Splenic Extramedullary Hematopoiesis in a Patient Receiving Intermittently Administered Granulocyte ColonyStimulating Factor

Case Report

A previously healthy 22-year-old man came to the oncology clinic for evaluation of a progressively enlarging right axillary mass. He denied having any B symptoms. Physical examination showed a 7 8 cm group of matted nodes in the right axilla that were nontender and fixed. Wedge biopsy showed a high-grade malignant lymphoma of large-cell, immunoblastic type. The tumor reacted with immunohistochemical stains for leukocyte common antigen Ber H2 (Ki-1 or CD 30) and epithelial membrane antigen. No B- and T-cell-associated antigens were detectable by antibody stains. Results of a complete blood count; electrolyte, lactate dehydrogenase, and serum calcium assessments; and liver function tests were normal. A serologic test for human immunodeficiency virus was negative. Bilateral bone marrow biopsy specimens showed no evidence of lymphoma. Computed tomographic scan of the chest showed the large axillary mass, and computed tomographic scan of the abdomen showed a spleen size in the upper range of normal. Results of these studies indicated stage I disease.

Combination chemotherapy was instituted. The regimen consisted of cyclophosphamide, doxorubicin, and vincristine on day 1; intravenous etoposide on days 1, 2, and 3; and prednisone daily for 5 days. The cycle was repeated every 3 weeks for four cycles. The patient also received G-CSF therapy, 5 g/kg subcutaneously daily, on days 5 to 19 of each cycle. The leukocyte count reached a nadir of 0.6 to 0.7 106/L at day 10 and a peak of 13 to 54 106/L before treatment. The patient became anemic and required blood transfusion at one point. Results of a computed tomographic scan of the chest and axilla, done after four cycles of therapy, were normal. A computed tomographic scan of the abdomen revealed an enlarged spleen that was also palpable at physical examination. Just before surgery, the leukocyte count was 4.9 106/L and results of blood chemistry studies were normal, except for an elevated LDH level (3.8 kat/L [228 U/L]; normal, 1.3 to 3.3 kat/L = [80 to 200 U/L]). He underwent exploratory laparotomy with splenectomy 6 weeks after his last dose of chemotherapy and 3 weeks after his last G-CSF therapy treatment. The spleen measured 15 11 5 cm and weighed 320 g. The cut surface appeared to be congested but showed no obvious focal abnormalities. Microscopic examination showed patchy extramedullary hematopoiesis of all three lineages, with focal collections of polymorphonuclear leukocytes and apparent congestion (Figure 1). No lymphomatous elements were identified. The patient remains in complete remission and has not received additional treatment.

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Figure 1. In this particular field, both a megakaryocyte ( ) and erythroid precursors (small cells with dense round nuclei located near the e) are present. (Hematoxylin and eosin; original magnification, 290). Spleen section showing extramedullary hematopoiesis.arrow

Discussion

We have described the occurrence of extramedullary hematopoiesis in the spleen of a patient receiving chemotherapy and intermittent G-CSF therapy. Splenomegaly was previously reported in a patient with nonmalignant disease who received continuous G-CSF therapy for several months, and extramedullary hematopoiesis was documented in that patient [1]. In our patient, foci of extramedullary hematopoiesis involved all three cell lineages. The direct effects of G-CSF therapy, however, are on the myeloid lineage. Administration of G-CSF results in a dose-dependent increase in the number of circulating neutrophils by expanding precursor compartments and decreasing the maturation time [2].

In a murine model, G-CSF also caused splenic extramedullary hematopoiesis of all three cell lineages by generating a factor-dependent hematopoietic microenvironment [3]. It is conceivable, then, that G-CSF may have a similar effect on human stromal cells, resulting in support of growth and differentiation of all three cell lineages. It is also possible that endogenous erythropoietin generated in response to anemia acted in concert with G-CSF to stimulate the erythroid elements.

The advent of colonystimulating factors has revolutionized cancer chemotherapy. Growth factors permit the use of higher drug doses in combination chemotherapy regimens and allow for shorter treatment intervals, resulting in greater benefits and less toxicity in patients with responsive carcinomas [4]. Because the use of growth factors will probably continue to increase, clinicians should be aware of the side effects that may be associated with the administration of growth factors. In our patient, the new finding of splenomegaly and the persistently elevated LDH level led to the decision to do the splenectomy because an elevated LDH level is a prognostic factor that portends residual disease in patients with aggressive lymphomas [5]. Our findings emphasize that G-CSF therapy, even when intermittently administered, can be associated with splenomegaly, which does not necessarily indicate refractory disease in patients treated for malignant lymphomas.