Mediastinal sarcomas: experience using fine needle aspiration cytopathology

Introduction

Several options exist for diagnostic pathologic sampling of mediastinal neoplasms. Among these are the surgical approaches of thoracoscopy (including video-assisted thoracoscopic surgery, VATS), mediastinoscopy, and mediastinotomy, and the less invasive endobronchial ultrasound-guided (EBUS) biopsy, transesophageal endoscopic ultrasound-guided (EUS) biopsy, and percutaneous CT-guided biopsy (1,2). Location within the mediastinum (anterior, middle, posterior) often dictates which interventional approach is used. Based on literature citations, cytopathology, either fine needle aspiration (FNA) biopsy cytopathology, or imprint cytopathology from core needle specimens appears to be underutilized in the diagnosis of all forms of mediastinal neoplasia, but particularly so for sarcomas in large part due to their rarity. This is in marked contrast to the routine use of FNA cytology in mediastinal lymph node staging for lung cancer and lymphoma (3-5).

A 10-year SEER database review of primary mediastinal sarcomas found the category of “sarcoma, NOS” to be more common that any specific sarcoma subtype. According to the author, this reflects the difficulty in obtaining adequate tissue to determine a specific histopathological classification (6). Virtually every sarcoma has been described in the mediastinum, but such instances are rare and typically the subject of small series and case reports. Thus, the cytopathology literature regarding these sarcomas would be expected to be scant also. To wit, one of the largest studies of mediastinal FNA biopsy consisting of 189 cases (71% of which represented neoplasms) from three separate institutions featured no examples of sarcoma (7). Several other studies reflecting the paucity of cytologic evaluation of mediastinal sarcomas include one with 102 mediastinal neoplasms only 2.9% of which were sarcomas (8), and another with 42 mediastinal aspirates but only 2 sarcomas (9). Marcus et al. reported that 4% of their 107 mediastinal fine needle aspirates were soft tissue tumors, but failed to specify whether they represented sarcomas or benign soft tissue neoplasms (10). Incomplete sampling remains a critical source of error in any type of biopsy procedure. Since various sarcomas may arise as components of mediastinal germ cell tumors, one must be cognizant of this possibility also (11). The purpose of this review is to spotlight the cytopathology of select examples of mediastinal sarcomas.

Diagnostic categories

Liposarcoma (LPS)

LPS is regarded as the most common mesenchymal sarcoma of the mediastinum (6,12,13). It occurs in all three mediastinal compartments, but primarily the anterior and posterior mediastinum. Each of the major subtypes of LPS (well-differentiated, myxoid, dedifferentiated, and pleomorphic) has been reported in this location, but well-differentiated and de-differentiated subtypes appear to be most common (13). The cytopathology mimics that seen in the somatic soft tissues. Two reports of primary mediastinal myxoid LPS and one of metastasis to the mediastinum showed similar features consisting of myxoid stroma, cytologically monotonous bland nuclei, variable cytoplasmic vacuolization, and arborizing thin capillaries (14-16) (Figure 1). Another example of primary mediastinal LPS described both myxoid and pleomorphic features, but failed to illustrate any cytologic images (17). Rather than being multi-vacuolated, the lipoblasts in myxoid LPS usually contain a single vacuole (18). A study of 39 LPS by Kapila et al. concluded that the role of FNA in identification of specific variants of LPS is limited (19). In more recent series, the added use of confirmatory FISH analysis for DDIT3 gene rearrangement is not only possible from smears and cytology cell-blocks, but also valuable for correctly confirming this diagnosis and distinguishing it from other myxoid neoplasms (20).

Figure 1 Myxoid liposarcoma. A microfragment of metachromatic staining myxoid stroma is seen at the left side of this field. Note the banal appearing nuclei and cytoplasmic vacuoles in the right sided cell cluster. Romanowsky stain, 20×.

Pleomorphic LPS (PLPS) is the least common form of LPS representing up to 5% of all LPS (21), and descriptions of its cytopathology are extremely rare in the mediastinum (22). Cytologic smears of PLPS are those of a high-grade sarcoma, but have been mistaken rarely by experienced observers as metastatic carcinoma (23). Aspirates are typically hypercellular containing isolated malignant cells and cell aggregates with striking anisonucleosis, spindle cells, epithelioid cells, multinucleated tumor giant cells, coarse chromatin, and cytoplasmic lipid-filled vacuoles (22,24) (Figure 2). A single mediastinal case reporting the cytopathology described fusiform cells with nuclear pleomorphism and cytoplasmic macrovacuoles (25). Unfortunately, this cytomorphology is less than specific overlapping to a considerable degree with other pleomorphic sarcoma subtypes [e.g., undifferentiated pleomorphic sarcoma, dedifferentiated LPS (DDLPS)]. As PLPS has no specific molecular signature or immunohistochemical (IHC) marker, distinction among these pleomorphic sarcomas is extremely challenging in cytology aspirates. The identification of large multivacuolated lipoblasts is critical to diagnostic recognition of PLPS; unfortunately, these cells can vary from <1% to 80% of the tumor area (21). Mariño-Enríquez et al. found variable and overlapping cytologic features in their large study comparing DDLPS and PLPS (including 1 mediastinal primary and 1 mediastinal metastasis) (22). They concluded that only coexpression of mdm2 and cdk4 IHC in the former helped to distinguish between the two tumors.

Figure 2 Pleomorphic liposarcoma. This aggregate shows obvious anisonucleosis and nuclear pleomorphism. Coarse lipid-filled cytoplasmic vacuoles are widely scattered throughout the image. Romanowsky stain, 20×.

An analogous problem exists in distinguishing well-differentiated LPS in aspirate smears from those of lipoma since the obligatory hyperchromic atypical cells necessary for diagnosis of the former may be widely scattered in an otherwise non-specific lipomatous background (23,26-28). A series using combined FNA and core needle biopsy on 67 non-mediastinal LPS cases showed a diagnostic yield using FNA alone in accurately determining subtype for all forms of LPS to be 64%. However, that yield dropped to 39% for recognition of well-differentiated LPS compared to 94% for myxoid LPS (29). Einarsdóttir et al. stressed the importance of comparison with image findings. Those tumors with a fat content <75% of tumor volume were more apt to represent LPS, and a diagnoses of lipoma or atypical lipoma should be questioned (26). Even more problematic is the example of mistaking mediastinal thymolipoma for well-differentiated LPS (30), or the possibility of misidentifying the multinucleated floret-type cells of pleomorphic lipoma for LPS (23,31).

Vascular sarcomas

Although many studies have described the cytomorphology of angiosarcoma (AS) and epithelioid hemangioendothelioma (EHE), no set of features is unequivocally diagnostic. Mediastinal EHE is rare (32,33). A large FNA series of EHE (14 cases) contained two examples in the mediastinum, one primary and one metastasis to a mediastinal lymph node (34). Both examples were diagnosed incorrectly cytologically as metastatic carcinoma. The series of VandenBussche et al. (15 cases) also contained two aspirates from the mediastinum (35). Cytomorphology consists of polygonal/epithelioid and even spindle-shaped cells dispersed in hypercellular clusters and as single forms. Nuclei are rounded or oval, hyperchromatic, eccentrically located in the cell resembling plasmacytoid or signet ring cells, and possess intranuclear cytoplasmic pseudoinclusions which may be common (34-36) (Figure 3). Cell cytoplasm is moderate in amount with single or multiple vacuoles. Only rarely are lumina containing entrapped intact and degenerating red cells present (34-36). In the mediastinum, the morphologic combination of cells in loose or tight clusters, an epithelioid configuration, and easily visible cytoplasmic vacuoles provides a strong mimic for adenocarcinoma or mesothelioma—tumors with which EHE is commonly confused (37-40). Most cytology reports fail to highlight the myxohyaline stroma that is commonly emphasized in histopathologic descriptions of EHE. Matrix material was found in only 20% of cases from the largest series (35). Definitive cytologic diagnosis of EHE requires awareness of the entity (often overlooked due to its rarity), and the application of IHC markers (CD31, ERG, CAMTA1) and/or FISH testing for WWTR1-CAMTA1 rearrangement (present in >90% of cases) from a cytology cell-block.

Figure 3 Epithelioid hemangioendothelioma. A loose cluster of epithelioid cells with rounded to oval nuclei and moderate amount of slightly opaque cytoplasm is present. Note the intranuclear cytoplasmic inclusion at the upper left, and the occasional binucleated cell. Papanicolaou stain, 20×.

In a study comparing the cytopathology of EHE with that of epithelioid angiosarcoma (EAS), VandenBussche et al. concluded that many cytomorphological features existed on a spectrum that overlapped considerably between the two (35). While nuclear pleomorphism varied among both tumors, only EAS cases exhibited marked nuclear pleomorphism, and about half of EHE cases contained nuclear grooves which were lacking in all EAS examples (35). Some authors describe rhabdoid morphology to the cells in EAS (41,42). Mitoses, typically readily found in EAS tissue specimens, cannot be relied upon in FNA specimens. They were absent or rare in both EHE and EAS cases from one study (35); however, another found abnormal mitoses in 85% of cases (43). Although the WHO classification of soft tissue tumors does not recognize specific subtypes of AS, the more common histo-and cyto-pathology of AS is that of a heterogenous cell population with a high percentage of spindle cells (44) along with epithelioid and giant cells in variable numbers (41,43,45). In some cases, smears may be hypocellular due to the dilutional effect of abundant blood being aspirated. The anastomosing vascular channels seen in tissue are, of course, usually invisible in cytologic preparations. Most aspirates display 3-dimensional clusters with moderate-marked nucleomegaly and nuclear pleomorphism (41,43) (Figure 4). Presumptive vasoformative features consisting of microacinar structures, arborizing microtissue fragments, intracytoplasmic lumina, signet-ring-like cells, and rare erythrophagocytosis have been emphasized by some authors (43-45). It is important to remember that both EHE and AS may stain with pan-keratin markers and EMA (particularly strong staining in EAS) in addition to previously alluded endothelial markers so a complete IHC panel is required (46).

Figure 4 Angiosarcoma. Large polygonal cells are dispersed as single forms and in a large 3-dimensional cluster. No vasoformative features are present which is often the case for this sarcoma. Romanowsky stain, 20×.

Malignant peripheral nerve sheath tumor (MPNST)

MPNST is a rare mediastinal malignancy, and when present primarily affects the posterior mediastinum. The three largest FNA cytology series of MPNST (82 total cases) mention only a single case from the mediastinum, although several cases are described as involving the chest wall (47-49).

Cytologic smears are moderately to highly cellular, but occasionally may be hypocellular. Spindle cells are dispersed both as individual forms, and in thinly or densely concentrated aggregates. Parallel orientation may commonly produce a fascicular pattern in smears. Nuclei are fusiform or blunt-ended with a smooth contour (Figure 5). Some authors have underscored that comma-shaped cells with twisted or wavy nuclei are the most reliable morphologic feature for suspecting MPNST (48); however, others note that “wavy” or “kinked” nuclear contour is an uncommon feature (47,50). There is usually some degree of anisonucleosis, but marked pleomorphism is seen only in high-grade/anaplastic MPNST. Cytoplasm is variable, usually sparse and tapered. Smear background is often “clean”, but individual cell necrosis may be present.

Figure 5 MPNST. A moderately cellular cell syncytial aggregate contains relatively uniform smoothly contoured spindled nuclei with thin bipolar cytoplasmic processes. The somewhat bland appearance is often deceiving in these examples of well-differentiated MPNST. Papanicolaou stain, 10×. MPNST, malignant peripheral nerve sheath tumor.

Primary conventional MPNST is extremely difficult to differentiate from other spindle cell malignancies without either a clinical history of NF-1, or knowledge that the neoplasm is in proximity to or appears to arise from a major nerve. To illustrate, none of eight (50), 1 of 13 (8%) (48), none of three (49), and 8 of 27 (30%) cases (47) of primary MPNST were correctly recognized using FNA cytology. Conversely, the ability to recognize MPNST in recurrent tumors is very high with a correct diagnosis in 93% of recurrent cases in the largest study (47). Smears of low-intermediate grade MPNST may be mistaken for other spindle cell sarcomas, and even schwannoma, particularly when “ancient” change with nuclear atypia is present (51). High-grade MPNST merely demonstrates the non-specific cytopathology of a pleomorphic sarcoma. The epithelioid variant of MPNST imitates a variety of mesenchymal and non-mesenchymal epithelioid neoplasms including malignant melanoma, epithelioid sarcoma, chordoma, and metastatic carcinoma (52). Ancillary IHC staining of conventional MPNST shows staining of S-100 and SOX-10 in only about half of cases, but since this staining is typically patchy it may be missed in a cytology cell-block specimen. Complete loss of staining with H3K27me3 antibody may assist with the diagnosis. However, this loss occurs more often in high-grade MPNST than in low-grade cases (53). In contrast, epithelioid MPNST exhibits strong and diffuse S100 and SOX1 staining, but without expression of SMARCB-1 and melanoma markers (54).

Unclassified sarcomas/ sarcomas of uncertain differentiation

Mediastinal synovial sarcoma (SS) is rare accounting for about 9% of intrathoracic SSs in one series (55). Most tumors occur in patients <50 years of age with monophasic SS being far more common than biphasic SS (56). Only single case reports constitute the FNA cytology of mediastinal SS (57,58). Large series of SS from soft tissue sites show hypercellular smears with cell clusters so thick that one cannot appreciate individual cells within these 3-dimensional aggregates. Relatively uniform rounded to spindle shaped cells have oval to oblong monotonous nuclei. These have evenly dispersed chromatin, inconspicuous to absent nucleoli, and smooth contours combined with scant non-vacuolated cytoplasm (Figure 6). Stripped nuclei are common and unless one captures a necrotic focus, there is minimal background stroma (59-62). The biphasic variant is difficult to appreciate on smears since these glandular structures which remain intact in tissue sections are often disrupted using FNA. A specific cytologic diagnosis is possible in >95% of primary neoplasms when ancillary IHC staining incorporating TLE-1 as part of a panel of stains is paired with fluorescence in-situ hybridization (FISH) or polymerase chain reaction (PCR) testing for SYT gene rearrangement (62).

Figure 6 Synovial sarcoma. Single cells, many with stripped euchromatic nuclei, cluster around thick spindle cell aggregates. Cellular monotony is commonplace in aspirates of synovial sarcoma. Papanicolaou stain, 20×.

Rare examples of “round cell” sarcomas have been reported as primary mediastinal neoplasms. The most common among these is the Ewing sarcoma/family of tumors (ES). As a mediastinal primary, ES is exceptionally rare in contrast to its more common thoracopulmonary location (63,64). Aspiration cytopathology consists of highly cellular smears with monotonous cells about 2–3 times the diameter of a mature lymphocyte dispersed individually with a minority in loose clusters. Nuclear molding and rarely acinar or pseudorosette formation may be seen. Nuclei are rounded to oval with indistinct nucleoli. Cell cytoplasm is usually meager, but not infrequently contains glycogenated cytoplasmic vacuoles. If numerous, these create a so-called “tigroid” background with naked strips of cytoplasm arranged in parallel or as a plexiform network (28,65,66) (Figure 7). Due to morphologic mimicry with other malignant “small” rounded cell sarcomas, genetic confirmation is nearly always required for a definitive diagnosis. This is often accomplished with FISH testing from a cytology cell-block. Most ES cases have the EWSR1-FLI1 fusion, about 10% harbor fusion of the EWSR1-ERG genes, and a smaller percentage partner with other ETS-family fusion genes. In addition to the non-specific, but still helpful CD99 staining, the newer NKX2.2 IHC stain has added greater specificity to recognizing ES (67). A rare cytologic example of CIC-rearranged sarcoma, CIC-DUX4, has been described in the mediastinum (68). The few reported examples of this sarcoma state that the cytopathology is somewhat more atypical than classic ES (68,69).

Figure 7 Ewing sarcoma. The cytologic picture is one of a malignant small rounded cell tumor. Numerous clear glycogen-filled cytoplasmic vacuoles are present. Disruption of cells leads to this background meshwork of stripped cytoplasm creating a so-called “tigroid” pattern. Romanowsky stain, 20×.

Conclusions

Based on citations from the English-based literature FNA cytology is uncommonly employed as a diagnostic modality for evaluating mediastinal sarcomas. Nonetheless, when cell morphology is paired with ancillary IHC staining and molecular methods (specifically FISH testing in selected sarcomas) diagnostic accuracy can be quite high and of clinical value.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Saul Suster and David Suster) for the series “Mediastinal Sarcomas” published in Mediastinum. The article was sent for external peer review organized by the Guest Editors and the editorial office.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/med-20-30). The series “Mediastinal Sarcomas” was commissioned by the editorial office without any funding or sponsorship. 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.

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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