Thymoma with Concomitant Pure Red Cell Aplasia, Good’s Syndrome and Myasthenia Gravis Responding to Rituximab

Abstract

Thymomas are often associated with a variety of autoimmune diseases, mostly myasthenia gravis. The association of thymomas with both pure red cell aplasia (PRCA) and Good’s syndrome is exceedingly rare. To the best of our knowledge, the combination of a thymoma with manifestations of myasthenia gravis, PRCA, and Good’s syndrome, as in our case herein, has not been described before in the medical literature. We present a 90-year-old man initially diagnosed with an asymptomatic thymoma. Later, he developed generalized muscle weakness and was found to have severe anemia. He was diagnosed with PRCA, myasthenia gravis and Good’s syndrome. He responded to rituximab with restoration of bone marrow erythroid maturation and stabilization of red blood cell counts.

Introduction

The thymus is a lymphatic organ responsible for production and “education” of T-lymphocytes. Thymomas represent benign epithelial tumors of the thymus [1] accounting for 20–25 % of all mediastinal tumors and 50 % of anterior mediastinal ones [2]. They are the most common human neoplasms associated with paraneoplastic autoimmune diseases, specifically myasthenia gravis (MG) [3] and less commonly Lambert-Eaton syndrome, bullous pemphigoid, systemic lupus erythematosus, pure red cell aplasia (PRCA), and immunodeficiency, among others [4]. The exact mechanism(s) by which thymomas induce autoreactivity remain to be better understood. A plausible explanation is a resulting damage induced by tumor growth within the thymus affecting its ability to maintain self-tolerance, hence leading to development of autoimmune diseases [4, 5]. The association of thymomas with both PRCA and Good’s syndrome is extremely rare and only few cases have been reported in the literature [6–9]. Here, we present the case of a man who was initially diagnosed with an asymptomatic thymoma in the year 2000 and refused surgical resection. Ten years later, he presented with three associated paraneoplastic autoimmune diseases: PRCA, Good’s syndrome and myasthenia gravis.

Case History

The patient initially presented with a mediastinal mass extending to the left hemithorax. Histopathologic analysis of the tumor confirmed a lymphocyte-rich thymoma type B1, based on World Health Organization (WHO) classification (Fig. 1) [1]. He refused surgical resection at the time of original diagnosis. He had a history of recurrent Herpes simplex virus-2 infections, including transverse myelitis, and diffuse skin disease, for which he was treated on several occasions between 2008 and 2011. He presented to our institution in November 2012, at 90 years of age, for symptoms of severe generalized weakness. A computed tomography scan of the chest showed again the mediastinal mass which has slightly increased in size. Laboratory analysis disclosed severe macrocytic anemia (Hemoglobin: 3.7 g/dL, Hematocrit: 10 %, Mean corpuscular volume: 111 fl) with a very low reticulocyte index (0.2). White blood cells and platelet counts were within normal limits. A bone marrow aspirate and biopsy revealed a markedly decreased erythroid lineage consistent with PRCA. Generalized weakness persisted despite blood transfusions. A neurologic consult was sought and a diagnosis of myasthenia gravis was confirmed by repetitive nerve stimulation studies that showed progressive decline in the compound muscle action potential amplitude with the first four stimuli in the left facial and right axillary nerves (a decremental response). Moreover, his history of recurrent HSV-2 infections raised suspicion for the possibility of Good’s syndrome (thymoma with immunodeficiency) as a potential etiology. Accordingly, we ordered lymphocyte subset profiles as well as immunoglobulin levels, which revealed hypogammaglobulinemia with markedly decreased B-lymphocytes, confirming the diagnosis of Good’s syndrome. Antinuclear antibodies, Anti-Double stranded DNA, C3, C4 testing were all unremarkable (Table 1).

Fig. 1.

Lymphocyte-rich thymoma type B1, H&E needle-core biopsy (mag. 100x & 200x) with scattered inconspicuous epithelial cells immunostaining with CK AE1/AE3 (c) (mag. 400x) (a, b)

Table 1.

Lymphocyte subset profiles by flow cytometry and immunoglobulin levels

Profile	Value	Reference range
White blood cells (/μL)	12,300	4,000–11,000
Lymphocytes (/μL)	4,932 (40 % white blood cells)	25–40 % of WBC
B-cell (CD19) (/μL)	13.8 (0.28 % lymphocytes)	100–400 cells/uL
T-cell (CD3) (/μL)	4,758 (96.48 % lymphocytes)	700–1,900 cells/uL
CD4 T cells (/μL)	2,596 (52.65 % lymphocytes)	400–1,300 cells/uL
CD8 T cells (/μL)	1,960 (39.75 % lymphocytes)	200–700 cells/uL
CD4/CD8 ratio	1.32
Immunoglobulin G (g/L)	2.91	7.00–16.00
Immunoglobulin A (g/L)	0.45	0.70–4.00
Immunoglobulin M (g/L)	<0.17	0.40–2.30

The patient was started on pyridostigmine, an acetylcholinesterase inhibitor, for the treatment of myasthenia gravis resulting in marked improvement of his muscle weakness within 2 weeks of initiation of therapy. He was not considered a surgical candidate for excision of his thymoma, due to associated comorbidities as well as the size and extent of the regional tumor spread. The age of the patient (90 years) and his comorbidities including the history of recurrent and diffuse Herpes simplex virus-2 infections demurred us from using corticosteroid as first line therapy. We prescribed rituximab based on published literature on its efficacy in treating various autoimmune disorders (e.g. Autoimmune hemolytic anemia, Idiopathic thrombocytopenic purpura). The patient received 375 mg/m² weekly for four consecutive weeks then every 3 weeks for five doses. After that, he received rituximab maintenance at a frequency of once a month. He received four units of packed red blood cells upon admission which consequently increased his hemoglobin to 8 g/dL. Furthermore, he reached a hemoglobin level of 11.2 g/dL with Hematocrit of 33 %, MCV of 93 fl, MCH of 32 pg and MCHC of 35 g/dL within 2 weeks of rituximab treatment, and the response was maintained 9 months later (Fig. 2). A repeat bone marrow analysis just after 1 month of treatment had already revealed recovery of erythropoiesis (Fig. 3).

Fig. 2.

A schematic representing the change of hemoglobin with time during the course of treatment. The black arrows represent the timing of rituximab dosing

Fig. 3.

Bone marrow aspirate following rituximab treatment revealing increased precursor erythroblasts (arrow) and polychromatic normoblasts (arrowhead) (mag. 1000x) (a). Separate areas with precursor erythroblasts (arrow) and orthochromatic normoblasts (arrowhead) (mag. 1000x), a finding consistent with recovery of the erythroid lineage (b)

Discussion

Thymectomy represents the first-line of therapy in thymomas with associated autoimmune disorders. It results in resolution of anemia in 25–30 % of cases of PRCA related to thymomas. In other cases, patients will require additional interventions such as immunosuppressive therapies [10]. Thymectomy also represents the first-line of therapy for myasthenia gravis-associated with thymomas before pharmacologic therapies are instituted [11].

Thymectomy combined with immunoglobulin replacement represents the mainstay in the treatment of concomitant Good’s syndrome and thymomas [12]. In our particular case, patient’s age and associated comorbidities as well as the critical anatomic location of his tumor precluded the option of surgery.

Immunosuppressive therapy has been shown to be effective not only in the upfront treatment of patients with thymomas and associated PRCA who did not undergo thymectomy, but also as an adjuvant treatment. Although the optimal management of this disorder remains unknown, a variety of immunosuppressive therapies, namely cyclosporine A and cyclophosphamide have shown efficacy in this setting [13, 14].

We opted to treat our patient with rituximab, which has proven to be beneficial in few cases of PRCA not necessarily related to thymomas with a good clinical response [15, 16]. Several reports have shown successful treatment of PRCA with rituximab in patients with B cell lymphoproliferative disorders, mostly chronic lymphocytic leukemia [15, 16]. Conversely, results of rituximab therapy have been disappointing in patients with severe, resistant and life-threatening PRCA refractory to conventional immunosuppression, as in idiopathic PRCA [17]. To our knowledge, our patient represents the first reported case of a thymoma with three associated paraneoplastic autoimmune disorders, namely PRCA, Good’s syndrome, and myasthenia gravis responding to anti-CD20 therapy, namely rituximab. Favorable response noted in our case support evaluating the role of rituximab in cases of unresectable thymomas with associated autoimmune disorders such as PRCA in the context of multicenter clinical trials. The optimal dose and frequency of rituximab therapy remain important research questions that need to be addressed in future studies.