Pure Red Cell Aplasia and Thymoma

Pure Red Cell Aplasia and ThymomaCarrie A. Thompson, MD
In this issue of the Journal, van der Marel et al.1 report a case of pure red cell aplasia (PRCA) and hypogammaglobulinemia complicating a thymoma. After surgical resection
of the thymoma, the patient experienced hematopoietic recovery but required ongoing treatment with replacement gamma globulin. This case illustrates two rare paraneoplastic syndromes that can be associated with a thymoma.
An association between thymomas and various paraneoplastic syndromes is well recognized, with the most common paraneoplastic syndrome being myasthenia gravis (MG), occurring in 30% to 46% of patients with a thymoma.2,3 There are at least 20 other syndromes that have been reported in association with thymoma, including PRCA, hypogammaglobulinemia, and a wide range of autoimmune disorders. More than 40% of patients with thymoma are afflicted with a so-called parathymic syndrome.4 This com- mentary focuses on the diagnosis and management of PRCA in association with a thymoma.
Among patients with thymoma, fewer than 10% will develop PRCA, whereas fewer than 5% of patients with PRCA have a thymoma. Other known associations with PRCA include medications such as erythropoietin, viral infections including parvovirus, immune disorders, ABO-incompatible hematopoietic stem cell or bone marrow transplantation, and other malignancies. PRCA can also present as a primary, idiopathic disease.5
PRCA is characterized by erythropoietic failure with preserved granulopoiesis and megakaryopoiesis. The diagnosis should be suspected in a patient with isolated anemia and absent reticulocytes and be confirmed with a bone marrow biopsy, which classically shows a selective decrease in erythroid precursors without other diagnostic morphological abnormalities.
The pathophysiology of PRCA and thymoma is not entirely understood, but it seems to be related to an autoimmune mechanism. In some cases, there has been evidence for antibodies against erythroblasts blocking differentiation of erythroid progenitors; antibod- ies directed against native erythropoietin blocking signaling by that cytokine; or cell- mediated suppression of erythropoiesis by autoreactive T cells, large granular lympho- cytes, or natural killer cells. In cases of drug- or virus-induced PRCA, a direct toxic effect of a virus or drug on erythroid precursors is suspected.5–7
Because of the rarity of PRCA in association with thymoma, there are no standard treatment guidelines. At the time of diagnosis, surgical resection of the thymoma is usually undertaken. Some patients experience restoration of normal hematopoiesis after resection of the thymoma, as demonstrated in the case presented in this issue.1 It has been reported that removal of the thymoma leads to remission of PRCA in 25% to 30% of cases,8 but modern series have suggested remission from surgery alone is actually quite rare and that most patients will require some other form of therapy.9
Multiple non-surgical interventions have been attempted in patients with PRCA and thymoma, including systemic corticosteroids, other immunosuppressant drugs, chemo- therapy, androgens, splenectomy, and monoclonal antibodies. In our case series of 13 patients, cyclosporine and anti-thymocyte globulin (ATG) were the most effective treatments in achieving transfusion independence.9 However, complications from therapy,
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota. Address for correspondence: Carrie A. Thompson, MD, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester MN 55905. E-mail: Thompson.
[email protected] Disclosure: The author declares no conflict of interest. Copyright © 2007 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/07/0204-0263
Journal of Thoracic Oncology • Volume 2, Number 4, April 2007 263
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particularly infections, were common. Several patients had hypogammaglobulinemia associated with their clinical syn- drome, which increased their risk of infection. Thrombotic thrombocytopenic purpura developed in two patients treated with cyclosporine. Therefore, side effects of treatment are common, and caution should be exercised when treating these patients.
When faced with a patient with a new diagnosis of anemia in conjunction with a thymoma, PRCA should be considered. Evaluation should include a peripheral reticulo- cyte count; if there is reticulocytopenia, a bone marrow biopsy is prudent. Before surgical resection of the thymoma, the possibility of occult myasthenia gravis should be consid- ered because this syndrome is seen so commonly in associ- ation with a thymoma and may have implications for delivery of appropriate anesthesia and perioperative care. Once PRCA has been diagnosed, blood counts and reticulocyte counts should be monitored carefully, and if erythropoiesis does not return within 4 to 6 weeks postoperatively, systemic cortico- steroids should be initiated. Standard therapy is prednisone, typically at a dose of 1 mg/kg by mouth daily, with plans to treat at full doses for approximately 4 weeks. If the patient remains transfusion-dependent despite steroid therapy, a rea- sonable next step would be initiation of ATG and cyclospor- ine. Cyclosporine trough blood levels need to be monitored to avoid toxicity. Once reticulocytosis has been restored, pred- nisone can be slowly tapered. If the patient remains stable, cyclosporine may also be discontinued. Other options for patients whose disease is refractory to these measures include alternative immunosuppressants, cyclophosphamide, or an- drogens. Monoclonal antibodies such as rituximab and ale- mtuzumab have been reported to be effective therapies in case reports of patients with PRCA, even in refractory dis-
ease, but there have been no reported cases of their use in patients with PRCA and thymoma.10
In summary, paraneoplastic syndromes are commonly seen in association with thymomas. Myasthenia gravis is the most common, followed by PRCA, hypogammaglobuline- mia, and other autoimmune phenomena. PRCA seems to be caused by an autoimmune mechanism, and treatment ap- proaches target the immune system. Initial therapy is surgical removal of the thymoma, but most patients will require additional treatments such as prednisone, ATG, and cyclo- sporine to restore erythropoiesis.
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Pure Red Cell Aplasia and Thymoma
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