To the Editor:
A 63-year-old woman was admitted in January 2012 with a 1-month history of general fatigue and jaundice. Physical examination revealed a pale conjunctiva, icteric sclera, and splenomegaly with no evidence of systemic lymphadenopathy. Laboratory findings revealed normocytic anemia (49 g/L) with increased reticulocyte count, decreased haptoglobin level, normal white cell count without villous lymphocytes, elevated serum indirect bilirubin level (60 mg/L), elevated lactate dehydrogenase level (450 IU/L) (Figure A), elevated soluble interleukin-2 receptor level (7230 U/L), and mild IgM paraproteinemia. The direct Coombs test was positive, whereas the test for hepatitis C virus antibody was negative. Computed tomography revealed massive splenomegaly with no lymphadenopathy (Figure B). Bone marrow aspirate revealed erythroid hyperplasia without villous lymphocytes (Figure C). Although autoimmune hemolytic anemia associated with splenic lymphoma was the most likely diagnosis, lymphoma cells were not detected. The patient was treated with prednisolone (1 mg/kg). Nevertheless, she developed hemolytic anemia. Subsequently, laparoscopic splenectomy was performed, and her total serum bilirubin level immediately decreased, with a gradual amelioration of anemia (Figure A). Histologic findings of the spleen revealed splenic marginal zone lymphoma (Figure D). A final diagnosis of autoimmune hemolytic anemia associated with splenic marginal zone lymphoma was made. She achieved complete remission after 8 cycles of rituximab containing chemotherapy, without any signs of recurrence.
Although corticosteroids represent the first-line treatment for patients with autoimmune hemolytic anemia, approximately 30% of patients require second-line treatment.1 Splenectomy and rituximab are pivotal second-line treatments demonstrating short-term efficacy. Among them, rituximab might now be the preferred second-line treatment over splenectomy in terms of efficacy and safety profiles, while taking into consideration complications.2However, we have some concerns regarding this second-line treatment strategy because of a lack of accurate definitive diagnosis (whether idiopathic or secondary autoimmune hemolytic anemia), caused by the inability to evaluate pathologic findings.
A second-line treatment is the definite treatment for underlying disease.1 As a matter of course, pathologic diagnosis is essential before deciding treatments for underlying disease. However, the differential diagnosis of patients with splenomegaly in the absence of systemic lymphadenopathy and abnormal lymphocytes, as in the case of our patient, can be challenging because it is difficult to distinguish pathologic conditions primarily involving the spleen from those in which splenomegaly presents itself as a phenomenon of hepatic or systemic diseases.
Splenectomy could be a diagnostic strategy that strongly contributes to definite diagnosis in this setting. In addition, splenectomy is safely performed using laparoscopy, demonstrating high short- and long-term efficacy. In some patients, such as those with autoimmune hemolytic anemia associated with splenic marginal zone lymphoma, splenectomy could provide favorable overall survival.3 Splenic marginal zone lymphoma is a rare subtype of non-Hodgkin lymphoma in which autoimmune manifestations, such as autoimmune hemolytic anemia with massive splenomegaly, are relatively common,4 indicating that steroid-refractory autoimmune hemolytic anemia with massive splenomegaly may often be involved in splenic marginal zone lymphoma.
Thus, we would recommend splenectomy to all steroid-refractory autoimmune hemolytic anemia patients with massive splenomegaly and uncertain pathologic diagnosis. The highlights of our case can be meaningful because they indicate the choice of second-line therapy for steroid-refractory autoimmune hemolytic anemia.
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– Hiroshi Ureshino, MD, Masaharu Miyahara, MD, PhD
This article originally appeared in the September 2017 issue of The American Journal of Medicine.
