Thymoma is a rare mediastinal tumour that originates from the epithelium of the thymus, with an incidence of 0.13–0.15 per 100,000 person-years (1, 2). Thymoma correlates with various autoimmune diseases, among which myasthenia gravis (MG) is the most prevalent and is found in up to 44% of cases (3, 4). Other autoimmune diseases, especially haematological diseases (HDs), are less frequently reported but may affect survival (5–7). Unlike thymoma-associated MG, surgical thymectomy for other autoimmune diseases remains under debate owing to the largely unknown efficacy and risks of disease progression (8, 9). Overall, there is a knowledge gap regarding the aetiological association between thymoma and autoimmune diseases, notably those other than MG.

Pure red cell aplasia (PRCA) is a rare acquired isolated erythropoietic failure and one of the most common thymoma-associated HDs. The incidence of PRCA is 2–5% in patients with thymoma, and a thymic tumour can be detected in 10–20% of patients with PRCA, suggesting autoimmune interaction (10–12). Thymoma-associated PRCA often accompanies other HDs, including Good's syndrome (thymoma plus hypogammaglobulinaemia), autoimmune haemolytic anaemia (AIHA) and other cytopaenias (11, 13). Unlike MG, remission of PRCA after thymectomy has yet to be determined, and several series have inconsistently reported remission rates of 5–25% (11, 14, 15). Interestingly, B cell aplasia and hypogammaglobulinaemia in Good's syndrome are largely unaffected by immunosuppressive therapy (IST) and thymectomy (13). Differences in characteristics, therapeutic responses, and chronological sequences highlight the complex interplay between thymoma and HDs.

Thymoma-associated PRCA and other HDs are to date only found in case reports or series. The disease trajectory and outcome of patients who have undergone thymectomy are also less reported. Hence, a systematic review may provide insight into rare but potentially devastating manifestations. In the present study, we retrospectively reviewed thymoma-associated HDs in a medical institute. A descriptive analysis was conducted to elucidate the characteristics, chronological sequences, treatments, remissions, and outcomes of these patients. The aim of the study was to reveal the features and long-term evaluation of thymoma-associated PRCA and other HDs. A systematic review incorporating case reports and series in the past 15 years is provided as well.

To the best of our knowledge, the current study represents one of the few published reports about thymoma-associated PRCA in the literature and the first series in Taiwan. We also incorporated a systematic review of the recent decade to define this rare but puzzling autoimmune manifestation. The incidence of thymoma-related PRCA (5%) and Good's syndrome (2%) in our series were consistent with published studies (4, 13, 23, 25). The complexity and scope of autoimmune manifestations were also similar, whereby MG was most common, accounting for nearly one-third of cases, followed by scattered cases of haematological, rheumatological and neurological disorders (4). Remission of autoimmune disease after thymectomy also varied largely between MG and those other than MG in our study. Together, these results indicate that the complex and aberrant immune dysregulation in thymoma may present with distinctive autoimmune manifestations.

Miscellaneous cytopaenias related to thymoma can be observed but are not limited to a specific haematopoietic lineage (23). In our pooled analysis, Good's syndrome, amegakaryocytic thrombocytopaenia, and AIHA in addition to PRCA accounted for 22% of cases. Therapeutic responses varied in different cytopaenias and relapsed or subsequent involvement of additional lineages was found. Conversely, thymectomy alone did not confer high and durable remission of PRCA. Although early reports indicate a remission rate of 25–30% in patients who undergo thymectomy, recent evidence suggests a contradictory result that remission is rarely durable with thymectomy alone (5, 15, 24, 26). For example, Hirokawa et al. reported that although first IST was effective in 74% of thymoma-associated PRCA, only 2 of 35 patients who received IST remained in sustained remission after discontinuation (11). In our series, only two patients responded to thymectomy, and three maintained remission under IST. In addition, we failed to observe patients with Good's syndrome to recover after thymectomy and other treatments. The United Kingdom-Primary Immune Deficiency registry indicated that patients with Good's syndrome fail to respond to thymectomy or IST and require prolonged IVIg prophylaxis, with 95% having complications of infection that lead to a mortality rate of 9% (13). Consistent with previous reports, our results reflect that long-term evaluation of the disease trajectory, such as cytopaenia or Good's syndrome, might be required and that infectious complications should be carefully accounted for in treating these patients.

Patients with MG constitute a distinctive disease population compared with other autoimmune diseases. We found a significantly higher remission rate after thymectomy with MG. Several hypotheses have been proposed to explain the link between thymoma and paraneoplastic autoimmunity, including immune escape, aberrant autoimmune selection, and genetic predisposition (27–29). In general, the discrepant remission rate in response to thymectomy may be explained by the central role of the thymus in MG but not in other HDs. In contrast, more complex cellular and humoural immune dysregulation is observed in HDs such as PRCA and Good's syndrome (30, 31). Thymectomy does not sufficiently ameliorate autoimmune interactions and requires additional immunomodulatory therapies to achieve durable remission.

In the chronological sequence of thymoma and PRCA, our series revealed a concurrent course in five of seven patients and PRCA after diagnosis of thymoma in 1 patient. In contrast, Hirokawa et al. reported that 60% of patients developed PRCA in a median interval of 80 months after the diagnosis of thymoma (11, 22). Our pooled analysis indicated that 44% of patients developed PRCA after thymoma, with 30% having a concurrent course. The discrepancy of the present series with the literature might have resulted from routine image evaluation for detecting asymptomatic thymomas and limited case numbers. Regardless, the results highlight the need for monitoring the development of subsequent HDs, even in patients who had received thymectomy long ago.

In this series, histology subtypes of thymoma varied and were associated with specific autoimmune manifestations. We observed that six of seven patients with thymoma-associated PRCA had cortical (WHO B1 and B2) or mixed (WHO AB) thymoma, and these tumours were abundantly infiltrated by immature terminal deoxynucleotidyl transferase-positive T cells. Similar results were found in pooled analysis, revealing that half of patients with thymoma-associated PRCA had lymphocyte-rich thymoma (WHO B1, B2, or AB). Although early reports have indicated that PRCA is found predominantly with the spindle cell type (WHO A), recent observations suggest that lymphocyte-rich tumours are prevalent (15, 32, 33). Zaman et al. reported a series of 78 patients with Good's syndrome, among whom 10% had concomitant PRCA, and reported that lymphocyte-rich thymoma constituted the majority of patients (72%), consistent with our results (13). Hoffacker et al. proposed that thymoma patients have higher circulating CD45RA⁺ CD8⁺ T cells with lymphocyte-rich thymoma than healthy controls and that autoimmune T cells respond to thymectomy (34). Despite a putative mechanistic correlation, more information is required to delineate the causal relationship between the development of HDs and autoimmune T cells in lymphocyte-rich thymoma.

The merit of the present study is the incorporation of published reports of extremely rare diseases with relatively adequate case numbers. We also describe detailed clinicopathological characteristics and therapeutic outcomes for a considerably long follow-up time. However, some limitations exist. First, this was a retrospective study, which cannot address causal relation disputes prospectively. Second, publication bias with regard to reporting of investigator-preferred and responsive patients was present among the included articles, with a limitation of case reports instead of large observational or collaborative studies. Our future work will focus on nationwide data to elucidate the interaction of thymectomy and associated HDs and predictors of IST efficacy.

In conclusion, we report a case series of thymoma-associated HDs such as PRCA and Good's syndrome in conjunction with a systematic review. Patients with autoimmune diseases other than MG have a lower remission rate after thymectomy than those with MG. Remission of thymoma-associated PRCA can be achieved by thymectomy and IST. Nonetheless, Good's syndrome is unaffected and associated with the risk of infections. Together, these results provide insight into extremely rare but puzzling autoimmune diseases.

The data that support the findings of this study are available from the Cancer Registry of the Electronic Medical Records in National Cheng Kung University Hospital, but restrictions apply to their availability. The data for the current study were used under specific permission and are not publicly available elsewhere. The data are, however, available from the authors upon reasonable request and with the permission from the corresponding author Prof. Tsai-Yun Chen. Division of Haematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. teresa@mail.ncku.edu.tw, No. 168, Sheng-Li Road, Tainan 70403, Taiwan.

The studies involving human participants were reviewed and approved by B-ER-110-170 National Cheng Kung University Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

C-CY and W-LH contributed for writing the manuscript and data management. S-SL and Y-PC assist in the manuscript writing and systematic review of the literature. Y-LT, Y-TY, and C-YC provide critical patient information. Y-TH and T-YC initiate the study design and investigations. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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