Introduction

Primary pulmonary myxoid sarcoma (PPMS) is an exceedingly rare, low-grade malignant sarcoma. It was initially described as a primary pulmonary endobronchial myxoid tumor in the study of Nicholson AG et al. in 1999 (Nicholson et al. 1999). PPMS stands out due to its distinctive morphological and genetic traits, notably the presence of the EWS RNA binding protein 1::cAMP response element binding protein 1 (EWSR1::CREB1) fusion gene and a remarkably low Ki-67 proliferation index (Wu et al. 2021). Thway K and associates further uncovered the relationship between characteristic chromosomal translocation t(2; 22) (q33; q12) and the occurrence of EWSR1::CREB1 fusion (Thway et al. 2011). PPMS was first recognized by World Health Organization (WHO) classification in 2015, which belonged to the category of mesenchymal tumors. Then it was classified as mesenchymal tumors specific to the lung in the 2021 WHO Classification of Lung Tumors (Travis et al. 2015; Nicholson et al. 2022). PPMS originates from mesenchymal components in the bronchial wall, pulmonary stroma, or blood vessels (Gołota et al. 2019). Its clinical presentation is generally unspecific, sometimes detectable only through physical examination, making it challenging to differentiate from other lung tumors. This article primarily aims to review the epidemiology, clinical characteristics, imaging, pathology, immunohistochemistry, diagnosis, differential diagnosis, treatment, and prognosis of PPMS with EWSR1::CREB1 fusion.

Epidemiology and clinical characteristics

PPMS is an exceptionally rare, low-grade sarcoma, with a total of 39 clinical cases compiled in Table 1 (Nicholson et al. 1999; Wu et al. 2021; Thway et al. 2011; Matsukuma et al. 2012; Chen et al. 2020; Inayama et al. 2001; Smith et al. 2014; Jeon et al. 2014; Kim et al. 2017; Yanagida et al. 2017; Agaimy et al. 2017; Koelsche et al. 2020; Opitz et al. 2019; Nishimura et al. 2023; Prieto-Granada et al. 2017). Most of the symptoms of PPMS that manifest clinically are non-specific, such as cough, hemoptysis, and weight loss. Among the 39 cases, 20 were in female patients and 19 in male patients, resulting in a male-to-female ratio of 0.95:1. The age range of PPMS cases spanned from 21 to 80 years, with a median age of 43.6. Among the documented cases, 12 individuals had never smoked, while 11 had a history of smoking. This suggests that the occurrence of PPMS is not directly linked to smoking history. PPMS does not display a specific predilection for a particular location within the lung; it can invade both the right and left lungs, though it is more frequently found in the right lung (59%, 23/39). PPMS commonly infiltrates bronchial tissues, with a tendency toward endobronchial growth observed in 17 out of 39 cases, while 4 cases exhibited no endobronchial involvement, and the remaining cases did not provide sufficient information. Nonetheless, this tumor can also develop outside the lung parenchyma, occurring within an interlobar fissure without parenchymal invasion (Kim et al. 2017).

Table 1 Clinical, histologic, and pathological features of PPMS
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Imaging characteristics

Currently, CT scans serve as the primary imaging modality for PPMS diagnosis, with X-rays providing supplementary assistance. However, the specific imaging features of this tumor remain somewhat uncertain. Existing literature reviews and pathology reports on PPMS emphasize the significance of CT findings in enhancing our understanding of the disease. On CT scans, PPMS is frequently found in close proximity to the bronchi and often infiltrates the lung parenchyma. Most PPMS cases observed in imaging reports indicate that the primary lung masses are predominantly located in the right lower lobe (28%, 11/39) and right upper lobe (23%, 9/39). These tumors typically appear as well-defined solid masses with sizes ranging from 1.4 cm to 14 cm. Contrast-enhanced CT scans typically reveal these lesions as mildly and heterogeneously enhanced masses (Yuliana and Hayati 2022), with contrast enhancement in both solid and cystic components. Additionally, X-ray images of PPMS exhibit a lung field mass shadow, which may resemble a pleural effusion (Yuliana and Hayati 2022).

Histopathologic characteristics

Macroscopically, PPMS lesions typically manifest as solitary, well-defined masses with a lobulated appearance and a pale, crystalline cut surface. These tumors vary in size, ranging from 1.4 cm to 14 cm, with an average size of 5 cm. Microscopically, most cases exhibit a lobulated architecture, featuring a reticular network composed of delicate, lace-like strands and cords of ovoid, spindle, or stellate cells within a prominent myxoid matrix. Thway et al. (2011) reported clinicopathological data on 10 PPMS cases, which displayed cords of polygonal, spindle, or stellate cells embedded within a myxoid stroma, resembling extraskeletal myxoid chondrosarcoma. Two cases described by Nicholson et al. (1999) demonstrated interweaving cords of small, uniform, rounded, or slightly elongated cells within a myxoid stroma. The stroma displayed positive staining with Alcian blue and was sensitive to hyaluronidase. Tumor cells contained a small amount of periodic acid-Schiff-positive eosinophilic cytoplasm. Ultrastructural studies revealed an excess of rough endoplasmic reticulum in tumor cells, with some cisternae appearing dilated and scalloping of cell surfaces, although no intracisternal tubules were identified (Nicholson et al. 1999). In most cases, a patchy background of inflammatory cells, primarily consisting of lymphocytes and plasma cells, is present, contributing to the tumor’s infiltrative appearance and occasional focal necrosis and inflammation. Additionally, Chen et al. (2020) expanded the morphological and cytological spectrum of PPMS. They documented an additional case of this rare tumor and reported the first occurrence of chondrocyte-like and physaliferous-like tumor cells within this tumor, with a more intense inflammatory infiltrate in their case. Furthermore, PPMS often exhibits mild to moderate atypia; in the study by Thway et al. (2011), four cases displayed no or minimal atypia, six showed focal pleomorphism, and five had necrosis. Mitotic indices varied, with most tumors not exceeding 5 mitoses per 10 high-power fields (Fig. 1).

Fig. 1
figure 1

Histopathologic characteristics of PPMS with EWSR1::CREB1 fusion

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Molecular genetics and immunohistochemistry

Recent studies have confirmed that the critical genetic feature of PPMS is the rearrangement of the EWSR1 gene and the formation of the EWSR1::CREB1 fusion gene. This genetic alteration serves as a crucial diagnostic marker. To identify the EWSR1 gene rearrangement, fluorescence in situ hybridization (FISH) can be conducted on formalin-fixed paraffin-embedded (FFPE) tissue samples. This test significantly enhances diagnostic accuracy. In Table 2 (Nicholson et al. 1999; Wu et al. 2021; Thway et al. 2011; Matsukuma et al. 2012; Chen et al. 2020; Inayama et al. 2001; Smith et al. 2014; Jeon et al. 2014; Kim et al. 2017; Yanagida et al. 2017; Agaimy et al. 2017; Koelsche et al. 2020; Opitz et al. 2019; Nishimura et al. 2023; Prieto-Granada et al. 2017), which compiles the 39 PPMS cases, FISH analysis was performed in 34 cases, revealing a positive EWSR1 gene rearrangement rate of 85% (29/34). Furthermore, the presence of the EWSR1::CREB1 fusion can be demonstrated through reverse transcription-polymerase chain reaction (RT-PCR) targeting specific fusion transcripts. EWSR1::CREB1 fusion is commonly found in various mesenchymal tumors occurring at different sites, displaying a broad spectrum of biological behaviors (Bale et al. 2018). Of the 26 cases in which RT-PCR was performed, the positive rate of EWSR1::CREB1 fusion is 73% (19/26). EWSR1::CREB1 fusion is an important characteristic of PPMS; however, it is essential to note that this fusion is not exclusive to PPMS but is also observed in other neoplasms, including angiomatoid fibrous histiocytoma (AFH), clear cell sarcoma, hyalinising clear cell carcinoma of the salivary gland, and clear cell carcinoma of the soft tissue or gastrointestinal tract (Thway and Fisher 2012; Cazzato et al. 2022; Stockman et al. 2012; Rossi et al. 2007). Additionally, Nishimura T et al. (Nishimura et al. 2023) reported a unique case of PPMS, harboring an EWSR1::ATF1 gene fusion. Both ATF1 and CREB1, belonging to the CREB family, can create fusion genes with EWSR1 (Kao et al. 2017). If an EWSR1::ATF1 fusion is detected in pulmonary myxoid sarcoma with EWSR1::CREB1 translocation, the tumor may be classified as “pulmonary myxoid sarcoma with EWSR1::CREB translocation” (Hashimoto et al. 2019).

Table 2 Reported cases of primary pulmonary myxoid sarcoma (PPMS)
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PPMS lacks highly specific immunohistochemical markers. Immunohistochemical analysis has shown that tumor cells consistently express epithelial membrane antigen (EMA) (Wu et al. 2021). Conversely, they do not exhibit immunoreactivity for cytokeratin (CK), thyroid transcription factor-1 (TTF-1), napsin A, S-100 protein, CAM5.2, CD10, CD31, CD34, desmin, smooth-muscle actin (SMA), p63, calponin, h-caldesmon, anaplastic lymphoma kinase (ALK), c-kit, melanocytic markers (HMB-45), synaptophysin, or glial fibrillary acid protein (GFAP) (Chen et al. 2020).

The key genetic characteristics of PPMS involve EWSR1 rearrangement and EWSR1::CREB1 fusion. Additionally, immunohistochemistry typically reveals positivity for EMA. The combination of these genetic and immunohistochemical features aids in the diagnosis of this tumor.

Diagnosis and differential diagnosis

PPMS lacks distinctive clinical manifestations, and routine blood tests and tumor marker levels typically fall within the normal range, making it challenging to differentiate from other lung conditions with similar clinical presentations. Therefore, the diagnosis of PPMS primarily relies on the tumor's location and histopathological features. Pathological diagnosis is typically obtained through needle biopsy, which serves as the gold standard for clinical diagnosis and holds significant importance for patient management. Differential diagnosis is crucial in the evaluation of PPMS. PPMS should be distinguished from several thoracic tumors:

Extraskeletal myxoid chondrosarcoma (EMC)

EMC is a rare tumor characterized by multinodular growth and short anastomotic strands of oval to spindle-shaped cells embedded in a rich myxoid matrix (Balanzá et al. 2016; Zhou et al. 2012). EMC possesses distinct ultrastructural features, with cords of cells immersed in a matrix rich in glycosaminoglycans (Goh et al. 2001). The key distinguishing factor between PPMS and EMC is their genetic differences. Genetically, gene fusions involving nuclear receptor subfamily 4 group A member 3 (NR4A3) and resulting in NR4A3 constitutive expression are exclusive to EMC and considered a hallmark of the disease (Stacchiotti et al. 2020). The primary fusion genes identified in EMC are EWSR1::NR4A3 and TATA-box binding protein-associated factor 15::nuclear receptor subfamily 4 group A member 3 (TAF15::NR4A3) gene fusions (Hisaoka and Hashimoto 2005), whereas PPMS is characterized by the EWSR1::CREB1 gene fusion.

AFH

AFH is a rare soft tissue mesenchymal neoplasm (Thway and Fisher 2015). According to a study by Gui et al. (2020), PPMS overlaps with a myxoid variant of AFH of the soft tissue morphologically. The myxoid variant of AFH occurs mainly in soft tissues and is rarely seen in the lungs, myxoid variant AFH exhibits distinct myxoid features and can often positively express EMA and EWSR1 gene rearrangements. As a result, it is difficult to distinguish from PPMS (Gong et al. 2018). But, the myxoid stroma of pulmonary AFH is usually focal. The most common morphological features of AFH cases include a peritumoral lymphoid cuff and whorled or storiform patterns, which are not typically described in PPMS. Immunophenotype differences also serve as distinguishing factors; AFH often exhibits positivity for CD68, CD163, desmin, EMA, and ALK (Wang et al. 2021). In contrast, PPMS is characterized by positivity for EMA, along with negativity for desmin and ALK. Moreover, low-to-intermediate malignant potential AFH can also exhibit EWSR1::CREB1 fusion due to t(2; 22) (q33; q12) (Antonescu et al. 2007; Costa and Weiss 1990). While EWSR1::ATF1 and fused in sarcoma::activating transcription factor 1 (FUS::ATF1) fusion genes can be detected in AFH, they are rarely found in PPMS cases (Chen et al. 2020).

Gui et al. (2020) noted that PPMS and AFH have similar histological features, clinical manifestations, immunophenotypic and molecular alterations, and that they are closely related in lineage and pathogenesis. However, whether EWSR1-positive PPMS and AFH may represent the lineage of the same disease, and whether they originate from primitive mesenchymal cells driven by the same or similar EWSR1 fusion gene products, remains to be further investigated.

Myoepithelial tumors (MT)

Myoepithelial tumors (MT) exhibit diverse morphological characteristics and immunophenotypes. They typically display a multinodular or lobular growth pattern, consisting of spindled, ovoid, or epithelioid cells. Immunohistochemically, over 44% of MT cases show the presence of EWSR1 gene rearrangement, and most MT cases test positive for CK, p63, S-100 protein, calponin, and SMA (Jo and Fletcher 2015), whereas these markers are negative in PPMS. Additionally, common fusion variants in MT include EWSR1::POU5F1, EWSR1::PBX1, and EWSR1::ZNF444 (Wang et al. 2021), while the primary fusion gene in PPMS is EWSR1::CREB1 fusion gene.

Inflammatory myofibroblastic tumor (IMT)

IMT is a distinct tumor characterized by myofibroblastic spindle cells and accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils (Khatri et al. 2018). IMTs are immunohistochemically positive for SMA, ALK-1, desmin, and calponin (Henriques de Gouveia 2023). Approximately 50–70% of IMTs harbor the ALK gene rearrangement (Gilani and Kowalski 2014), while PPMS is negative for these markers.

Low-grade myxoid liposarcoma (LGML)

LGML is a malignant adipogenic neoplasm with prominent arborizing capillaries, occasional lipoblasts, and primitive spindle cells in a myxoid background. LGML often involves DNA damage-inducible transcript 3 (DDIT3) gene rearrangement (Scapa et al. 2021), which is not present in PPMS.

Pulmonary microcystic fibromyxoma (PMF)

PMF is well circumscribed with notable cystic changes and a myxoid stroma. Microscopically, PMF features innocuous, widely spaced, spindled to stellate tumor cells with minimal nuclear pleomorphism, and no mitotic activity. These uniform nuclei are widely dispersed within a fibromyxoid stroma, which stains positively with Alcian blue and is sensitive to hyaluronidase. PMF is distinct in its unique microcystic histology, which is absent in PPMS. PMF does not exhibit diagnostic molecular genetic changes, and it does not present with endobronchial localization (Shilo et al. 2006) (Fig. 2).

Fig. 2
figure 2

The diagnostic flow chart of PPMS with EWSR1::CREB1 fusion

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Therapy strategies

Currently, the primary treatment for PPMS with EWSR1::CREB1 fusion is surgery. Given the rarity and non-specific clinical features of PPMS, there are no definite factors known to impact its prognosis.

Surgery

Surgical excision is commonly performed as the primary treatment for all patients with PPMS (Wu et al. 2021). It is essential to closely monitor patients post-surgery to assess the effectiveness of the treatment and the prognosis. PPMS, being a well-defined, low-grade malignant solid sarcoma with a low Ki-67 index, has shown favorable clinical outcomes following surgical resection (Wu et al. 2021). According to existing literature, surgery is the primary treatment approach for most patients. The available surgical excision options include wedge resection, segment resection, lobectomy, and pneumonectomy, depending on tumor size and stage. For instance, Wu et al. (2021) reported a case where a patient with PPMS had primary thyroid cancer with lymph node and lung metastases. In this case, the patient underwent thoracoscopic right upper lobectomy and lymph node dissection, followed by bilateral total thyroidectomy and neck lymph node dissection three months later. There were no signs of recurrence or metastasis during the 12-month follow-up period. Additionally, Kim et al. (2017) described a case where the mass was located in the interlobar fissure of the left lung without definite parenchymal invasion. They successfully removed the mass via video-assisted thoracoscopic surgery without the need for pulmonary parenchymal resection. Thus, a comprehensive treatment approach, with surgery as the primary mode and active management of the primary disease, can improve the condition and quality of life for PPMS patients. Accurate TNM staging and molecular pathological classification can guide postoperative comprehensive treatment. In summary, surgical treatment is the mainstay for PPMS patients and can yield positive outcomes. For patients who are not suitable for surgical resection, alternative treatments such as medication may be considered.

Chemotherapy

Currently, there are limited data on chemotherapy for PPMS, and its effectiveness remains unclear, warranting further investigation. Garnier et al. (2021) initially reported a doxorubicin-based chemotherapy regimen used to treat intracranial non-myxoid angiomatoid fibrous histiocytoma with EWSR1::CREB1 transcript fusion, which resulted in prolonged stable disease for fourteen months after treatment discontinuation. Although PPMS shares the EWSR1::CREB1 fusion with AFH, there have been no reports indicating that doxorubicin can produce a significant therapeutic effect in PPMS with EWSR1::CREB1 fusion. Consequently, the chemotherapy regimens for PPMS with EWSR1::CREB1 fusion remain uncertain.

Molecularly targeted therapy

While EWSR1 gene rearrangement and EWSR1::CREB1 fusion are distinctive features of PPMS, the current understanding of this target remains limited. Therefore, it is necessary to investigate the potential effectiveness of targeted therapy in treating PPMS. Subbiah et al. (2016) have explored the use of the cellular mesenchymal–epithelial transition factor (c-Met)/ALK inhibitor crizotinib and the multi-kinase vascular endothelial growth factor (VEGF) inhibitor pazopanib in metastatic gastrointestinal neuroectodermal tumor (GNET) with EWSR1::CREB1 fusion. These two drugs demonstrated a sustained, nearly complete response in GNET. Additionally, the study included 11 cases of patients with the same EWSR1::CREB1 fusion, encompassing sarcomas not otherwise specified (NOS), malignant neoplasms of unknown primary, melanoma, and head and neck mucoepidermoid carcinoma. EWSR1::CREB1 fusion was identified as the primary driver in these cases. Subbiah et al. (2016) suggested that patients with this EWSR1::CREB1 fusion could also benefit from crizotinib and pazopanib. Furthermore, Ngo et al. (2022) reported a durable response to crizotinib in metastatic angiomatoid fibrous histiocytoma with EWSR1::CREB1 fusion and ALK overexpression. However, the use of crizotinib and pazopanib in clinical treatment for PPMS with EWSR1::CREB1 fusion has not been studied yet. The effectiveness of these two drugs in PPMS cases with EWSR1::CREB1 fusion remains uncertain, and further data are needed to determine their suitability for treating PPMS with EWSR1::CREB1 fusion.

Prognosis

Based on available research findings, the clinical stage of the tumor, the overall health of the patients, their age, and gender all play significant roles as prognostic factors. Retrospective studies indicate that most patients showed good recovery following surgery, with no evidence of recurrence or metastasis. According to Table 2, the rate of metastasis after surgical interventions for PPMS is 14.7% (5/34), with only one fatality resulting from brain metastases after surgery (Thway et al. 2011). Among the 34 patients who underwent surgery, 85.3% (29/34) survived at the final follow-up with NED. The NED duration for these 29 patients ranged from 0.1 to 15 years, with an average NED of 3.5 years. However, based on retrospective studies, there is no conclusive clinical evidence establishing a direct link between post-surgery metastasis and the presence of EWSR1 gene rearrangement or EWSR1::CREB1 fusion. The role of these genetic abnormalities in predicting the prognosis of PPMS remains uncertain and requires further investigation in the future.

Conclusion

PPMS with EWSR1::CREB1 fusion is an exceedingly rare low-grade malignant sarcoma, typically found in the bronchi and lung parenchyma. Microscopically, PPMS is characterized by a reticular network with delicate lace-like strands and cords of ovoid, spindle, or stellate cells in a prominent myxoid matrix. EWSR1 rearrangement and EWSR1::CREB1 fusion are crucial genetic features of PPMS and serve as important diagnostic markers. Immunohistochemically, PPMS tests positive for EMA. In terms of treatment, surgery has been the primary approach in recent years. Therefore, the efficacy of other treatments such as radiotherapy, chemotherapy, and immunotargeted therapy still requires further investigation.