The most frequently reported pattern is a single, well-defined, expansile soft-tissue mass with intraparenchymal growth, often showing close association with or involvement of segmental or mainstem bronchi.

The radiographic presentation exhibits a significant range.

Preoperatively, the non-specific radiologic appearance of CCST-L frequently leads to initial interpretations suggestive of more common entities such as infection (pneumonia), benign lesions, or other mesenchymal tumors (e.g., synovial sarcoma, PEComa). This underscores that imaging cannot reliably differentiate CCST-L from its mimics; its primary role lies in defining disease extent (localized vs. multifocal) and identifying features (e.g., nodal disease) that correlate with aggressive behavior, thereby guiding clinical management.

Among primary thoracic neoplasms, hemangioblastoma shows histological overlap with CCST-L and demonstrates diffuse IHC expression of Vimentin, S100, NSE, and α-inhibin. However, primary pulmonary hemangioblastoma is exceedingly rare, with most pulmonary cases representing metastases, often associated with von Hippel-Lindau (VHL) syndrome. The clear cytoplasm in CCST-L is more likely attributable to glycogen rather than the lipid accumulation typical of hemangioblastoma (3).

A significant and complex differential diagnosis is the perivascular epithelioid cell tumor (PEComa) family, including pulmonary clear cell “sugar” tumor. There is marked morphological and immunophenotypic overlap, further complicated by the fact that a subset of PEComas harbor TFE3 rearrangements (including YAP1::TFE3 in inflammatory spindle cell variants) and can thus show TFE3 protein overexpression (14, 15). The critical discriminator is the consistent absence of myomelanocytic markers (SMA, HMB45, Melan-A, MITF) in CCST-L, which are typically expressed in PEComas.

Epithelioid hemangioendothelioma (EHE) is another important mimic, particularly as some CCST-L cases exhibit predominantly eosinophilic cytology with diffuse CD34 expression. While both tumors may share CD34 positivity and can harbor YAP1::TFE3 fusions, EHE consistently expresses other definitive vascular markers such as CD31 and ERG, which are absent in CCST-L. The distinctive myxohyaline matrix of EHE is also a useful histological clue.

Sclerosing pneumocytoma can be distinguished by its biphasic population of surface (EMA+/TTF-1+) and stromal cells, a feature absent in CCST-L. Solitary fibrous tumor is composed of haphazardly arranged spindled to ovoid cells with indistinct, pale eosinophilic cytoplasm within a variably collagenous stroma, admixed with branching and hyalinized staghorn-shaped blood vessels. Solitary fibrous tumor is typically pleura-based and exhibits strong nuclear STAT6 and CD34 expression, NAB2::STAT6 gene rearrangement, contrasting with the STAT6-negative, TFE3-positive profile, YAP1::TFE3 fusion of parenchyma-based CCST-L.

In the context of multifocal lung lesions, metastatic tumors become the primary diagnostic concern. The most common mimics include metastatic clear cell renal cell carcinoma (RCC) and Müllerian clear cell carcinoma, which can be identified using organ-specific IHC markers (e.g., PAX8, CA-IX, Napsin A) in conjunction with clinical history and imaging.

Metastatic clear cell sarcoma and melanoma are also critical exclusions. Clear cell sarcoma consistently expresses melanocytic markers (S100, SOX10, HMB45, Melan-A) and harbors EWSR1::ATF1 or EWSR1::CREB1 fusions. Melanoma, while morphologically versatile, lacks specific translocations and shows variable melanocytic marker expression. In both, the absence of TFE3 expression and the YAP1::TFE3 fusion are key distinguishing features from CCST-L.

In diagnostically challenging cases with ambiguous morphology or immunophenotype, molecular analysis is definitive. For instance, rare CCST-L cases may be considered in the differential of GLI1-fusion-positive mesenchymal neoplasms, with targeted RNA sequencing resolving the diagnosis by identifying YAP1::TFE3 fusion (3). This underscores that in the modern diagnostic workflow, molecular confirmation remains the ultimate arbiter for CCST-L and its mimics.

Immunohistochemistry (IHC): Nuclear TFE3 expression was reported in approximately 95% (22/23) of published cases. It serves as a rapid and cost-effective screening tool prior to molecular confirmation. Fluorescence In Situ Hybridization (FISH): The YAP1::TFE3 fusion was confirmed by FISH in about 86% (18/21) of cases. It provides direct genetic evidence and helps rule out IHC false positives. Immunohistochemistry for YAP1 C-terminus (YAP1-CT) and TFE3 serves as a reliable surrogate marker for detecting YAP1::TFE3 fusions. The combined pattern of YAP1-CT loss with concurrent TFE3 nuclear overexpression demonstrates higher sensitivity than TFE3 FISH in predicting molecularly confirmed fusions (10). Next-Generation Sequencing (NGS): RNA-based NGS or targeted DNA/RNA panels can definitively identify the YAP1::TFE3 fusion and concurrently detect other genetic alterations (e.g.,STED2 mutations), offering a comprehensive molecular profile.

The diagnosis of CCST-L follows a stepwise, multimodal approach that begins with histomorphologic suspicion and culminates in molecular confirmation. A comprehensive diagnostic algorithm integrating these steps is provided in Figure 2.

The diagnostic pathway is initiated for pulmonary neoplasms exhibiting characteristic morphology, including sheets or nests of clear to eosinophilic cells within a sinusoidal vascular network and low mitotic activity. Immunohistochemistry (IHC) plays a dual pivotal role. First, as a screening tool, nuclear TFE3 positivity (noting its high sensitivity but potential for false positives) coupled with diffuse, strong vimentin co-expression provides a crucial initial clue toward CCST-L. Second, and equally critical, is the systematic use of an exclusion IHC panel, including CK, HMB45, Melan-A, SMA, STAT6, CD31, ERG, TTF-1, Napsin A, HNF 1β and PAX8, to definitively rule out key histological mimics such as PEComa, vascular tumors (e.g., epithelioid hemangioendothelioma), solitary fibrous tumor, and metastatic carcinomas.

Molecular confirmation remains the diagnostic cornerstone. The gold standard is RNA-based next-generation sequencing (NGS), which definitively identifies the YAP1::TFE3 gene fusion. Surrogate and complementary tests include the highly specific IHC pattern of YAP1 C-terminal loss with concurrent TFE3 nuclear overexpression, and YAP1::TFE3 fluorescence in situ hybridization (FISH), the latter of which carries a risk of false negatives and cannot discriminate between fusion isoforms. NGS is strongly indicated for all suspected cases, particularly those with an atypical immunophenotype, diagnostic difficulty, or negative FISH results, as it provides definitive diagnosis and can identify prognostically relevant fusion variants.

Special clinical and logistical scenarios require tailored approaches. In settings with limited access to molecular tests, a confident diagnosis can be established using a strict morphology-driven IHC approach, provided all criteria(characteristic histology, TFE3/vimentin co-expression, and negativity for the full exclusion marker panel) are met, while explicitly acknowledging the limitations of this method. For patients presenting with multifocal disease, metastatic tumors must be rigorously excluded first through close integration of clinical history, imaging studies, and an expanded IHC panel. Finally, for suspected cases that test negative for the YAP1::TFE3 fusion, comprehensive NGS profiling is recommended to search for alternative genetic drivers, thereby preventing the misdiagnosis of rare CCST-L subtypes or other novel entities.

No standardized treatment guidelines exist for CCST-L due to its extreme rarity. Analysis of aggregated case data reveals the following:

It is imperative to recognize that CCST-L exhibits a biological spectrum, and a distinct subset pursues an aggressive clinical course. Approximately 23.3% (7/30) of reported patients developed documented metastasis or progressive disease (3, 8, 11). Multifocality at presentation, particularly bilateral lung involvement, emerges as a strong clinical indicator of this aggressive phenotype (8, 11). Histologically, most aggressive cases do not display overtly high-grade morphology. Commonly observed features include a prominent stromal inflammatory infiltrate (lymphocytes, plasma cells, histiocytes) and, in some instances, geographic necrosis. The exceptional fatal case reported by Dehner et al. demonstrated geographic necrosis and unequivocally elevated mitotic activity (6 per 2 mm²) (11).

Necessity for Long-Term Surveillance: Given the documented potential for late recurrence and metastasis, prolonged, likely lifelong, clinical and radiographic follow-up is strongly recommended for all patients diagnosed with CCST-L, irrespective of the initial disease stage.

Toward a Standardized Management Strategy: Existing evidence highlights the urgent need to establish consensus-driven management guidelines. These should address the role of adjuvant therapy in high-risk scenarios and create a framework for evaluating systemic agents in advanced disease.

Future Research Imperative: International multi-institutional collaboration is paramount to accrue sufficient data on advanced cases. This effort is essential to identify reliable predictive biomarkers and to facilitate the development of meaningful clinical trials for metastatic CCST-L.

The constitutive activation driven by the YAP1::TFE3 fusion oncoprotein is central to tumorigenesis in CCST-L. YAP1, a core effector of the Hippo pathway, regulates cell proliferation and anti-apoptosis, while TFE3 is a transcription factor that activates genes involved in lysosomal biogenesis and angiogenesis (16). The chimeric protein resulting from their fusion amplifies both oncogenic functions, directly driving hyperproliferation, conferring early migratory capacity, and conferring inherent resistance to apoptosis. This foundational mechanism can be further potentiated by secondary events and the tumor microenvironment, which likely underpin the aggressive behavior observed in cases with multifocal or metastatic disease.

In addition to the primary fusion event, secondary genomic alterations may modulate tumor behavior. The current evidence for such events in CCST-L is emerging, and some mechanisms are proposed based on analogies with other tumor types.

The existence of fusion-negative cases highlights key unknowns in CCST-L biology and presents several non-mutually exclusive possibilities.

Comprehensive analysis of all 30 reported cases-integrating clinical presentation, imaging, nodal/metastatic status, histopathology, and outcomes-demonstrates that CCST-L exhibits a clinicopathological spectrum ranging from indolent to locally aggressive/metastatic disease. It is important to note the following limitations of this study.

To overcome these limitations, we emphasize the critical need for large-scale, multi-institutional collaboration. Such efforts are essential to fully characterize the clinicopathological and molecular spectrum of CCST-L. Such collaborative efforts can: (i) aggregate cases across centers to build a larger, more representative cohort for analysis; (ii) establish standardized protocols for collecting clinical, pathological, and follow-up data, thereby reducing heterogeneity and information bias; and (iii) consolidate technical and intellectual resources to systematically investigate underlying molecular mechanisms and evaluate potential therapeutic approaches, ultimately accelerating translational progress in this rare disease.