Atypical type A thymoma: a narrative review of a distinct and progressive variant of low-risk thymoma

Introduction

Thymoma is the most frequently encountered primary epithelial tumor among anterior mediastinal masses in adults and is a rare disease, accounting for 0.2–1.5% of all malignancies (1,2). Its biological behavior is diverse, ranging from tumors with an extremely favorable prognosis and indolent growth to more aggressive conditions, including local invasion and distant metastasis. Although tumor stage remains one of the most important predictors of clinical outcome, the disease course is also strongly influenced by histological subtype. The most frequently used classification of thymomas is the World Health Organization (WHO) classification, which was first published in 1999 (3). The WHO classification categorizes thymomas into five types— A, AB, B1, B2, and B3—based on the morphology and atypia of the thymic epithelial cells and the proportion of lymphocytes, and generally reflects the prognosis and malignancy grade well (3-6). Among these, type A thymomas are classified as the group with the best prognosis and the lowest malignancy grade. Its 5- and 10-year survival rates are reported to be close to 100% (7-9). Despite its generally favorable prognosis, type A thymoma with atypical features results in postoperative recurrence and distant metastasis, which has been reported (10,11). To distinguish these atypical cases, the concept of atypical type A thymoma was recently proposed (4,6,11). Atypical type A thymoma is a rare disease with few reports. Since studies on atypical type A thymoma are largely case reports/series-based, many clinicopathological details remain unclear. Aggressive behavior has also been reported in conventional type A thymomas; however, its relationship with atypical type A thymomas remains unclear. In this review, we aimed to integrate the latest knowledge regarding the clinicopathological characteristics, pathological diagnostic criteria, differential diagnoses, molecular pathology, and treatment of atypical type A thymoma. Simultaneously, type A thymomas exhibiting aggressive behavior were reviewed. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-63/rc).

Methods

To ensure transparency and reproducibility, the study selection process followed the reporting principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with detailed documentation of the number of records identified, screened, excluded, and included, as well as the search strategy. The search criteria focused on patients diagnosed with atypical type A thymoma or tumors containing an atypical type A component and their clinical outcomes. Clinical details from individual cases in the identified reports were extracted to provide a descriptive overview of clinicopathological features, recurrence, and survival outcomes. A narrative review was conducted by searching the PubMed database for articles published between January 1990 and July 2025. The search strategy combined Medical Subject Headings and free-text terms as follows: (“Thymoma” OR “Thymus Neoplasms”) AND (“medullary”[tiab] OR “spindle cell”[tiab] OR “type A”[tiab] OR “type AB”[tiab]) AND (“atypia”[tiab] OR “atypical”[tiab] OR “atypical A thymoma”[tiab] OR “atypical features”[tiab] OR “atypical type A thymoma”[tiab] OR “focal atypia”[tiab] OR “hypercellularity”[tiab] OR “invasive”[tiab] OR “mitosis”[tiab] OR “mitotic”[tiab] OR “mitotic activity”[tiab] OR “necrosis”[tiab] OR “unusual histology”[tiab] OR “unusual morphology”[tiab]). A total of 166 records were initially identified. After screening titles and abstracts, 146 English-language articles were selected for further evaluation. Exclusion criteria included studies focusing on non-thymic epithelial tumors (TETs), TET subtypes other than type A or AB, ectopic presentations, and review articles without primary clinicopathological data. Of 48 full-text articles assessed in detail, 31 were excluded for the following reasons: ineligible histological subtype (n=14), insufficient description of the atypical type A component (n=10), and lack of primary data in a review article (n=1). Furthermore, six original studies that mentioned atypical type A thymoma were strictly excluded because they lacked detailed individual clinicopathological data (10,12-16). In addition, manual reference screening identified two further relevant study not indexed in PubMed. Table 1 summarizes the search strategies used in this study. Two original studies (11,17) and 16 case reports or series concerning atypical type A thymoma or tumors containing an atypical type A component (18-33) were identified. By analyzing data from selected case reports/series (with <10 cases of type A or atypical type A thymoma) and original reports with comprehensive clinicopathological and survival data on atypical type A thymoma, we aimed to build a deeper understanding of this rare thymoma subtype. Overall survival (OS) was defined as the interval between initial treatment and death or last follow-up. Survival curves were constructed using the Kaplan-Meier method, and all statistical analyses were performed using SPSS^® version 29.0 (IBM Corp., Armonk, NY, USA). Given the small sample size and the potential for inter-observer variability across institutions, survival and recurrence data are presented as descriptive and exploratory benchmarks for this rare entity.

Histological classification of thymoma: changes focusing on the type A subtype

Type A thymomas are histologically characterized by bland spindle or oval epithelial cells arranged in fascicles, swirls, whorls, rosettes, and sheets, admixed with few or no lymphocytes (6). Necrosis and mitotic counts are typically absent. In the International Thymic Malignancy Interest Group database, type A thymoma is the least frequent subtype, accounting for approximately 11% of all thymomas (2,7,11,34-36). According to the WHO classification, type A thymomas traditionally account for approximately 90% of stage I–II thymomas (6-9,34,37-41), whereas only 1–5% present at stage IV (2,6,7,9,34,37,41). While type A thymomas have conventionally been regarded as low-grade malignancies, recent pathological studies have revealed that a subset of cases exhibits more invasive behavior, including postoperative recurrence and distant metastasis. This subgroup has been recognized as an atypical type A thymoma (10,11). Atypical type A thymomas were first reported by Nonaka et al. in 2012 (11). Subsequently, the “atypical type A thymoma variant” was introduced as a provisional category in the 4th edition of the WHO classification in 2015 (4,42) and was formally added as one of the new subtypes in the 5th edition in 2021 (6). Atypical type A thymomas maintain the fundamental histological features of conventional type A thymomas, while possessing the following atypical characteristics: (I) increased mitotic counts; (II) hypercellularity; and (III) focal necrosis (6). Atypical type A thymomas were defined as those with one or more of the following pathological features (Figure 1A,1B): While a quantitative standard for mitotic counts has not been explicitly stated, conventional type A thymoma is defined as ≤4 mitotic cells/2 mm² (4,6,42), and a count ≥5 cells/2 mm² is generally considered the threshold (6). Moreover, no quantitative definition of hypercellularity is provided in the WHO criteria (6). As a result, the diagnosis of atypical type A thymoma remains partly subjective, potentially leading to inter-observer variability across the published literature. Consequently, the clinicopathological trends identified in this retrospective review should be interpreted as preliminary rather than definitive, and caution is warranted when drawing firm conclusions.

Figure 1 A case of type AB thymoma with atypical type A component. (A) Representative histological appearance of type AB thymoma showing spindle-shaped epithelial cells and lymphocyte-rich areas (hematoxylin-eosin staining; magnification: ×100). (B) Atypical type A component. Hypercellularity and increased mitotic counts of 5–6 cells/2 mm² were present. No focal necrosis was detected (hematoxylin-eosin staining; magnification: ×400).

Suster et al. classified moderately differentiated TETs as atypical thymomas (ATs), with a departure from the purely morphological WHO classification (43,44). Recently, the progressive clinical course of atypical type A thymomas has been shown to resemble that of conventional type B3 thymomas rather than that of conventional type A thymomas (17,45). Consequently, Suster et al. recently proposed that atypical type A thymoma should be regarded as the spindle cell counterpart of type B3 thymoma, classifying AT into epithelioid (“squamoid”) AT (conventional type B3 thymoma) and spindle cell AT (atypical type A thymoma) (17,45). This conceptual framework positions atypical type A thymoma as a spindle cell variant of type B3 thymoma, with both subtypes occupying an intermediate biological position along the spectrum of malignant progression between low-risk thymomas and thymic carcinomas (TCs). Such a model aligns observed clinical behavior more closely with histopathological features and highlights that atypical type A thymoma behaves biologically more like type B3 thymoma than like the indolent conventional type A subtype.

Clinicopathological features of atypical type A thymoma (pure atypical type A thymoma and thymoma with atypical type A component)

Due to their rarity, epidemiological information on atypical type A thymomas is limited. Atypical type A thymomas are not exclusively associated with type A thymomas; they have been reported to coexist with type AB thymoma (21,28,30,43). Similarly, Suster et al. reported that atypical type A thymomas (spindle cell AT) coexist with B1/2 and B3 thymomas (squamoid AT) (17,45). These cases were classified as AB thymomas based on current WHO criteria (6), and associations between micronodular thymoma and TC have also been reported (17,45). Atypical type A thymomas can coexist with various subtypes; in this review, we investigated atypical type A thymomas: pure atypical type A thymomas (only a type A component) and thymomas with an atypical type A component. Atypical type A thymoma patients with TC were excluded. From two original reports and 16 case reports or series describing atypical type A thymoma or thymoma with an atypical type A component (11,17-33), a total of 67 cases (pure atypical type A thymoma: n=43; thymoma with an atypical type A component: n=24) were identified and are summarized in Table 2. To facilitate more nuanced interpretation, the two entities were analyzed separately. This approach acknowledges the potential influence of mixed histological components on clinical outcomes while providing a comprehensive overview of this rare entity.

Clinical and radiological findings

The median age of all patients with atypical type A thymomas was 65 years (range, 19–84 years). Moreover, the mean age of patients with pure atypical type A thymomas was 66 years (range, 32–84 years). The male:female ratios for all atypical type A thymomas and pure atypical type A thymomas were 1.2:1 and 1.4:1, respectively. For conventional type A thymomas, the mean age was 64 years (range, 8–88 years), with a male-to-female ratio of 1:1.4 (6,41,46). Although there was a slight male predominance of pure atypical type A thymomas, there was no significant difference between the two subtypes. Information regarding the symptoms was available for 31 patients. Fifteen patients (48.4%) were asymptomatic and were detected incidentally on radiological examination. Twelve cases presented with dyspnea, cough, chest pain, and chest discomfort due to the large mediastinal masses, and one case presented with fever (11,24,26,31-33). Moreover, thymomas are widely associated with paraneoplastic syndromes, and the development of myasthenia gravis (MG) often triggers their discovery. Compared to other subtypes, type A thymoma has a lower incidence of concurrent MG, reported to be approximately 17% (6,41,46). In all atypical type A thymomas, MG were observed in 6 of 67 cases (9.0%). Other paraneoplastic syndromes included a case of Good syndrome, polymyalgia rheumatica, and thrombocytopenia (11,17,25). In pure atypical type A thymoma, MG was detected in only one case (2.3%), which tended to be less than the typical cases.

Radiologically, the median tumor size of the atypical type A thymoma was 6.3 (range, 1.2–15) cm. In pure atypical type A cases, the mean tumor size was 6.0 (range, 1.2–14) cm. This is consistent with the reports for conventional type A thymoma of median size of 6.0–7.9 cm (9,34). Positron emission tomography (PET)-CT has been reported to be useful for evaluating the malignancy of thymoma and determining treatment strategies (47-50). PET/CT data were available for only 7 cases (18,23-25,27-29). The median maximum standardized uptake value (SUV) was 3.5 (range, 1.5–6.1). The SUVmax of low-risk (types A, AB, and B1) and high-risk thymomas (types B2 and B3) were approximately 3.5 and 4.0, respectively (48,49). Regardless of its invasiveness, fluorodeoxyglucose uptake in atypical type A thymomas is similar to that in low-risk thymomas. The characteristic radiological findings of atypical type A thymomas have not been reported; hence, they are difficult to differentiate based on radiological imaging alone.

Treatment

Excluding one case in which treatment information was unavailable, complete surgical resection was planned as the initial treatment in 58 of the 66 cases. Among these, 11 had positive surgical margins (17). The efficacy of debulking surgery for thymoma has been reported (51-53) and was performed in six cases (17,23,27). Other initial treatment included one case of chemoradiotherapy and one case of diagnostic lung biopsy (20,32).

Following the initial treatment, chemotherapy, radiotherapy, or metastasectomy was administered based on the residual disease and recurrence site. Detailed information regarding chemotherapy regimens is scarce, but there is currently no specific regimen for atypical type A thymomas. Thus, chemotherapy regimens have been established for typical thymomas (32). Therefore, it is important to determine treatment strategies using a multidisciplinary approach.

Pathologic findings

Yanagiya et al. reported a case in which conventional and atypical type A thymomas were adjacent to the tumor, suggesting that atypical type A thymomas may arise from conventional thymomas (27). A previous report described frequent GTF2I mutations in 82% and 75% of types A and AB thymomas, respectively, but rarely in other thymomas (54). This GTF2I mutation has also been detected in the atypical type A component (21), supporting this suggestion.

Focal necrosis and high mitotic counts are the diagnostic factors for atypical type A thymoma (4-6). Conventional type A thymomas generally show absent or lobular (ischemic) necrosis, whereas atypical type A thymomas show small coagulative tumor necrosis or comedo-like necrosis, in contrast to ischemic or biopsy-induced necrosis (11,55). In the case reports/series, necrosis was observed in nine of 13 cases (19-22,24,26,28,29,31). Nonaka et al. reported small foci of necrosis in of 7/13 cases (11).

Information on mitotic activity was available for 13 cases from the case reports/series (18-21,23,26-28,30,31,33). The mean mitotic count was 5.1 mitoses (range, 0–11.8)/2 mm² [10 high-power fields (HPF) =2.37 mm² as previously reported (56)]. Nine of the 13 patients met the criterion of >5 mitotic count/2 mm². Nonaka et al. reported a median of 7 [5–13] mitotic cells per 10 HPF (11). Conversely, Suster et al. reported a somewhat lower mitotic activity of 2.5 (range, 0–12) per 10 HPF (17).

Representative immunohistochemistry findings in case reports/series were as follows; positive rate for AE1/AE3, p40/63, BCL-2, CD5, and CD117 were 6/6 (100%), 10/10 (100%), 3/4 (75%), 1/9 (11.1%), and 0/7 (0%), respectively (18,19,21,23,26-29,31-33). Furthermore, CD5 and CD117 positive cases have been previously reported in original reports (11,17). The expression of CD5 and 117 in TETs is widely accepted as highly suggestive of TC (6); hence, this presents a potential diagnostic pitfall in differentiating atypical type A and TC.

Ki-67 index (MIB-1 index) is an indicator of cell proliferation. The Ki-67 index of TETs were 1.2%±0.6%, 4.5%±2.9%, 4.7%±2.6%, 6.4%±3.0%, 7.0%±3.2%, 16.6%±12.1% in type A, AB, B1, B2, B3, and TC, respectively (57). Type A thymomas generally have a low Ki-67 index, but the atypical subtype showed a median 14.5% (range, 3–15%) (for 10 cases with available data in the case report/series) (18-21,23,27,28,30-32). Similarly, the original report showed a median Ki-67 index of 10–13.7% (11,17). Metastatic/recurrent lesions tended to have a higher index (19,32). These results provide evidence that atypical type A possesses a proliferative capacity closer to that of types B3 and TC.

Recurrence pattern and prognosis of atypical type A thymoma

The Masaoka stages for all 67 patients were 9, 31, 12, 1, 7, and 7 in stages I, II, III, IV, IVa, and IVb, respectively. Follow-up data of 44 patients with atypical type A thymoma were used to assess patterns of recurrence and prognosis. The median follow-up period was 5 years (range, 9 days–20 years). Tumor recurrence was observed in 12 (27.3%) patients. In pure atypical type A, tumor recurrence was detected in 3/26 cases (11.5%), with a median follow-up of 3.9 years (range, 1–20 years). Compared to the reported recurrence rates of 4% and 2% for type A and AB thymomas, this rate is notably higher (34). The most common sites of recurrence were the lungs (8 cases), followed by the rib or chest wall (4 cases), pleura (3 cases), and brain (3 cases). Single cases of recurrence were reported in the spine, liver, kidney, pericardium, paraspinal region, and bone. The median tumor size in recurrent cases was 10.6 (range, 5.8–15) cm compared to the 6.0 (range, 1.2–14) cm of non-recurrence cases. The stage of recurrence was stage I in one case, stage II in three cases, stage III in four cases, and stage IV in four cases. Recurrence was more frequent with upstaging, although we need to pay attention to the fact that recurrence also occurred in stage I. The median time to first recurrence was 4 years (range, 1–10 years). Given that some cases recur nearly 10 years after the initial treatment, a follow-up of 10 years or more is advisable, similar to conventional thymomas (58,59).

Of the 44 patients, 13 (29.5%) died, with six tumor-related deaths. The median time to death was 9 years (range, 9 days–20 years). The 5-year OS of atypical type A thymoma in this review was 91.9%. In patients with pure atypical type A disease, the 3-year OS was 96.3%. This prognosis is more favorable than that reported for type B2–B3 thymomas, which have 5- and 10-year OS rates of 70–100% and 60–86% for B2, and 45–82% and 50–70% for B3, respectively), and is comparable to that of conventional type A and AB thymomas (6-8,38). Despite this favorable survival, the recurrence rate of 27.3% is substantially higher than the 2–4% reported for conventional type A or AB thymomas (34). This indicates that atypical type A thymoma, while associated with good OS, follows a more progressive clinical course with a greater propensity for recurrence and metastasis (11,17,45). The median time from first recurrence to tumor-related death was 4 years (range, 0–9 years). Because of this rare entity, the prognostic indicators of atypical type A thymomas have not been well evaluated. A previous report showed that necrotic foci correlate with recurrence, extrathoracic metastasis, and an increase in stage (10,12). The tumor size, mitotic activity, and stage at diagnosis were not considered to be associated (12). However, these analyses also included conventional type A thymomas and did not evaluate purely atypical features. Further case studies are required to confirm this hypothesis.

Type A thymoma exhibiting aggressive behavior

As mentioned previously, not all type A thymomas that exhibit aggressive behavior or distant metastasis necessarily contain an atypical type A component; conventional type A thymomas can also metastasize, albeit extremely rarely. Therefore, we reviewed reports on type A thymomas that demonstrate aggressive behavior (10,12,13).

Moran et al. evaluated 41 patients. Their ages ranged from 38 to 80 years old. The tumor sizes ranged from 3 to 18 cm. The Masaoka stages were stage II in 34 patients, stage III in 6 patients, and stage IV in 1 patient. Follow-up data were available for 39 patients, 38 of whom remained recurrence-free during a follow-up period of up to 96 months. Only one patient died 10 months after the initial diagnosis (no information about the cause of death). Overall, none of the tumors showed necrosis, and in a few cases, rare mitotic figures were present (13). Green et al. retrospectively examined 68 type A thymomas with atypical features (nuclear pleomorphism, mitotic activity, and necrosis). The median patient age was 65 years (interquartile range, 57–71 years). Stages I and II accounted for 94.1% of patients, and stages III and IV accounted for 5.8%. This study evaluated both type A and AB cases; thus, concrete mitotic counts and the presence of necrosis in type A thymomas alone were not available. No recurrence or tumor-related deaths were recorded (12). Vladislav et al. reviewed 23 cases of type A thymoma. The median patient age was 54 [40–88] years. Nine patients were stage II, six were stage III, and five were stage IV. Recurrence was observed during the follow-up period (median, 18 months) in 9 cases (39.1%). Seven patients experienced local recurrence in the pleura and lungs. Six patients developed distant metastases to the liver (four patients), neck (two patients), and bone (one patient), including one case of concurrent liver and bone metastases, 7–107 months after the initial diagnosis. A high mitotic count was present in only one patient with stage IVa disease (10 mitotic counts/10 HPF). Foci of necrosis were noted in 4 of 23 cases (2 cases in stage I/II and 2 cases in stage III/IV) (10). These high recurrence rates in apparently conventional type A thymomas suggest that some cases may have harbored unrecognized atypical components. Indeed, atypical type A components are sometimes detected only after resection of recurrent lesions (30). We previously reported a case initially diagnosed as type AB thymoma in which re-evaluation of both the primary and metastatic lesions, prompted by pulmonary metastasectomy 11 years after the initial surgery, revealed an atypical type A component (30). Because the primary surgery in that case was performed before 2015, when atypical type A thymoma was formally recognized, the atypical component may have been overlooked. Therefore, when distant metastasis is suspected after resection of a type A or AB thymoma, particularly in cases treated before 2015, recurrence of an atypical type A component should be strongly considered, and active pathological re-evaluation of both the recurrent and primary tumors is warranted.

As none of these reports explicitly mentioned the specific proportion of atypical type A cases, it is likely that atypical cases constitute a minority of reported cohort, given the low overall case numbers exhibiting necrosis and a high mitotic count. Therefore, the actual frequency of aggressive typical type A thymomas and their clinical features remain unknown. However, it is crucial to understand that even conventional type A tumors, although rare, can metastasize and recur. Active pathological reevaluation is necessary to determine whether conventional type A metastatic cases contain overlooked atypical components. Characterizing these clinical features may aid in refining postoperative follow-up strategies.

Differential diagnoses

The two important differential diagnoses of atypical type A thymomas are type B3 thymoma and TC. When a portion of a type B3 thymoma shows spindle cells, it must be differentiated from an atypical type A thymoma. Prominent and abundant perivascular spaces with surrounding epithelial palisading would strongly favor the diagnosis of type B3 thymoma (42). Staining for CD20 and Claudin-4 as markers for type A and thymoproteasome β5t subunit as a marker for type B is also helpful (6,60).

For TC, squamous cell and sarcomatoid carcinomas must be differentiated from atypical type A thymomas. A key distinguishing feature is that atypical type A thymomas are typically mixed with lymphocytes, whereas TCs show minimal or no lymphocyte infiltration (61). The qualitative assessment of necrosis patterns is also important. Typically, atypical type A tumors exhibit small foci of coagulative necrosis. This contrasts with the large, confluent coagulative necrosis of the TC (11). Immunobiologically, TCs are generally positive for the CD5 and CD117 proteins. Conventional type A thymomas are negative, but atypical type A thymomas are sometimes positive. Therefore, it is essential to assess the entire tumor. Attention must also be paid to cases where atypical type A thymoma and TC coexist (17,45). The epithelial expression of CD20 is a potential marker of type A thymomas, but is infrequently present in atypical type A thymomas (19,21,31,32,55). Based on these findings, the differentiation from TC can sometimes be difficult, necessitating the development of new subtype-specific markers (55).

Future directions

Atypical type A thymoma is a rare tumor, and further clinicopathological elucidation through the accumulation of more cases is desired. Furthermore, the development of prognostic prediction models based on long-term follow-up is necessary. Moreover, regarding the differential diagnosis of conventional metastatic type A thymomas, performing analyses that clearly distinguish between the two subtypes will lead to a deeper understanding of the disease concept of type A thymoma and clarify its correct classification. Achieving this goal requires the establishment of standardized pathological diagnostic criteria, including defined methods for counting mitoses and quantifying hypercellularity, as well as clearer guidance on the assessment of focal necrosis (6). Standardization of these criteria is essential to minimize diagnostic variability among pathologists and to enable more accurate characterization of the true biological behavior of atypical type A thymoma, including its prognosis and risk of recurrence.

Suster et al. advocated the abolition of the current alphanumeric WHO classification, arguing that it should be replaced with more intuitive and understandable terminology (45). Specifically, they proposed a new classification system for thymomas that divides them into epithelioid and spindle cell types. Furthermore, if the current WHO classification is continued, they propose classifying Type A thymoma as follows: type A1 thymoma, lymphocyte-rich spindle cell thymoma (formerly type AB); type A2 thymoma, lymphocyte-poor spindle cell thymoma (formerly Type A), and type A3 thymoma, spindle cell thymoma with atypical features (formerly atypical type A thymoma) (45,62). An appropriate classification system is required for the correct understanding of a new subtype.

Genetic mutation analyses of thymomas have been actively pursued recently. Bürger et al. reported two cases of atypical type A thymoma with gains in chromosome 17q and losses in chromosome 17p (20). The latter has previously been preferentially observed in TC (63,64) and is rare in type A thymomas (64). This finding may be helpful in differentiating conventional type A from the progressive system of TC. Conversely, next-generation sequencing of 47 cases did not detect mutations that were actionable for current targeted therapies. Further genomic investigations are required to guide targeted treatments (17).

Furthermore, the immunobiology of TETs is still poorly understood (65). PD-L1 expression and the percentage expression of PD-L1 are significantly higher in aggressive thymomas such as type B2 or B3. Progress in this research area of atypical type A thymomas may lead to the application of new immune checkpoint inhibitor regimens in advanced or recurrent cases.

Conclusions

This review summarizes current knowledge on the rare entity of atypical type A thymoma. Although OS more closely resembles that of conventional type A and AB thymomas, atypical type A thymoma shows a more progressive clinical course, with recurrence rates exceeding those of types A and AB and approaching those of type B3 thymoma. This discrepancy supports the recent concept of atypical type A thymoma as the spindle cell counterpart of type B3 thymoma, occupying an intermediate biological position between low-risk thymomas and TCs. Therefore, atypical type A thymomas should be distinguished from conventional type A thymomas. On the other hand, in terms of type A thymomas with aggressive behavior, previous studies included a mix of atypical and typical cases, and therefore did not accurately reflect the frequency and clinical features of metastatic type A thymomas. Although this review provides a useful clinical benchmark based on 67 identified cases, the inherent limitations of a literature-based analysis and the small sample size should be acknowledged. Further accumulation of cases, long-term follow-ups, establishment of strict diagnostic criteria, and clinicopathological evaluation of atypical type A are essential for understanding this rare tumor.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-63/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-63/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-63/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010;5:S260-5. [Crossref] [PubMed]
2. de Jong WK, Blaauwgeers JL, Schaapveld M, et al. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008;44:123-30. [Crossref] [PubMed]
3. Rosai J, Sobin LH. World Health Organization International Histological Classification of Tumours, Histological Typing of Tumours of the Thymus. 2nd ed. Berlin: Springer; 1999.
4. Travis WD, Brambilla E, Müller-Hermelink HK, et al. WHO classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon: International Agency for Research on Cancer; 2015.
5. Marx A, Chan JK, Coindre JM, et al. The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes. J Thorac Oncol 2015;10:1383-95. [Crossref] [PubMed]
6. WHO Classification of Tumours Editorial Board. Thoracic Tumours. th ed. Lyon: International Agency for Research on Cance; 2021.
7. Okumura M, Ohta M, Tateyama H, et al. The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 2002;94:624-32. [Crossref] [PubMed]
8. Ströbel P, Bauer A, Puppe B, et al. Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol 2004;22:1501-9. [Crossref] [PubMed]
9. Nakagawa K, Asamura H, Matsuno Y, et al. Thymoma: a clinicopathologic study based on the new World Health Organization classification. J Thorac Cardiovasc Surg 2003;126:1134-40. [Crossref] [PubMed]
10. Vladislav IT, Gökmen-Polar Y, Kesler KA, et al. The role of histology in predicting recurrence of type A thymomas: a clinicopathologic correlation of 23 cases. Mod Pathol 2013;26:1059-64. [Crossref] [PubMed]
11. Nonaka D, Rosai J. Is there a spectrum of cytologic atypia in type a thymomas analogous to that seen in type B thymomas? A pilot study of 13 cases. Am J Surg Pathol 2012;36:889-94. [Crossref] [PubMed]
12. Green AC, Marx A, Ströbel P, et al. Type A and AB thymomas: histological features associated with increased stage. Histopathology 2015;66:884-91. [Crossref] [PubMed]
13. Moran CA, Kalhor N, Suster S. Invasive spindle cell thymomas (WHO Type A): a clinicopathologic correlation of 41 cases. Am J Clin Pathol 2010;134:793-8. [Crossref] [PubMed]
14. Thomas de Montpréville V, Quilhot P, Chalabreysse L, et al. Glut-1 intensity and pattern of expression in thymic epithelial tumors are predictive of WHO subtypes. Pathol Res Pract 2015;211:996-1002. [Crossref] [PubMed]
15. Zhao T, Wu J, Liu X, et al. Diagnosis of thymic epithelial tumor subtypes by a quantitative proteomic approach. Analyst 2018;143:2491-500. [Crossref] [PubMed]
16. Wells K, Lamrca A, Papaxoinis G, et al. Unique correlation between GTF2I mutation and spindle cell morphology in thymomas (type A and AB thymomas). J Clin Pathol 2023;76:463-6. [Crossref] [PubMed]
17. Suster DI, Craig Mackinnon A, DiStasio M, et al. Atypical thymomas with squamoid and spindle cell features: clinicopathologic, immunohistochemical and molecular genetic study of 120 cases with long-term follow-up. Mod Pathol 2022;35:875-94. [Crossref] [PubMed]
18. Hashimoto M, Shimizu S, Takuwa T, et al. A case of atypical type A thymoma variant. Surg Case Rep 2016;2:116. [Crossref] [PubMed]
19. Toyada T, Matsunaga A, Shiba M, et al. An atypical type A thymoma with lung invasion and pleural metastasis: a case report. Hum Pathol Case Rep 2017;8:46-50.
20. Bürger T, Schaefer IM, Küffer S, et al. Metastatic type A thymoma: morphological and genetic correlation. Histopathology 2017;70:704-10. [Crossref] [PubMed]
21. Grajkowska W, Matyja E, Kunicki J, et al. AB thymoma with atypical type A component with delayed multiple lung and brain metastases. J Thorac Dis 2017;9:E808-14. [Crossref] [PubMed]
22. Hashimoto M, Tsukamoto Y, Matsuo S, et al. Lung metastases in an atypical type A thymoma variant. J Thorac Dis 2017;9:E805-7. [Crossref] [PubMed]
23. Kawakita N, Kondo K, Toba H, et al. A case of atypical type A thymoma with vascular invasion and lung metastasis. Gen Thorac Cardiovasc Surg 2018;66:239-42. [Crossref] [PubMed]
24. Chiappetta M, Marino M, Facciolo F. Unique case of atypical type A thymoma with vertebral metastasis and high 18-fluorodeoxyglucose avidity. ANZ J Surg 2019;89:E450-1. [Crossref] [PubMed]
25. Yanagiya M, Hamaya H, Matsuzaki H, et al. Atypical Type A Thymoma Variant Manifesting Polymyalgia Rheumatica. Ann Thorac Surg 2020;110:e253-5. [Crossref] [PubMed]
26. Kar A, Pandita A. Report of a type AB thymoma with an atypical type A component. Clin Med Rep 2020;3:1-2.
27. Yanagiya M, Horiuchi H, Hiyama N, et al. Histopathological heterogeneity in an atypical type A thymoma variant with pulmonary metastases. Pathol Int 2021;71:438-40. [Crossref] [PubMed]
28. Jimbo N, Tateyama H, Komatsu M, et al. A case of type AB thymoma with atypical histological features: Is atypical type AB thymoma an acceptable variant of thymoma? Pathol Int 2021;71:272-4. [Crossref] [PubMed]
29. Kawagishi S, Maniwa T, Watari H, et al. Small-sized type A thymoma with pulmonary metastasis: a case report. Surg Case Rep 2022;8:15. [Crossref] [PubMed]
30. Hirai M, Suzuki M, Imoto T, et al. Atypical type A thymoma component identified by pulmonary metastasectomy 11 years after surgery of type AB thymoma. Respir Med Case Rep 2023;46:101944. [Crossref] [PubMed]
31. Qin L, Wang F, Chen L, et al. Rare atypical type a thymoma: a case report and literature review. Diagn Pathol 2024;19:145. [Crossref] [PubMed]
32. Wang XX, Zhao XD, Wang M. Case Report: Type A invasive thymoma with renal metastasis. Front Oncol 2025;15:1448753. [Crossref] [PubMed]
33. Shen X, Jin Y, Shen L, et al. Thymoma and thymic carcinoma associated with multilocular thymic cyst: a clinicopathologic analysis of 18 cases. Diagn Pathol 2018;13:41. [Crossref] [PubMed]
34. Weis CA, Yao X, Deng Y, et al. The impact of thymoma histotype on prognosis in a worldwide database. J Thorac Oncol 2015;10:367-72. [Crossref] [PubMed]
35. Marchevsky AM, McKenna RJ Jr, Gupta R. Thymic epithelial neoplasms: a review of current concepts using an evidence-based pathology approach. Hematol Oncol Clin North Am 2008;22:543-62. [Crossref] [PubMed]
36. Marchevsky AM, Gupta R, Casadio C, et al. World Health Organization classification of thymomas provides significant prognostic information for selected stage III patients: evidence from an international thymoma study group. Hum Pathol 2010;41:1413-21. [Crossref] [PubMed]
37. Zhao Y, Shi J, Fan L, et al. Surgical treatment of thymoma: an 11-year experience with 761 patients. Eur J Cardiothorac Surg 2016;49:1144-9. [Crossref] [PubMed]
38. Chen G, Marx A, Chen WH, et al. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 2002;95:420-9. [Crossref] [PubMed]
39. Park MS, Chung KY, Kim KD, et al. Prognosis of thymic epithelial tumors according to the new World Health Organization histologic classification. Ann Thorac Surg 2004;78:992-7; discussion 997-8. [Crossref] [PubMed]
40. Kondo K, Yoshizawa K, Tsuyuguchi M, et al. WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg 2004;77:1183-8. [Crossref] [PubMed]
41. Jain RK, Mehta RJ, Henley JD, et al. WHO types A and AB thymomas: not always benign. Mod Pathol 2010;23:1641-9. [Crossref] [PubMed]
42. Marx A, Ströbel P, Badve SS, et al. ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting. J Thorac Oncol 2014;9:596-611. [Crossref] [PubMed]
43. Suster S, Moran CA. Thymoma, atypical thymoma, and thymic carcinoma. A novel conceptual approach to the classification of thymic epithelial neoplasms. Am J Clin Pathol 1999;111:826-33. [Crossref] [PubMed]
44. Weissferdt A, Moran CA. Atypical thymoma (epithelial-rich thymoma, well-differentiated thymic carcinoma, WHO type B3 thymoma): A conundrum. Pathol Res Pract 2023;245:154459. [Crossref] [PubMed]
45. Suster DI, Suster S. Histologic features, growth patterns and classification of atypical thymomas. Mediastinum 2025;9:20. [Crossref] [PubMed]
46. Chabchoub Ben Abdallah R, Maalej B, Abdelmoulla S, et al. Thymoma in children: a report of one case. Arch Pediatr 2011;18:745-9. [Crossref] [PubMed]
47. Nakagawa K. Practical value of fluorodeoxyglucose positron emission tomography in treatment strategies for thymic epithelial tumors: implications for more specific use in routine clinical practice. Mediastinum 2025;9:7. [Crossref] [PubMed]
48. Akamine T, Nakagawa K, Ito K, et al. Impact of (18)F-FDG PET on TNM Staging and Prognosis in Thymic Epithelial Tumors. Ann Surg Oncol 2024;31:192-200. [Crossref] [PubMed]
49. Akamine T, Nakagawa K, Ito K, et al. Role of fluorine-18-fluorodeoxyglucose positron emission tomography in selecting candidates for a minimally invasive approach for thymic epithelial tumour resection. Interdiscip Cardiovasc Thorac Surg 2023;36:ivad082. [Crossref] [PubMed]
50. Endo M, Nakagawa K, Ohde Y, et al. Utility of 18FDG-PET for differentiating the grade of malignancy in thymic epithelial tumors. Lung Cancer 2008;61:350-5. [Crossref] [PubMed]
51. Mastromarino MG, Bacchin D, Aprile V, et al. Unradical Surgery for Locally-Advanced Thymoma: Is it time to evolve Perspectives? Lung Cancer 2023;180:107214. [Crossref] [PubMed]
52. Hamaji M, Kojima F, Omasa M, et al. A meta-analysis of debulking surgery versus surgical biopsy for unresectable thymoma. Eur J Cardiothorac Surg 2015;47:602-7. [Crossref] [PubMed]
53. Kondo K, Monden Y. Lymphogenous and hematogenous metastasis of thymic epithelial tumors. Ann Thorac Surg 2003;76:1859-64; discussion 1864-5. [Crossref] [PubMed]
54. Petrini I, Meltzer PS, Kim IK, et al. A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nat Genet 2014;46:844-9. [Crossref] [PubMed]
55. Pan CC, Chen WY, Chiang H. Spindle cell and mixed spindle/lymphocytic thymomas: an integrated clinicopathologic and immunohistochemical study of 81 cases. Am J Surg Pathol 2001;25:111-20. [Crossref] [PubMed]
56. Meuten DJ, Moore FM, George JW. Mitotic Count and the Field of View Area: Time to Standardize. Vet Pathol 2016;53:7-9. [Crossref] [PubMed]
57. Hiroshima K, Iyoda A, Toyozaki T, et al. Proliferative activity and apoptosis in thymic epithelial neoplasms. Mod Pathol 2002;15:1326-32. [Crossref] [PubMed]
58. Hamaji M, Ali SO, Burt BM. A meta-analysis of surgical versus nonsurgical management of recurrent thymoma. Ann Thorac Surg 2014;98:748-55. [Crossref] [PubMed]
59. Mizuno T, Okumura M, Asamura H, et al. Surgical management of recurrent thymic epithelial tumors: a retrospective analysis based on the Japanese nationwide database. J Thorac Oncol 2015;10:199-205. [Crossref] [PubMed]
60. Yamada Y, Tomaru U, Ishizu A, et al. Expression of proteasome subunit β5t in thymic epithelial tumors. Am J Surg Pathol 2011;35:1296-304. [Crossref] [PubMed]
61. Weissferdt A. Spindle cell thymoma and its histological mimickers. Mediastinum 2023;7:25. [Crossref] [PubMed]
62. Suster D, Suster S. On the Histologic Classification of Thymoma. Adv Anat Pathol 2024;31:22-33. [Crossref] [PubMed]
63. Girard N, Shen R, Guo T, et al. Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas. Clin Cancer Res 2009;15:6790-9. [Crossref] [PubMed]
64. Zettl A, Ströbel P, Wagner K, et al. Recurrent genetic aberrations in thymoma and thymic carcinoma. Am J Pathol 2000;157:257-66. [Crossref] [PubMed]
65. Higuchi R, Goto T, Hirotsu Y, et al. PD-L1 Expression and Tumor-Infiltrating Lymphocytes in Thymic Epithelial Neoplasms. J Clin Med 2019;8:1833. [Crossref] [PubMed]