Myelodysplasia followed by Good's Syndrome: A unique manifestation associated with thymoma

Abstract

Good's syndrome, also known as thymoma with combined immunodeficiency, is rare. The immunodeficiency may precede, arise concurrently with or follow the diagnosis of thymoma. In addition to myasthenia gravis and Good's syndrome, paraneoplastic syndromes associated with thymoma can also be manifested with hematological disorders, such as pure red cell aplasia, aplastic anemia, agranulocytosis, hemolytic anemia, pernicious anemia, and paroxysmal nocturnal hemoglobinuria. Myelodysplastic syndrome is a group of clonal hematopoietic stem cell diseases characterized by cytopenia(s), dysplasia in one or more lineages, ineffective hematopoiesis, and potential precursors of acute leukemia. One proposed pathogenesis of myelodysplasia is autoantibodies that directly reject against hematopoietic cells, but this situation is rare in thymoma. Herein, we report a thymoma patient with unique paraneoplastic syndromes who developed myelodysplasia prior to Good's syndrome. Early and accurate diagnosis of myelodysplastic syndrome is important for disease management, especially in patients whose myelodysplastic syndrome is possibly derived from autoimmunity. For thymoma patients with recurrent infections, comprehensive immunologic studies to exclude the possibility of Good's syndrome and prophylactic intravenous immunoglobulin infusion in suitable candidates are warranted.

Introduction

Good's syndrome (thymoma with combined immunodeficiency) is rare and comprises less than 5% of thymoma patients. The main immunological abnormalities include hypogammaglobulinemia, few or absence of B lymphocytes, inversion of the CD4/CD8 T cell ratio, low level of CD4 T cells, and impaired T cell mitogenic response [1]. Due to the dysfunction of both B and T lymphocytes, patients with Good's syndrome are more vulnerable to various pathogens, such as encapsulated bacteria, virus, fungus, and opportunistic infections. In addition to myasthenia gravis and Good's syndrome, paraneoplastic syndromes associated with thymoma (parathymic syndromes) could also present with autoimmune‐mediated hematological disorders, such as pure red cell aplasia, aplastic anemia, agranulocytosis, hemolytic anemia, pernicious anemia, and paroxysmal nocturnal hemoglobinuria [[1], [2], [3], [4], [5], [6]]. Furthermore, myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell diseases characterized by cytopenia(s), dysplasia in one or more lineages, and ineffective hematopoiesis, and is associated with a variable risk of transformation to acute leukemia. For patients with MDS, the infection episodes usually depend on the severity of neutropenia. To our knowledge, only one case with Good's syndrome followed by myelodysplasia was reported in the literature [7]. Herein, we report a thymoma patient who manifested with repeated infections and unique paraneoplastic syndromes, and where the onset of myelodysplasia was before the diagnosis of Good's syndrome.

Case report

A 50‐year‐old woman initially presented with carbuncle in the tragus of the right ear in November 2006. Her initial white blood cell (WBC) count was 4.52 × 10⁹/L with differential counts as follows: segment, 28%, band, 7%, and lymphocyte, 51%. Her condition improved after receiving incision and debridement plus antibiotics therapy. However, about 10 months later, in September 2007, she was hospitalized again for urinary tract infection (UTI) with Escherichia coli (E. coli) bacteremia. Her hemogram revealed a WBC count as 2.61 × 10⁹/L with 17% Pelger‐Huet‐like cells in the peripheral blood. The chest X‐ray disclosed presence of a mediastinal mass. Chest computed tomography (CT) scan further documented multiple confluent lobulated lymph nodes in the anterior mediastinum (Fig. 1). Type AB thymoma was confirmed by CT‐guided biopsy and she received thymectomy in October 2007 (Fig. 2). Acute E. coil pyelonephritis occurred in November 2007. Moreover, chronic diarrhea, pathology‐proven multiple furuncles, and folliculitis of trunk developed frequently after the operation.

Figure 1.

Chest X‐ray showed a geographic pattern of soft tissue mass at the left mediastinum. Chest computed tomography demonstrated multiple bulky confluent lobulated lymph nodes in the anterior mediastinum (inset).

Figure 2.

Microscopically, two areas were sharply demarcated into upper left and lower right. Type AB thymoma was supported by the lymphocyte‐poor type A area which contained neoplastic spindle epithelial cells and a more lymphocyte‐rich type B component (H&E, ×40).

In December 2008, she suffered from left gluteal cellulitis with oxacillin‐resistant Staphylococcus aureus (ORSA) isolated. In addition, another episode of E. coli UTI occurred. The laboratory data is summarized in Table 1. The abnormal data included: WBC count, 3.53 × 10⁹/L, hemoglobin, 9.3 g/dL, Pelger‐Huet‐like cell, 45% (Fig. 3A), immunoglobulin (Ig) M, 15.9 mg/dL (reference range, 46–304 mg/dL), CD4, 25% (reference range, 35–55%), CD3, 92% (reference range, 65–85%), CD8, 61% (reference range, 20–36%), CD19, 0% (reference range, 5–15%), and ratio of CD4/CD8, 0.44 (reference range, 1.5–2). Bone marrow aspiration revealed normal cellularity (Fig. 3B) and increasing small‐sized mononuclear megakaryocytes (Fig. 3C and 3D). Microscopically, numerous defective neutrophils bore nuclei without segmentation (Fig. 3E and 3F), and neither excess of blasts nor ringed‐sideroblasts were shown in the iron staining, which was consistent with manifestations of MDS, the subtype of refractory cytopenia with multilineage dysplasia. In order to exclude the possibility of an incomplete resection or recurrence of thymoma, a chest CT scan was performed but it demonstrated no evidence of residual thymoma. The presence of thymoma with hypogammaglobulinemia confirmed the diagnosis of Good's syndrome. She received antibiotics therapy, incision, and debridement plus intravenous immunoglobulin (IVIG) infusion for infection control. She was lost to follow‐up after the infection resolved.

Table 1.

Summarized laboratory data of this patient.

Parameters Date	Nov 2006	Sep 2007	Dec 2008	Reference range
White blood cell (×109/L)	4.52	2.61	3.53	4–9.9
Hemoglobin (g/dL)	11.7	11.7	9.3	12.0–16.0
Platelet (×109/L)	231	202	204	150–450
Pelger‐Huet‐like cell (%)	0	17	45	0
IgG (mg/dL)			752.0	751–1560
IgA (mg/dL)			166.0	82–453
IgM (mg/dL)			15.9	46–304
Lymphocyte subpopulations
CD3 (%)			92	65–85
CD4 (%)			25	35–55
CD8 (%)			61	20–36
CD19 (%)			0	5–15
CD4/CD8			0.44	1.5–2
Human immunodeficiency virus			Negative	Negative
Antinuclear antibodies			Negative	Negative

CD  =  cluster of differentiation; Ig  =  immunoglobulin.

Figure 3.

Dysplasia showed in both myeloid series and megakaryocytes. (A) Normal nuclear segmentation of eosinophil versus Pelger‐Huet‐like cell (arrow) with round nuclei, dense clumped coarse chromatin and normal cytoplasmic granules in the peripheral blood (Wright's stain, ×1000). (B) Normal cellularity showed in bone marrow biopsy (H&E stain, ×400). (C) Increased number of small‐sized megakaryocytes in the bone marrow aspiration (Wright's stain, ×100). (D) Mononucleated medium‐sized megakaryocyte (Wright's stain, ×1000). (E) Two Pelger‐Huet‐like cells in the bone marrow were pointed out by arrow (Wright's stain, ×1000). (F) One Auer rod was found in the cytoplasm of a Pelger‐Huet‐like cell, shown by arrow (Wright's stain, ×1000).

Discussion

Paraneoplastic syndromes of thymoma are presumed to derive from autoimmunity. Except antibodies for the antiacetylcholine receptor in myasthenia gravis, the specific antibodies for parathymic syndromes have yet to be identified. Paraneoplastic syndromes, such as immunodeficiency and hematological disorders, may precede, arise concurrently with or follow the diagnosis of thymoma. At the same time, parathymic syndromes may or may not respond to thymectomy.

There are some hypotheses of immunodeficiency in Good's syndrome. For example, the main function of the fetal thymus is T‐cell depletion of autoreactive clones and the presence of thymoma breaks the balance of immunosurveillance; the compensation of immunodeficiency is presented by hyperplasia of the thymus; there are irrelative events of immunodeficiency and thymoma, such as cytokines released from bone marrow stromal cells, influencing both thymic and B cell precursors [8]. Around 50% of Good's syndrome patients are characterized with B‐lymphopenia and 20% with panhypogammaglobulinemia. The level of immunoglobulin is a good predictor of immunity but has a poor sensitivity for infections [9]. Recurrent sinopulmonary infection and chronic diarrhea are the most common manifestations in Good's syndrome. Due to impaired humoral and cellular immunity, Haemophilus influenzae, Streptococcus pneumoniae, and infection with Pseudomonas species or Klebsiella species are the most common infection situations a Good's syndrome patient could encounter. Opportunistic viral infections of Cytomegalovirus and Herpes simplex virus are also common [1]. Although no identical pathogen was identified in most cases with Good's syndrome, the major cause of chronic diarrhea is Giardia lamblia. For most patients with Good's syndrome, the hypogammaglobulinemia lasts or even worsens after the removal of the thymus. In order to reduce the risk of various infections, the maintenance of adequate IgG by prophylactic IVIG is recommended [1].

Concurrently, 12–16.2% of patients with MDS coexist with autoimmune disorders [10]. One proposed pathogenesis in MDS is autoantibodies that directly reject against hematopoietic cells, which was supported by the similar immune dysregulation of CD4 and CD8 T cells found in Good's syndrome [[11], [12]]. In addition, CD8 T cells are proved to be involved in damaging hematopoietic precursors [6]. In the National Comprehensive Cancer Network guidelines of MDS, immunosuppressive treatments are reasonable choices in patients with MDS and hypocellular bone marrow, HLA‐DR15, and positive clones of PNH or young individuals at low‐ to intermediate‐risk. Some thymoma patients with cytopenia(s) improved after thymectomy and some were responsive to adjuvant immunosuppressive agents (steroid, cyclophosphamide, vincristine) or monoclonal antibody (anti‐CD52; Campath‐1H) [13]. In the previously reported 72‐year‐old man with Good's syndrome and myelodysplasia, the myelodysplasia was diagnosed 8 years after thymectomy. He became transfusion‐independent after cyclosporine therapy [7]. Furthermore, the survival of MDS patients with immunological abnormalities was significantly worse than those without immunological abnormalities, and the outcomes of patients with an inverted CD4/CD8 ratio were poorer than those with CD4/CD8 ratio >1 [14].

In our study case, the Pelger‐Huet‐like cells in peripheral blood were found before the diagnosis of thymoma. Although the diagnosis of MDS and Good's syndrome was confirmed 14 months after thymectomy, delayed diagnosis was possible given because of the occurrence of similar infections before and after the operation. Furthermore, hypogammaglobulinemia was restricted to IgM despite of undetectable peripheral pre‐B or B cells. The presumed cause of falsely elevated values of IgG or IgA may be due to the coexisting monoclonal IgG or IgA [15]. Since she had dysfunction of both innate (neutrophil granulocytes) and adaptive immunity (B and T lymphocytes), she presented with uncommon bacterial soft tissue and urinary tract infection instead of sinopulmonary infection. At the same time, unusual pathogens of E. coli and ORSA were isolated. Moreover, cytopenias in MDS were defined as hemoglobin <10 g/dL, absolute neutrophil count <1.8 × 10⁹/L and platelets <100 × 10⁹/L by WHO classification. The diagnosis of MDS can be made in patients with typical morphological and/or cytogenetic abnormalities, but their hemograms are normal. In this case, her platelet count was within normal range during the whole course even though definite mononucleated megakaryocytes showed in the bone marrow. Since the incidence of thrombocytopenia correlated with disease severity classified by the International Prognostic Scoring System (IPSS) [16], an increased number of dysmegakaryocytes to compensate ineffective megakaryopoiesis was presumed. Due to repeated infection, reactive thrombocytosis might also play a role. However, it was rather a pitfall for not performing a cytogenetic examination for this patient, that we were unable to classify her risk level according to the IPSS. Immunosuppressive treatment was considered reasonable for her due to her high possibility of having autoimmunity‐associated young MDS. Although theoretically beneficial, there was no direct evidence to support our treatment strategy since this patient was lost to follow‐up.

In conclusion, it is important to recognize the presence of autoimmune‐mediated myelodysplastic syndrome and adopt immunosuppressive treatment as needed. For thymoma patients with recurrent infections, Good's syndrome must be excluded by comprehensive immunologic investigations and prophylactic IVIG should be prescribed in suitable candidates.