Narrative review: this or that?—uncommon challenges in mediastinal pathology

Introduction

Background

Mediastinal tumors are relatively uncommon in the general population, with a reported incidence of approximately 0.5 in 100,000 (1). With the more widespread use of computed tomography (CT) imaging screening the detection of incidental lesions in this site has increased (2,3). Given their relatively low frequency, diagnostic evaluation of mediastinal tumors may pose significant challenges in the general practice of surgical pathology. Accurate diagnosis of newly found mediastinal lesion is critical, since it guides subsequent treatment. Biopsies of mediastinal lesions are rarely procured, as most common mediastinal lesions are surgically managed. Biopsies are needed when there is a suspicion of diseases that can be treated non-surgically with chemotherapy and/or radiation such as hematopoietic neoplasms and germ cell tumors or when radiographic studies suggest an invasive process into adjacent organs, which often requires an initial non-surgical approach. The distinction of thymoma from thymic carcinoma is paramount in the latter situation, as the regimen for systemic therapy differs.

Rationale and knowledge gap

In adults, thymic epithelial neoplasms are the most common primary tumors arising in the mediastinum, representing up to 50% of the lesions (4). However, a broad spectrum of less common neoplasms may arise in this location, for which accurate diagnosis is crucial to establish appropriate therapy.

In this article, we review some uncommon diagnostic challenges in the diagnosis of mediastinal tumors, based on six unique clinical cases with overlapping histological features, with the objective of refining the diagnosis of uncommon neoplasms that involve the mediastinum and highlight potential diagnostic challenges. These cases were selected due to their challenging nature, overlapping morphologic features, and relevance to subsequent treatment. We review the judicious use of immunohistochemistry and other ancillary tools to accurately diagnose these diseases. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-25-13/rc).

Methods

Unique clinical cases are discussed, and their diagnostic rationale is supported by review of the literature. These cases were selected based on their overlapping morphologic features, rarity, and the importance of their accurate recognition for surgical or medical treatment. We focused on malignant neoplasms that may be easily mistaken for each other. Benign lesions and conventional thymic epithelial neoplasms were excluded. Sources were obtained via PubMed search and include original studies and review articles published in the English language between 1990 and 2025. Search terms include the diagnostic entities discussed in the article (please see separate search strategy form in Table 1).

Case 1

A 57-year-old man with history of heavy smoking presented with a mediastinal mass which appear to invade the pulmonary parenchyma. Biopsy of the lesion contained a discohesive neoplasm composed of sheets of epithelioid to rhabdoid cells with moderate amounts of brightly eosinophilic cytoplasm, marked nuclear pleomorphism, and conspicuous nucleoli. Mitotic activity was brisk and there was extensive tumor necrosis (Figure 1A,1B).

Figure 1 Histologic and immunophenotypic features of SMARCA4-deficient undifferentiated tumor. (A,B) SMARCA4-deficient undifferentiated tumor composed of solid sheets of highly pleomorphic epithelioid to rhabdoid cells containing brightly eosinophilic cytoplasm (hematoxylin and eosin stain; magnification 100× and 400×, respectively). (C,D) Expression of keratins is typically negative to patchy positivity, in this case there is focal and weak staining for the marker (AE1/AE3; immunohistochemical stain; magnification 400×) with loss of SMARCA4 (BRG-1) expression (immunohistochemical stain; magnification 400×). BRG-1, Brahma-related gene 1; SMARCA4, switch/sucrose non-fermentable-related, matrix-associated, actin-dependent chromatin regulator, subfamily a, member 4.

Immunohistochemical stains were weakly and focally positive for epithelial markers (AE1/AE3), and negative for melanocytic markers such as S100, SRY-box transcription factor 10 (SOX10), lung carcinoma markers [thyroid transcription factor 1 (TTF-1) and p40], vascular [ETS-related gene (ERG) rules out angiosarcoma], and nuclear antigen in testis (NUT). An additional immunohistochemical stain for Brahma-related gene 1 (BRG-1) had loss of nuclear expression (Figure 1C,1D).

Final diagnosis: switch/sucrose non-fermentable-related, matrix-associated, actin-dependent chromatin regulator, subfamily a, member 4 (SMARCA4)-deficient undifferentiated tumor

Neoplasms with SMARCA4 deficiency represent a wide spectrum of rare malignancies, which can range from conventional carcinomas to undifferentiated neoplasms with round cell to rhabdoid morphologic features (5). Regardless of their histological appearance, thoracic tumors with SMARCA4 loss tend to share aggressive clinical behavior and occur predominantly in smokers (5). It is common for these lesions to present with advanced nodal disease at the time of initial diagnosis (5,6). Its morphologic differential diagnosis is broad and may include poorly differentiated lung adenocarcinoma, NUT carcinoma, epithelioid angiosarcoma, melanoma, and proximal-type epithelioid sarcoma, among others.

The tumor is more commonly seen in the lungs than the mediastinum. In the lungs, loss of SMARCA4 expression can be seen in adenocarcinomas and squamous cell carcinomas without the characteristic morphologic and immunophenotypic features of undifferentiated SMARCA4-deficient thoracic neoplasm. Mutations in SMARCA4 have been reported to occur in 5% to 10% of non-small cell lung cancers (7,8). These lesions may retain at least partial immunohistochemical expression of TTF-1 and p40 and typically retain expression of SMARCA2 [Brahma homologue (BRM)]. In addition, some lesions may have combined elements of non-small cell carcinoma and SMARCA4-undifferentiated neoplasm. In the thymus, the association of SMARCA4-deficient/loss with other types of thymic carcinoma has not been reported (9).

At the opposite end of the spectrum, SMARCA4-deficient undifferentiated tumors are high-grade neoplasms composed of pleomorphic cells with prominent eosinophilic cytoplasm or round cell features, which often contain tumor necrosis and brisk mitotic activity (8). From an immunophenotypic standpoint, they tend to have only focal expression of keratins, such as in the current case and may often express spalt-like transcription factor 4 (SALL4) (5,10). Loss of nuclear expression of SMARCA4 is necessary for the diagnosis and is accompanied by loss of SMARCA2 (BRM) in most cases.

From a molecular standpoint, these lesions typically harbor loss-of-function mutations in SMARCA4, which correlate with immunohistochemical loss of this marker. In the lungs where the molecular profile of these tumors are betters characterized, they may be accompanied by other alterations commonly seen in lung cancer, including point mutations in epidermal growth factor receptor (EGFR) (11) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (8), as well as anaplastic lymphoma kinase (ALK) rearrangements (12), supporting that these lesions may ultimately represent higher grade transformation of non-small cell lung carcinoma (5). Association with other mutations has not been reported in the thymic tumors.

Case 2

A 45-year-old man presented with an anterior mediastinal mass, which was rapidly growing.

Histologic examination of a biopsy specimen contains a poorly differentiated neoplasm composed of solid sheets of vaguely epithelioid cells with scant amphophilic cytoplasm and prominent nucleoli. There is brisk mitotic activity. Focal necrosis is present (Figure 2A,2B). Immunohistochemical stains are notable for having diffuse AE1/AE3 reactivity, as well as patchy p40 expression (Figure 2C). Cluster of differentiation (CD)5 and CD117, more common markers of thymic carcinoma are negative. BRG-1 is retained. An additional immunohistochemical stain for NUT is diffusely positive in the tumor cells (Figure 2D). Confirmatory molecular testing demonstrated a gene fusion involving bromodomain-containing protein 3 (BRD3) (exon 10) and nuclear antigen in testis (NUTM1) (exon 2).

Figure 2 Histologic and immunophenotypic features of NUT carcinoma. (A,B) Histologic characteristics of NUT carcinoma include solid nests of pleomorphic epithelial cells with moderate amounts of amphophilic cytoplasm interspersed with conspicuous neutrophilic inflammation. There is no evidence of abrupt keratinization in this biopsy specimen (hematoxylin and eosin stain; magnification 100× and 200×, respectively). (C,D) Immunohistochemical stain for p40 (magnification 400×) and NUT (magnification 400×) show diffused reactivity in the tumor cells. Note speckled pattern of reactivity for NUT in tumor nuclei. NUT, nuclear antigen in testis.

Final diagnosis: NUT carcinoma

NUT carcinoma is a very rare type of carcinoma with dismal prognosis, which harbors recurrent gene fusions involving NUT, with the most common fusion partners being BRD3 and BRD4 (13). Other reported fusion partners include nuclear receptor-binding SET domain protein 3 (NSD3), zinc finger protein 532 (ZNF532), ZNF592, and others (14-16).

NUT carcinoma may arise in patients of any age and sex, and although they typically occur in midline structures above the diaphragm, such as the mediastinum (17), other anatomic locations are possible, including lung, primary skin (18), and bone (15). Accurate identification of these tumors is important for these patients to receive appropriate systemic therapy, due to the aggressive behavior and high mortality rate or inclusion into clinical trials. A clinical trial for bromodomain inhibitors is available (14,19). This possibility emphasizes the importance of accurate diagnosis of this disease.

Histologically, these tumors are usually composed of monotonous, undifferentiated round cells with vesicular nuclei with prominent nucleoli and scant cytoplasm, interspersed with focal areas of abrupt squamous differentiation and keratinization, which may be absent in small biopsy specimens (13,15). These tumors typically have diffuse expression of keratins with reactivity for markers of squamous differentiation, such as p40 and p63. However, tumor cells may show focal positivity for neuroendocrine markers or other organ-specific markers. Immunohistochemistry for NUT is positive with a speckled nuclear pattern (Figure 2D) (13). Demonstration of NUT protein expression and/or NUTM1 gene rearrangement is necessary to confirm this diagnosis (15). Morphologic differential diagnoses can include squamous cell carcinoma, neuroendocrine carcinoma, SMARCA4-deficient neoplasms, and sarcomas with NUT rearrangements, among others.

However, not all malignancies harboring NUTM1 gene rearrangements are NUT carcinoma. Other neoplasms harboring these fusions include acute lymphoblastic leukemia (20,21), poroma (22), and a novel group of aggressive sarcomas which, unlike NUT carcinoma, lack expression of keratins in most cases (23-25). These sarcomas are composed by densely populated ovoid to round cells interspersed with a collagenous stroma containing characteristic amianthoid-like fibers (23-25). These latter tumors have not been described in the mediastinum.

Case 3

A 30-year-old woman with history of heart failure was found to have an anterior mediastinal mass during evaluation for transplant. A biopsy of the mass contained a discohesive neoplasm composed of large cells with pleomorphic nuclei and moderate amounts of pale cytoplasm. Mitotic activity was brisk, and no definitive tumor necrosis was identified (Figure 3A,3B). Initial immunohistochemical studies were negative for AE1/AE3, Cam5.2, TTF-1, p40, and NUT. BRG-1 had retained nuclear expression. Subsequent immunohistochemical stains were positive for CD45 and CD20, with variable reactivity for cellular myelocytomatosis oncogene (c-MYC) and expression of CD30 in a small subset of cells. Ki-67 highlighted approximately 70% of the tumor nuclei (Figure 3C-3F).

Figure 3 Histologic and immunophenotypic features of mediastinal large B-cell lymphoma. (A,B) Primary mediastinal large B-cell lymphoma composed of large, highly atypical single cells. The tumor nuclei have vesicular chromatin with prominent nucleoli (hematoxylin and eosin stain; magnification 100× and 200×, respectively). (C,D) Immunohistochemical stains show diffuse reactivity for CD20 (magnification 100×), variably reactivity for c-MYC (magnification 200×). (E) Ki-67 shows a high proliferation rate with positive stain in most tumor cell nuclei (immunohistochemical stain; magnification 200×). (F) CD30 is negative (immunohistochemical stain; magnification 200×). c-MYC, cellular myelocytomatosis oncogene; CD, cluster of differentiation.

Final diagnosis: primary mediastinal large B-cell lymphoma

Primary mediastinal large B-cell lymphoma is an aggressive type of B-cell lymphoma, presumed to arise from thymic B-cells (26). Although initially considered to be a variant of diffuse large B-cell lymphoma, it is now considered to be a separate entity based on its clinical, immunophenotypic, and genetic characteristics, and more closely related to classical Hodgkin lymphoma (26,27). In contrast to diffuse large B-cell lymphoma, these tumors tend to occur in young adults and are typically present as large mediastinal masses that may involve adjacent structures. Histologically, primary mediastinal B-cell lymphoma has overlapping features of diffuse large B-cell lymphoma and classic Hodgkin lymphoma. It typically consists of a diffuse proliferation of large, highly atypical B-cells, interspersed with occasional Reed-Sternberg cells and variable areas of fibrosis (26,28). It usually expresses pan-B cell markers such as CD19, CD20, paired box 5 (PAX-5), and CD79a, and has weak, variable CD30 reactivity. CD15 is rarely expressed, and Immunoglobulins are negative (26).

Prognostically, primary mediastinal B-cell lymphoma tends to have a favorable response to systemic treatment when appropriately diagnosed, with an overall survival around 85% at 5 years (26). The morphologic differential diagnosis of these tumors includes anaplastic T-cell lymphoma, classic Hodgkin lymphoma, mediastinal grey zone lymphoma, seminoma, and less likely, poorly differentiated carcinomas. Detection of immunohistochemical markers of B-lymphocytic differentiation, as described above, are valuable tools to support this diagnosis. Accurate recognition of this entity is important to establish prompt systemic therapy. Surgical resection of this disease is not indicated.

Case 4

A 22-year-old man presented to the emergency room with cough and chest pain. CT imaging during his evaluation demonstrated an anterior mediastinal mass, which was biopsied. The biopsy specimen contained a neoplasm composed of monotonous round cells with enlarged central nuclei with prominent nucleoli and abundant pale cytoplasm, accompanied by prominent lymphocytic inflammation. Immunohistochemical stains had focal dot-like keratin reactivity and were negative for p40, CD20, and NUT. BRG-1 had retained nuclear expression. Subsequent immunohistochemical stains were diffusely positive for SALL4, D2-40, and c-kit. CD30 and glypican 3 were negative (Figure 4).

Figure 4 Histologic and immunophenotypic features of seminoma involving the mediastinum. (A) Histological features of seminoma consist of clusters and single cells with enlarged nuclei and pale to eosinophilic cytoplasm, accompanied by prominent lymphohistiocytic inflammation. Frequently, non-necrotizing granulomas can obscure neoplastic cells (hematoxylin and eosin stain; magnification 400×). (B-D) Immunohistochemical studies show diffuse reactivity for D2-40 (magnification 200×), SALL4, a pan-germ cell tumor marker (magnification 200×), and CD117 (magnification 200×). CD, cluster of differentiation; SALL4, spalt-like transcription factor 4.

Final diagnosis: seminoma

Extragonadal germ cell tumors are considered to arise from embryologic remnants arrested during migration (29). Compared to their primary testicular or ovarian counterparts, primary extragonadal germ cell tumors are uncommon (30). However, among extragonadal sites, the mediastinum is the most common primary location, representing 38% to 70% of the extragonadal tumors (30,31).

Histologically, tumors of a single lineage are slightly more common than mixed germ cell tumors in this location, with non-seminomatous lesions being more common overall (29-31). Interestingly, malignant mediastinal germ cell tumors have an overwhelming male predominance, with rare cases described in women (31,32). In addition, non-seminomatous germ cell tumors of the mediastinum are considered to have a higher propensity to develop secondary somatic malignancies (30).

From a diagnostic standpoint, it is crucial to accurately characterize the individual components of germ cell tumors for adequate treatment and prognosis. In particular, the presence of seminoma is associated with excellent response to platinum-based chemotherapy and radiation (29,32), while choriocarcinoma has a typically poor response.

Although some histological subtypes, such as yolk sac tumor and choriocarcinoma, may be associated with elevation of serum tumor markers, others such as seminoma and embryonal carcinoma, are not. Therefore, histological sampling is necessary for definitive diagnosis (33,34). However, complete evaluation of mixed germ cell tumors may not be possible in small biopsy specimens.

Histologically, seminomas are composed of solid nests and sheets of monotonous cells with large central nuclei with prominent nucleoli and moderate amounts of clear to lightly eosinophilic cytoplasm. A brisk lymphocytic inflammatory infiltrate is common (32). Compared to primary gonadal tumors, mediastinal seminomas tend to have prominent fibrous septa and a pronounced granulomatous inflammatory reaction (32), which may obscure their diagnostic features, particularly in small biopsy specimens. The histologic differential diagnosis of these tumors includes primarily other germ cell neoplasms (including different elements of mixed germ cell neoplasm), lymphomas such as acute lymphoblastic leukemia/lymphoma and poorly differentiated carcinomas. The expression of markers of germ cell differentiation, in the absence of markers of lymphocytic and epithelial differentiation can help support this diagnosis.

Immunohistochemistry is an important tool to accurately classify germ cell tumors and, given that these markers are not entirely specific, evaluation should generally include a panel containing the following antibodies (29,32,35,36): SALL4 (expressed in all non-teratoma germ cell tumors), octamer-binding transcription factor 4 (OCT4; expressed in both seminoma and embryonal carcinoma), c-kit (typically expressed in seminoma), CD30 (expressed in most embryonal carcinomas), glypican 3 (expressed in yolk sac tumor and choriocarcinoma), and keratins (which may be positive in the epithelial elements of teratoma, yolk sac tumor, embryonal carcinoma, choriocarcinoma and in a subset of seminoma).

Case 5

A 50-year-old man had an anterior mediastinal mass incidentally identified on a chest CT imaging study. Biopsy of the lesion contains a neoplasm composed of cords and solid sheets of monotonous, cytologically bland spindled to epithelioid cells with granular pale to lightly eosinophilic cytoplasm and nuclei with speckled chromatin. Mitotic activity is up to 4 figures/2 mm². No tumor necrosis was identified. Immunohistochemical stains performed on the biopsy specimen are positive for Cam5.2, chromogranin, and synaptophysin (Figure 5). Ki-67 highlights up to 1% of the tumor nuclei.

Figure 5 Histologic and immunophenotypic features of atypical carcinoid tumor. (A) Atypical carcinoid tumor is characterized by solid nests and pseudo rosettes lined by epithelioid to plasmacytoid cells with monotonous nuclei containing speckled chromatin and moderate amounts of amphophilic cytoplasm (hematoxylin and eosin stain; magnification 200×). (B-D) Immunohistochemical stain for Cam5.2 is diffusely positive (magnification 400×), as well as for chromogranin (magnification 200×), and synaptophysin (magnification 200×), thus confirming neuroendocrine differentiation.

Final diagnosis: atypical carcinoid tumor

Neuroendocrine tumors of the thymus are relatively uncommon, corresponding to less than 5% of neoplasms in this location (37,38). Currently, thymic neuroendocrine neoplasms are classified following the same criteria as neuroendocrine neoplasms of the lung, and divided as typical carcinoid tumor, atypical carcinoid tumor, large cell neuroendocrine carcinoma, and small cell carcinoma. This classification correlates well with increased aggressive behavior (37,38). Regardless of their histological grade, all tumors have metastatic potential. In contrast to the lungs, where typical carcinoid tumors are more prevalent, atypical carcinoids are the most prevalent neuroendocrine neoplasm in the thymus. The treatment of typical and atypical carcinoid tumors is predominantly surgical and may include postoperative radiation therapy (39). Advances in the use of systemic therapy in neuroendocrine tumors have been reported (40-42).

Histologically, carcinoid tumors are composed of monotonous epithelial cells with spindled, plasmacytoid, oncocytic, and polygonal features, among others, containing bland nuclei with fine, granular chromatin. The tumor cells may be arranged in solid nests, cords, and rosettes (43). Immunohistochemically, these tumors typically have diffuse expression of keratins, as well as neuroendocrine markers such as chromogranin, synaptophysin, and insulinoma-associated protein 1 (INSM1) (43,44). Most tumors are negative for TTF-1 (43). Positivity for PAX-8 has been reported and is dependent on antibody clone (45,46).

Under the current World Health Organization (WHO) classification, typical carcinoids lack conspicuous tumor necrosis and have less than 2 mitotic figures/2 mm², while atypical carcinoids have mitotic activity between 2 and 10 figures/2 mm² and may have areas of punctate necrosis (38,47). Both large cell neuroendocrine carcinoma and small cell carcinoma have greater than 10 mitotic figures/2 mm² and have distinct cytologic and architectural features beyond the scope of this article.

In the lung, where these tumors are more common, a new diagnostic category (atypical carcinoid with elevated mitotic count) has been proposed for tumors with carcinoid-like morphology that have mitotic counts greater than 10 figures/2 mm² (48,49), and have diverse molecular features that more closely resemble carcinoid tumors, rather than large cell neuroendocrine carcinoma (50). Atypical carcinoid with elevated mitotic count tumors are postulated to have a biological behavior between atypical carcinoid and large cell neuroendocrine carcinoma (49). Atypical carcinoids with elevated mitotic count have been described in the mediastinum (47).

The histologic differential diagnosis of carcinoid tumors includes large cell neuroendocrine carcinoma, small cell carcinoma (as discussed above), and other lesions with similar cytologic features such as melanoma and plasma cell neoplasm. These diagnoses, however, are easily excluded with lack of reactivity for markers of melanocytic/neurocristic differentiation (such as SOX10 or S100) and plasma cell differentiation [such as multiple myeloma-1 (MUM-1) or CD138].

Case 6

A 77-year-old man with a history of smoking and multiple comorbidities was found to have an anterior mediastinal mass. Biopsy of the lesion contained a neoplasm composed of solid sheets of discohesive cells with monotonous eccentric nuclei containing speckled chromatin and prominent lightly basophilic granular cytoplasm. Immunohistochemical stains were negative for keratin, p40, NUT, chromogranin, synaptophysin, CD45, SOX10, and S100. BRG-1 was retained. Additional immunohistochemical stains were positive for CD138. In-situ hybridization was positive for kappa light chains and negative for lambda (Figure 6). Subsequent imaging studies demonstrated multiple lytic lesions in the ribs, pelvis, and skull.

Figure 6 Histologic and immunophenotypic features of plasma cell neoplasm involving the mediastinum. (A) The neoplasm is composed of solid sheets of monotonous cells with eccentric nuclei and lightly basophilic cytoplasm (hematoxylin and eosin stain). (B) Immunohistochemical studies show diffuse reactivity for CD138. (C,D) Chromogenic in-situ hybridization demonstrates kappa light chain restriction. All images are magnification 200× . CD, cluster of differentiation.

Final diagnosis: plasma cell neoplasm

Most plasma cell neoplasms, whether solitary (plasmacytoma) or diffuse (multiple myeloma) occur in the skeleton, particularly in flat bones. Solitary plasmacytoma is rare, accounting for 3–6% of plasma cell neoplasms (51). Primary extraosseous presentation of these lesions is uncommon, with their most frequent sites being in the upper respiratory tract, particularly the nasopharynx (52). Extraosseous involvement in the setting of multiple myeloma is associated with adverse prognosis (53). Mediastinal involvement by plasma cell neoplasm, although uncommon, has been described in the prevascular and paravertebral mediastinum (52,54-56), both as solitary plasmacytoma and in the setting of systemic disease. Histologically, these lesions are composed of solid sheets of plasma cell with characteristic eccentric nuclei and amphophilic cytoplasm. Intracytoplasmic accumulation of immunoglobulins may be seen in some cases, as well as more overt nuclear pleomorphism. Immunohistochemical expressions of plasma cell markers, such as CD138 and MUM-1 (interferon regulatory factor 4 protein), as well as immunoglobulin light chain restriction is helpful to confirm this diagnosis. The treatment of these lesions is based on systemic chemotherapy and bone marrow stem cell transplant. Surgery is typically not part of the treatment of these neoplasms (57), hence the importance of distinguishing them from other diseases. The histologic differential diagnosis of these lesions may include carcinoid tumor, metastatic melanoma, other mediastinal lymphomas and carcinomas with plasmacytoid features.

Conclusions

Besides thymic epithelial tumors such as thymoma and thymic carcinoma, a wide variety of neoplasms may primarily present as mediastinal masses. Given their relative rarity, these lesions may pose a diagnostic challenge to most pathologists, especially as many tumors may share morphological similarities. Relevant examples of some of these entities are discussed in this article. Understanding clinical presentation, the histological, immunophenotypic, and genetic features of these lesions is important for their accurate diagnosis and subsequent treatment. In general, the diagnostic work-up of these tumors should be guided by their morphologic features. For instance, in high-grade pleomorphic disease, it is important to consider the possibility of SMARCA4-deficient carcinoma and NUT carcinoma, in addition to the more prevalent thymic carcinomas, while in the case of monotonous, discohesive tumors, the differential considerations include lymphoma, seminoma, and plasma cell neoplasm, among others.

Better understanding of potential prognostic features and therapeutic targets of some of these uncommon entities (such as SMARCA4-deficient tumors and NUT carcinoma) is necessary.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Malgorzata Szolkowska) for “The Series Dedicated to the 14^th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” published in Mediastinum. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-25-13/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-25-13/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-25-13/coif). “The Series Dedicated to the 14^th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” was commissioned by the editorial office without any funding or sponsorship. A.L.M. serves as an unpaid editorial board member of Mediastinum from January 2024 to December 2025. A.L.M. reports Bristol Meyer Squibb-grant to evaluated expression of LAG3 in renal cell carcinoma and colon carcinoma, with payments made to his institution. He reports receiving royalties from Springer Nature Switzerland AG for textbook “mediastinal lesions” (less than $100 USD) and receives payment from the Merk speaker bureau. J.G.M. reports receiving royalties from Springer Nature Switzerland AG for textbook “Xu, Ricciotti, Mantilla: Practical Lung Pathology” (less than $200 USD). He also serves as Chair of the Resident Question Bank Committee for 2025 (unpaid) in the American Society of Clinical Pathology. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This is a case-based discussion involving anonymized cases; therefore, written informed consent and IRB review were exempt.

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/.

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