10 to 55 mg/mL), vitamin D (1,25-hydroxy) 168 pg/mL (15 to 60 pg/mL), and beta-2 microglobulin 3.2 mg/dL (1.85 mg/dL). While he was being restaged, the nodes abruptly grew over 1 week to 12 cm on the right and 7 cm on the left, and he was admitted with symptomatic hypercalcemia unresponsive to calcitonin, steroids, pamidronate, and zoledronic acid and barely controllable with hydration and furosemide. The repeat node biopsy showed a diffuse large-cell lymphoma (Fig 1 ), CD10+, and CD20+. Chest CT was normal, but CT of abdomen/pelvis demonstrated a significant increase in pelvic and intra-abdominal nodes (Fig 2) with bilateral hydronephrosis, creat 1.7. He developed a right DVT, treated with enoxaparin sodium and warfarin, with impressive right leg, scrotal, and penile swelling. Tumor necrosis factor alpha (TNF- ) was less than 15.6 pg/mL (< 25.0 pg/mL) and interleukin-6 (IL-6) less than 50 pg/mL ( 62 pg/mL). Skeletal survey showed no lytic lesions but mild osteopenia. He was started on rituximab and CHOP (cyclosporine, doxorubicin, vincristine, and prednisone). Gallium scan, completed a few days after treatment was started, was positive in the anterior cervical, left supraclavicular, bilateral inguinal areas and in the spleen. Within 1 week, the adenopathy improved dramatically and was confirmed on abdominal CT performed 12 days later. The patient seemed to be in a complete remission after two cycles. He developed hypocalcemia, requiring replacement therapy (Fig 3).
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Fig 2. Computed tomography of abdomen/pelvis showing a significant increase in pelvic and intra-abdominal nodes.
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Hypercalcemia is reported in 0.3% to 4% of lymphoma patients. It is described mostly in T-cell lymphomas with associated bony lesions.1 The mechanism in Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL) has been attributed predominantly to elevated calcitriol 1,25 (OH) vitamin D levels produced by the malignancy. In other solid tumors, PTH-rP, cytokines, and prostaglandins have been implicated.2,3 Review of the literature in English over 10 years demonstrates approximately 70 cases of chronic lymphocytic leukemia (CLL)/lymphoma associated with hypercalcemia, the majority described as B cell or not specified. There were variable evaluations of various markers and bone x-rays, often not specified. About 25% of the cases noted an increased PTH-rP. TNF- was elevated in several cases, IL-6 in a few, and calcitriol in approximately 50%. There were lytic lesions mentioned only in a minority of patients. Hypercalcemia in Richter’s syndrome (CLL or NHL higher grade lymphoma) is rare, particularly for NHL. Two cases that presented with hypercalcemia and a concurrent aggressive NHL previously had a history of a low-grade NHL or Waldenstrom’s macroglobulinemia. Most patients improved with saline, pamidronate, mithramycin, or calcitonin.4 Reports from the literature are variable, but to the best of our knowledge, our patient seems to be unique as an individual whose severe refractory hypercalcemia preceded the clinical transformation from a low-grade to a high-grade NHL. His calcium levels responded only to treatment of the underlying disorder. Both calcitriol and PTH-rP may play a critical role (possibly synergistic) in the mechanism of lymphoma-associated hypercalcemia, particularly in those cases without bone lesions,5 perhaps explaining the refractory nature. Hypercalcemia in patients with lymphoma may portend a transformation to a more aggressive subtype, and biopsy and treatment of the lymphoma should occur expeditiously.
ACKNOWLEDGMENTS
We thank Michael Klein, MD, acting chief of pathology, for his support in preparing the pathology photomicrographs.
REFERENCES
1. Muggia F: Overview of cancer-related hypercalcemia: Epidemiology and etiology. Semin Oncol 17:3–25, 1990[Medline]
2. Gagel R, Seymour J: Calcitriol: The major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphoma. Blood 82:1383–1394, 1993[Free Full Text]
3. Seymour J, Gagel R, Hagemeister F, et al: Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma. Ann Intern Med 121:633–640, 1994[Abstract/Free Full Text]
4. Beaudreuil J, Lortholary O, Martin A, et al: Hypercalcemia may indicate Richter’s syndrome. Cancer 79:1211–1215, 1997[CrossRef][Medline]
5. Daroszewska A, Bucknall R, Chu P, et al: Severe hypercalcemia in B-cell lymphoma: Combined effects of PTH-rP, IL-6, and TNF. Postgrad Med J 75:672–681, 1999[Abstract/Free Full Text]
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