Mesenchymal tumors of the lung comprise benign and malignant neoplasms. Among the benign lesions, pulmonary hamartoma represents the most common mesenchymal lung tumor. Its unique radiological and histomorphological features do not typically cause diagnostic difficulties. Primary pulmonary sarcomas (PPS), on the other hand, are very rare and aggressive malignancies originating in the mesenchymal tissues of the bronchi, blood vessels, and lung parenchyma. As a group, they account for less than 0.5 % of all malignant lung tumors and approximately 9 % of all sarcomas.1,2 The diagnosis of PPS can be challenging due to the difficulty of distinguishing PPS from non-mesenchymal neoplasms with spindle cell features, such as sarcomatoid carcinoma or sarcomatoid mesothelioma or from metastatic sarcomas of extrathoracic origin. While many PPS resemble their soft tissue counterparts and are classified accordingly, several mesenchymal entities exist that exclusively arise in a pulmonary location and that have not been described in other anatomic locations, for instance, primary pulmonary myxoid sarcoma or clear cell stromal tumor of the lung.

As a result, comprehensive multidisciplinary assessment, including clinical history, radiologic examination, and detailed evaluation of pathological samples, to include ancillary testing is required to confirm a diagnosis of PPS.3 One helpful tool in the diagnosis of sarcomas is the identification of characteristic molecular aberrations, such as fusion genes, that can be attributed to specific sarcoma types. Such alterations cannot only be used to confirm or refine a specific sarcoma diagnosis but may also provide prognostic and predictive insight as well as guide treatment decisions.

Primary pulmonary sarcomas are aggressive neoplasms that exhibit worse prognosis compared to non-small cell lung cancer (NSCLC) (5-year overall survival: 44 % vs 54 %, p < 0.001) and soft tissue sarcomas of the extremities (5-year overall survival: 35 % versus 71 %, p < 0.001), making accurate diagnosis even more important.4, 5, 6, 7

This review outlines the spectrum of primary pulmonary mesenchymal tumors with neoplastic potential, emphasizing novel diagnostic techniques, diagnostic pitfalls and the differential diagnosis with more prevalent spindle cell tumors of pulmonary origin.

Solitary fibrous tumors (SFT) are soft tissue neoplasms believed to originate from primitive mesenchymal cells.8,9 While these tumors are ubiquitous and very common in the pleura, the lung parenchyma is only rarely the site of origin of SFT. In 2013, the largest series of intrapulmonary SFT was published, summarizing the authors’ experience with 24 such cases.10

Histologically, pulmonary SFT are well circumscribed tumors composed of fibroblastic spindle cells arranged in a characteristic “patternless” pattern including alternating hypo- and hypercellular areas and dense collagenous stroma with rope-like appearance.10 The vasculature often displays a hemangiopericytoma-like or antler-like growth pattern (Fig. 1A). Tumor cells are typically bland with no or little atypia and low mitotic activity. Due to the location in the lung parenchyma, entrapped respiratory epithelium may be identified. Immunohistochemically, the tumor cells are positive for CD34, BCL2 and CD99; more recently, identification of recurrent NAB2::STAT6 fusions in SFT has led to the use of STAT6 protein expression as a reliable diagnostic marker for SFT of all sites (Fig. 1B).11,12 Although large size, cytologic atypia, increased cellularity, increased mitotic activity (≥4 mitoses per 10 high power fields [HPF]), and tumor necrosis are generally associated with more aggressive clinical course,13,14 the prognosis for intrapulmonary SFT appears to rely more on complete surgical resection and long-term follow up since recurrence or metastasis have also been reported in tumors lacking adverse histological features (Table 1).10 On rare occasions, SFT may undergo progression to a morphologically non-distinctive high-grade sarcoma that lacks the characteristic histological features of conventional SFT. These tumors are referred to as dedifferentiated SFT.15 Despite their altered morphology, dedifferentiated SFT frequently retain NAB2::STAT6 gene fusions, often involving truncation of the STAT6 gene, and commonly exhibit additional genetic alterations, including mutations in TP53, RB1, and the TERT promoter. Notably, nuclear STAT6 expression is diminished or lost in approximately 35 % of these cases, posing a significant diagnostic challenge. Clinically, dedifferentiated SFT are associated with markedly aggressive behavior, and loss of STAT6 expression has been correlated with significantly reduced disease-specific survival.16

Despite their name, synovial sarcomas do not originate from synovium but rather from primitive or specialized mesenchyme.17,18 Primary pulmonary synovial sarcomas typically occur in an older patient population (4th to 6th decade) than their soft tissue counterparts and classically present as large, circumscribed lesions in the subpleural lung parenchyma.17,19,20 Synovial sarcoma can be divided into 3 subtypes, including monophasic, biphasic, and poorly differentiated variants.17,19,21 In the lung, monophasic synovial sarcoma is the most common subtype and composed of compact fascicles of monomorphic spindle cells with high nuclear-cytoplasmic ratio and elevated mitotic activity whereas the biphasic subtype contains additional glandular elements, often containing eosinophilic secretions (Fig. 1C). Poorly differentiated synovial sarcomas on the other hand, show less well-developed features and frequently consist of sheets of round epithelioid cells with or without rhabdoid cytoplasmic inclusions. Hemangiopericytoma-like blood vessels, stromal mast cells, myxoid stromal changes, and cystic degeneration are common findings, as are areas of necrosis.17,19,21 On an immunohistochemical level, synovial sarcomas are known to express BCL2, CD99, and S100 to varying levels. They may also be positive for epithelial markers (pancytokeratin, epithelial membrane antigen), especially in the glandular structures of the biphasic variant. The recent development of TLE1 and SS18-SSX antibodies has led to the availability of more specific markers for synovial sarcoma, with the latter being considered particularly sensitive and specific for this tumor type (Fig. 1D).22 Genetically, synovial sarcomas harbor a specific translocation, t(X;18)(p11;q11), resulting in SS18::SSX1/2/4 gene fusions. Rare SSX1 fusions to non-SS18 partners have been reported in some cases.23,24 Compared to soft tissue synovial sarcomas, pulmonary synovial sarcomas demonstrate more aggressive clinical behavior, likely due to delayed diagnosis (Table 1).17,19,21

Pulmonary inflammatory myofibroblastic tumor (IMT), formerly also known as inflammatory pseudotumor is a tumor of presumed mesenchymal origin that primarily affects children and young adults.25,26 At the microscopic level, IMT consist of a proliferation of bland myofibroblastic spindle cells often arranged in storiform patterns admixed with variable numbers of inflammatory cells, most commonly lymphocytes and plasma cells. Depending on the prominence of the inflammatory cells, the tumors can be divided into those with little lymphoplasmacytic component (fibrohistiocytic variant) and those with abundant inflammatory cells (plasma cell granuloma) (Fig. 1E). The stroma is generally subtle and can show myxoid or collagenous patterns; the mitotic activity is low. The myofibroblastic cells are often positive for smooth muscle actin (SMA) and vimentin and generally negative for cytokeratins and S100 (Fig. 1F).27,28 Since ALK and ROS1 gene rearrangements has been identified in a subset of IMT, expression of ALK and ROS1 may be detected at the protein level in such cases.29,30 The prognosis for completely resected IMT of the lung is excellent, especially for ALK-rearranged IMT (Table 1).25,31

Pulmonary artery intimal sarcomas (PAIS) are tumors arising from the arterial intima of elastic-type arteries of the lung, growing intraluminally and spreading along the intima with relative sparing of the media.32,33 As a result of the growth characteristics, pulmonary embolism, thromboembolic disease and pulmonary hypertension may ensue.34,35 Patients commonly present in the 6th decade of life with no distinct sex predilection.36 The tumor histology of PAIS is variable and can range from undifferentiated myofibroblastic sarcomas to more differentiated ones, including leiomyosarcoma, rhabdomyosarcoma, or angiosarcoma, among others (Fig. 2A).35,37,38 While most of the tumors are hypercellular lesions, necrosis and mitotic activity may vary depending on tumor subtype. In a similar manner, the immunophenotype will very much depend on tumor differentiation (Fig. 2B). Nonetheless, 70 % of PAIS overexpress MDM2 as a result of MDM2 gene amplification (often co-existing with PDGFRA amplification) which can be used to support the diagnosis (Table 1).37,39

Epithelioid hemangioendothelioma (EHE) is a malignant vascular neoplasm that can occur in multiple sites, most commonly the liver, lung, bone and soft tissue.40 The lung is one of the most common primary sites, affected alone or along with other organ systems. In the majority of cases, pulmonary EHE presents with multiple bilateral lung nodules. Most patients are in the 4th to 5th decade of life and many of them lack any respiratory symptoms. Females are more frequently affected than males.41, 42, 43 Histologically, EHE impress with a prominent intraalveolar growth pattern forming oval nodules within and expanding pre-existing alveolar spaces. Individual lesions show a gradient of cellularity with hypocellular sclerotic centers and a more cellular outer rim (Fig. 2C). The lesions are accompanied by a chondromyxoid stroma and tumor cells are arranged in cords, nests or solid clusters. They generally consist of spindled or epithelioid cells with bland cytologic features. Intracytoplasmic lumina (blister cells) are a characteristic finding and diagnostic clue (Fig. 2C inset). Obvious cytologic atypia, high mitotic activity and necrosis are rare features and, if present, associated with more aggressive clinical course. Epithelioid hemangioendothelioma has a vascular immunophenotype characterized by immunoreactivity for CD34, CD31 and ERG (Fig. 2D). Of note, up to 50 % of EHE also react with pancytokeratin which can lead to an erroneous diagnosis of a carcinoma.44, 45, 46 In addition, EHE have been found to harbor WWTR1::CAMTA1 fusions in about 90 % of cases and less often YAP1::TFE3 fusions (<10 %).47,48 Hence, expression of CAMTA1 or TFE3 at the protein level provides another helpful diagnostic tool (Table 1).49,50

The category of undifferentiated small round cell sarcoma (USRCS) encompasses a family of tumors that are characterized by a proliferation of undifferentiated small round cells, including Ewing sarcoma, CIC-rearranged sarcoma, sarcoma with BCOR alterations and round cell sarcomas with EWSR1::non-ETS fusions.51,52 Similar to their bone and soft tissue counterparts, these tumors primarily affect children and young adults and histologically consist of a uniform proliferation of sheets, nests, and cords of small round to spindled cells with scant cytoplasm (Fig. 2E). The stroma can have fibrohyaline or myxohyaline qualities or may be inconspicuous. The presence of mitotic activity and necrosis can be highly variable.51,52 Immunohistochemically, Ewing sarcoma displays reactivity for CD99 and NKX2.2, CIC-rearranged sarcomas are typically positive for CD99, WT-1 and ETV4 (Fig. 2F), sarcomas with BCOR alterations express BCOR, SATB2, TLE1 and cyclin D1 and round cell sarcomas with EWSR1::non-ETS fusions can show variable reactivity with CD99, PAX7, and NKX2.2. Genetic confirmation is required for definitive diagnosis of these tumors. The most common gene fusion in Ewing sarcoma is EWSR1::FLI1 (85 %) followed by EWSR1::ERG in 10 % of cases.51,52 Identification of CIC::DUX4 fusion is diagnostic of CIC-rearranged sarcoma and can be seen in up to 95 % of cases.51,52 Sarcomas with BCOR alterations most commonly demonstrate BCOR::CCNB3 fusion and round cell sarcomas with EWSR1::non-ETS fusions include those with EWSR1::NFATC2, FUS::NFATC2 and EWSR1::PATZ1 gene fusions.51,52 Undifferentiated small round cell sarcomas of the lung are highly aggressive neoplasms with 4-year survival rates of <10 % after multimodal treatment (Table 1).53

Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms of presumed perivascular epithelioid cell origin that can occur anywhere in the body.54 In the lung, these tumors were initially designated as clear cell sugar tumor due to their abundant cellular glycogen content until their relationship to PEComas of other organ sites was recognized.54,55 In the lung, PEComas typically behave in a benign fashion. Contrary to PEComas of other organ systems, they appear to be more common in male patients and occur over a wider age range.56,57 Macroscopically, primary pulmonary PEComas are well circumscribed solitary lesions often located in the peripheral lung parenchyma. Microscopically, the tumors are characterized by large epithelioid cells with abundant clear to eosinophilic cytoplasm, eccentric nuclei, small nucleoli and distinct cellular borders. They are typically arranged in nested or sheet-like patterns. The stroma is highly vascularized and tumor cells are often arranged radially around thin-walled, sinusoidal vessels (Fig. 3A). Cytologic atypia and mitotic activity are low or absent. Marked cytologic atypia, presence of hemorrhage and necrosis, and high mitotic activity are signs of malignancy in PEComa and should raise concern for a metastatic process to the lung.58, 59, 60 Immunohistochemically, PEComas are characterized by myomelanocytic differentiation and expression of markers such as HMB45, melan A and MITF as well as SMA, desmin or caldesmon (Fig. 3B).61 Histochemical reactivity with periodid acid Schiff (PAS) can be used to highlight the glycogen content of the tumor cells.62 Approximately 80 % of PEComas harbor TSC2 gene mutations and fall into the spectrum of TSC2-linked neoplasms.63 Recently, a small subset of lung PEComas that lack TSC2 gene mutations have been found to demonstrate TFE3 gene fusions, including TFE3::SFPQ and YAP1::TFE3. These fusions expand the spectrum of molecular alterations seen in PEComa and raise the possibility of a relationship with other YAP1::TFE3 fused neoplasms, including clear cell stromal tumor of the lung and epithelioid hemangioendothelioma. 63,64 Of note, nuclear reactivity with TFE3 can be seen in such tumors (Table 1).64

Clear cell stromal tumor (CCST) of the lung is a recently defined entity that was first described under the name of hemangioblastoma-like stromal tumor of the lung due to its morphological similarity to hemangioblastomas of central nervous system origin.65 Clear cell stromal tumors have not been described outside of the lungs and are currently considered low-grade mesenchymal tumors of presumed stromal origin. In 2021, a recurrent YAP1::TFE3 fusion gene was identified in these tumors, establishing CCST as a new tumor entity unrelated to hemangioblastoma.66 Clear cell stromal tumors are typically solitary lesions involving the peripheral lung parenchyma of adult female patients in the 6th decade of life.67 Less commonly, patients present with multiple lung lesions mimicking a metastatic process to the lungs and multifocality has been associated with a protracted clinical course compared to solitary CCST.67 The tumors are composed of cells centered around bronchial structures and set within a rich vascular stroma. Individual tumor cells are small to medium-sized, ovoid to fusiform with relatively little clear or eosinophilic cytoplasm, vesicular chromatin and inconspicuous nucleoli. In addition, to the vascular stroma, hemangiopericytoma-like blood vessels may also be identified (Fig. 3C). Mixed among the tumor cells are variable numbers of inflammatory cells, including lymphocytes, plasma cells and eosinophils. Larger tumor cells with lobulated or multinucleated features resembling mummified cells can be identified in some cases but cytologic atypia, increased mitotic activity and necrosis are not commonly seen.66, 67, 68 Diffuse nuclear expression of TFE3 characterizes the immunophenotype of CCST which is otherwise non-specific, lacking reactivity with epithelial, melanocytic, and neuroendocrine markers (Fig. 3D) (Table 1).66, 67, 68

Primary pulmonary myxoid sarcoma (PPMS) is a lung-specific, low-grade sarcoma with prominent endobronchial growth.69 The tumor predominantly affects middle-aged adults, more commonly women and usually presents as a solitary, multilobulated lesion in the bronchial tree. The histogenesis of PPMS remains uncertain although an origin from primitive peribronchial mesenchymal cells has been suggested.70 Macroscopically, PPMS are circumscribed, lobulated and gelatinous-appearing lesions involving the bronchus. Histologically, the tumors are composed of nodules of spindled, stellate or epithelioid cells with reticular or lace-like architecture and prominent myxoid stroma (Fig. 3E). The tumor cellularity is generally low but can vary from area to area. Cytologic atypia is mild to moderate and mitotic activity is generally low. A lymphoplasmacytic infiltrate is often observed in these tumors, primarily in the periphery of the tumor nodules.69, 70, 71, 72 The immunophenotype is non-specific demonstrating weak reactivity with epithelial membrane antigen (EMA) while generally negative for cytokeratins, neuroendocrine or smooth muscle markers (Fig. 3F).69, 70, 71, 72 The defining feature, identified in more than 80 % of cases, is an EWSR1::CREB1 fusion transcript which appears to underlie the pathogenesis of PPMS. Since similar tumor morphology and the presence of an EWSR1::CREB1 fusion gene can also be seen in angiomatoid fibrous histiocytoma, a histogenetic relationship between the two tumors has been proposed, possibly representing variants of the same clinicopathologic entity (Table 1).73,74

Except for the rare mesenchymal neoplasms that are unique to the pulmonary system, a metastatic process to the lung typically needs to be excluded for those tumors that more commonly arise in other organ systems. This particularly applies to the group of sarcomas that often have their origin in the soft tissue or bones and have a preponderance to metastasize to the lungs. Such metastases usually share morphological, immunohistochemical and molecular similarities with their primary tumors and identification of the primary site often relies on careful review of clinicoradiological parameters and discussion in a multidisciplinary setting.

A more complex problem may be the separation of primary pulmonary mesenchymal lesions from the more common non-mesenchymal tumors of lung origin that may share similar morphological features. For instance, those tumors with predominant spindle cell morphology, including SFT, IMT, synovial sarcoma, PAIS and PPMS can be mistaken for non-small cell lung carcinoma (NSCLC) with spindle cell features (sarcomatoid carcinoma) (Fig. 4A). In some of these cases, tumor morphology alone may not be sufficiently discriminative to confidently arrive at a diagnosis, especially if the tumor sample consists of a small volume lung biopsy. In this scenario, use of immunohistochemical and molecular testing becomes indispensable. Sarcomatoid carcinomas of the lung are poorly differentiated NSCLC and as such typically express cytokeratins. They may also show reactivity for more specific markers, for instance TTF-1 or p40 indicating varying degrees of glandular or squamous differentiation (Fig. 4B).75 Contrary to that, SFT, IMT, synovial sarcoma, PAIS and PPMS are usually negative for these markers. In addition, sarcomatoid carcinomas lack the characteristic genetic aberrations associated with SFT (NAB2::STAT6 gene fusion), synovial sarcoma (SS18::SSX1/2/4 gene fusions), PAIS (MDM2 gene amplification) and PPMS (EWSR1::CREB1 gene fusion) (Table 2).

The most important differential diagnosis for EHE is pulmonary adenocarcinoma. Both tumors can share similar morphological features, including epithelioid tumor cells with variable cytologic atypia and mitotic activity (Fig. 4C). Close attention should be paid to subtle microscopic characteristics in EHE, such as blister cells or the chondromyxoid stroma. On an immunohistochemical level, EHE can be positive for cytokeratin in about half of all cases adding further difficulty to the diagnostic process. Once EHE enters the differential diagnosis, addition of vascular markers (CD34, CD31, ERG) and CAMTA1/TFE3 and/or molecular analysis for WWTR1::CAMTA1 or YAP1::TFE3 gene fusions may be necessary to confirm the true nature of the neoplasm (Fig. 4D) (Table 2).

Some NSCLC, primarily adenocarcinomas and squamous cell carcinomas (SCC) can show striking clear cell changes similar to the ones displayed by either CCST or pulmonary PEComas (Fig. 4E). In this scenario, close attention should be paid to the cytologic features of the tumor cells which are typically benign or low-grade appearing in CCST and PEComas while as a group, NSCLC are often poorly differentiated neoplasms. Standard diagnostic immunohistochemical markers for NSCLC (cytokeratins, TTF-1 and p40) should be helpful to differentiate these carcinomas from CCST (cytokeratin -, TFE-3+) and PEComas (cytokeratin-, myomelanocytic markers +) (Fig. 4F) (Table 2).

In addition to NSCLC, some pulmonary mesenchymal tumors may also be confused with neuroendocrine neoplasms, such as carcinoid tumors or small cell carcinoma. This applies especially to mesenchymal tumors with small round cell morphology. Separating USRCS from small cell carcinoma is a prime example in this scenario. Both tumors are composed of small round cells with high nuclear-cytoplasmic ratio, high mitotic activity and areas of necrosis (Fig. 5A). Additionally, growth patterns in both tumors often show sheet-like growth with or without rosette-like structures. While small cell carcinoma typically demonstrates expression of cytokeratin, synaptophysin and/or chromogranin, no specific immunomarkers exist for USRCS. Although most USRCS are negative for keratins and neuroendocrine markers, in some cases, these markers show variable reactivity, including diffuse expression of these antibodies.76,77 Based on this, TTF-1 may be a better discriminatory marker in this context with reactivity in up to 85 % of small cell carcinomas while generally negative in USRCS (Fig. 5B).53 Molecular analysis to search for gene fusions commonly associated with the family of USRCS may ultimately be required to distinguish this group of tumors from small cell carcinoma (Table 2).

Further mesenchymal tumors that can present with small cell change are poorly differentiated synovial sarcoma and SFT and their occurrence in the lung may lead to an erroneous diagnosis of a neuroendocrine neoplasm.78 In addition, both tumors may be positive for synaptophysin so that a wider immunopanel, to include TLE1, SS18SX and STAT6 or molecular testing (SS18::SSX1/2/4 and NAB2::STAT6 gene fusions) may be needed to further classify the lesion. Furthermore, the tumor morphology of CCST with its monomorphic proliferation of small oval cells and highly vascular stroma is also reminiscent of a neuroendocrine neoplasm, namely carcinoid tumor (Fig. 5C). Application of cytokeratin and neuroendocrine markers should help in this context, as none of the CCST described so far have shown expression of these markers (Fig. 5D) (Table 2).

Lastly, several of the mesenchymal neoplasms described above may also be difficult to distinguish from each other. For instance, USRCS and poorly differentiated synovial sarcoma can show overlapping small round cell morphology. In a similar manner, the spindle cells of monophasic synovial sarcoma and SFT can be difficult to distinguish based on tumor morphology alone. Pulmonary artery intimal sarcoma can assume many different histological patterns and closely mimic other sarcoma types; imaging findings to demonstrate a close relationship with the central pulmonary vasculature or heart and comprehensive clinical history become indispensable in such cases. Moreover, a close histological mimic of EHE is angiosarcoma. The latter more often shows true vasoformation and sheet-like growth and more pronounced cytologic atypia as opposed to EHE. In all these cases, immunohistochemical and/or molecular workup is often required before a definitive diagnosis can be rendered (Table 2).