Introduction

Primary sarcomas of the head and neck region are rare tumors, comprising <1% of primary malignancies in this region [1]. Primary head and neck sarcomas affect both adults and children. Some of the most frequently encountered sarcomas include rhabdomyosarcoma and Ewing sarcoma in children and young adults, and rhabdomyosarcoma, synovial sarcoma, Kaposi sarcoma, and angiosarcoma in older adults [2, 3]. Primary head and neck sarcomas commonly involve the scalp, face, and nasal cavity, while the larynx and upper airway are more unusual sites [1, 4, 5]. The prognosis is related to the tumor type and extent of resection, which is often incomplete due to anatomic restrictions [5].

Low-grade fibromyxoid sarcoma (LGFMS) is a deceptively bland malignancy with potential for late recurrence and metastasis [6]. LGFMS typically affects young adults, although children and older adults are also affected [7–9]. LGFMS occurs most commonly in the deep soft tissues of the proximal extremities and trunk, with only isolated head and neck cases reported [7, 9–14]. Most LGFMSs harbor a characteristic gene fusion of FUS/CREB3L2, and recently MUC4 immunostaining has been found to be highly sensitive and specific for the diagnosis [15, 16]. We present a dedicated series of head and neck LGFMS, including the first reported laryngeal case.

Methods

The surgical pathology archives of The Johns Hopkins Hospital, H. Lee Moffitt Cancer Center, and Southern California Permanente Medical Group were searched for cases of LGFMS arising within the head and neck. Hematoxylin and eosin stained slides were reviewed and immunohistochemistry was performed on an automated immunostainer for CK (pck-26, Ventana, pre-diluted), p63 (4a4, BioCare, pre-diluted), p40 (BC28, BioCare, 1:100), EMA (E29, Ventana, 5 mL/5mcg), S100 protein (4C4.0, Ventana, pre-diluted), muscle specific actin (HHF35, Ventana, pre-diluted), β-catenin (Transductinon Laboratories, 1:1000), CD34 (QBE-10, Ventana, 5 mL/5 mcg), and MUC4 (EPR9308; ABCAM; 1:400 dilution). All available clinical and follow-up information was reviewed.

Results

Four head and neck LGFMSs were identified, of which three cases were external consultations (Table 1). The patients ranged from 6 to 73 years in age (mean 41.8 years) at the time of diagnosis and included three males and one female. The tumors were located in the posterior cervical spine, facial skin, mandible, and larynx. One patient had a history of radiation to the tumor bed more than 10 years prior for excessive bone growth following trauma. All of the tumors were treated with wide surgical excision. Histologic examination showed the typical features of LGFMS. At low power, three of the tumors were poorly circumscribed, while one was fairly well demarcated. The tumors were characterized by alternating myxoid and fibrous areas with areas of prominent curvilinear or plexiform vasculature (Fig. 1a, b). The tumor cells contained monotonous, hyperchromatic nuclei with only rare mitoses (Fig. 1c). While none of the tumors exhibited the so-called “giant rosettes” that can be seen in LGFMS, three tumors had areas of whorled tumor cells suggesting early rosette formation (Fig. 1c).

Table 1 Clinical features of head and neck low-grade fibromyxoidsarcomas
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Fig. 1
figure 1

a Low-grade fibromyxoid sarcoma characteristically exhibits alternating fibroblastic and myxoid zones at low-power (hematoxylin and eosin, X100). b In the more myxoid areas, a plexiform arrangement of delicate curvilinear vessels are noted (hematoxylin and eosin, X100). c In other areas, the tumor cells are arranged in characteristic whorls. The tumor cells are elongated and hyperchromatic, without pleomorphism or mitotic activity (hematoxylin and eosin, X200)

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By immunohistochemistry, all tumors were diffusely and strongly MUC4 cytoplasmic positive (Fig. 2a). Additionally, 2/4 (50%) were diffusely p63 nuclear positive (Fig. 2b), and 1/4 (25%) showed focal EMA cytoplasmic positivity (Fig. 2c). All four were negative for p40 (Fig. 2d), CD34, β-catenin, cytokeratin, muscle specific actin, and S100 protein. Follow up information was available for only two patients. One patient was disease-free at 12 months post-excision. The other patient was alive 10 months after surgery with multiple sub-centimeter pulmonary nodules too small to biopsy and enlarged post-tracheal and jugular chain lymph nodes (up to 1.4 cm) suggesting disseminated disease.

Fig. 2
figure 2

a All three cases of low-grade fibromyxoid sarcoma were strongly positive for MUC4 (MUC4 immunohistochemistry, X400). b Two cases were diffusely positive for p63. c One case was focally positive for EMA, findings that could raise concern for the possibility of a sarcomatoid carcinoma (p63 and EMA immunohistochemistry, X400). d All cases of LGFMS were negative for p40, the more specific isoform of p63 (p40 immunohistochemistry, X400)

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Discussion

LGFMS is an uncommon sarcoma with a known propensity for late recurrence and metastasis. Young adults are primarily affected, with mean reported ages ranging from late 3rd to 4th decades. Despite the metastatic potential of these tumors, even decades after the initial resection, patients can survive for many years with metastatic disease [7, 8, 11]. LGFMS primarily occurs in the soft tissues of the extremities, but cases have been reported involving the thoracic cavity, abdomen and bowel, and perineum [17–19].

Characteristic morphologic features of LGFMS include the alternating myxoid and fibrous areas with prominent arching vasculature and bland tumor cells. Tumors may also have collagen rosettes. Initially, tumors displaying these collagen rosettes were described separately due to an apparent benign clinical behavior, named hyalinizing spindle cell tumor with giant rosettes [20]. However, subsequent studies revealed the metastatic potential of these tumors and suggested they were within the spectrum of LGFMS [7, 8]. Further, molecular studies identified the same chromosomal translocation as LGFMS [21].

Immunohistochemically, LGFMS may be positive for EMA, CD99, and bcl-2. Rarely LGFMS reacts with CD34 and SMA. LGFMS is generally negative for S100, desmin, caldesmon, cytokeratin, and CD117 [10, 22]. Recently, MUC4 has been shown to be a sensitive and specific marker for LGFMS, with 100 % of tested LGFMS MUC4 positive and most other spindle cell neoplasms in the differential, including desmoid tumor and perineurioma, non-reactive [15]. Although these earlier studies showed universal positivity in LGFMS, there are now reports of MUC4 negative tumors with the characteristic morphological features of LGFMS and molecular analysis demonstrating the FUS-CREB3L2 rearrangement. MUC4 is not 100 % specific, and other tumors may stain with MUC4, including synovial sarcoma (30–90%) and sclerosing epithelioid fibrosarcoma (SEF, 78%) [15, 23]. In practice, the morphologic features of LGFMS generally do not overlap with synovial sarcoma and thus unlikely the tumors would be in the same differential diagnosis. The distinction with SEF may be troublesome since a subset of SEF has FUS translocations and it has been suggested that these tumors are related to LGFMS [8, 9].

Molecularly, LGFMS is characterized by a translocation of chromosomes 7 and 16, leading to the fusion product FUS/CREB3L2 (t(7;16)(q32–34; p11) is the most common in 90% of cases) or FUS/CREB3L1 (t(11;16)(p11; p11)) [16, 24–26]. However, a lack of FUS gene rearrangement should not be used to exclude the diagnosis of LGFMS, as occasional cases of LGFMS have been reported which lack FUS rearrangements and instead harbor an EWSR1-CREB3L1 fusion [27, 28]. Interestingly, the EWSR1-CREB3L1 gene fusion is more commonly reported in sclerosing epithelioid fibrosarcoma (SEF) which exists on an overlapping morphologic spectrum with LGFMS and similarly exhibits frequent MUC4 positivity [29–31].

A review of the previous literature on LGFMS yielded only 20 head and neck cases of over 400 total, many as part of earlier series or case reports (Table 2). Notably, several recent larger series of LGFMS did not identify any cases in the head and neck region [4, 5]. Many authors did not specify the location beyond “head/neck”. Of the eight cases that did specify a more detailed location, only two involved deep anatomic locations: one in the left maxillary sinus and the second in the anterior neck which clinically simulated a thyroid nodule [32, 33]. Outcomes that were reported found one patient died of disease after 42 years, and four patients had recurrences and/or late metastases.

Table 2 Previous reported LGFMS in the head and neck
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Spindle cell neoplasms in the head and neck present a unique set of diagnostic challenges. In particular, spindle cell “sarcomatoid” squamous cell carcinoma (SCSCC) should top the differential diagnosis, especially in older individuals. In one study, 70% of spindle cell lesions in the head and neck were spindle cell squamous cell carcinoma [34]. SCSCC sometimes contain a collagenous or myxoid background and deceptively bland areas, but the cells usually display pleomorphism and increased mitoses at least focally, which would not be expected in LGFMS. The presence of surface squamous dysplasia or a conventional epithelial component is very helpful in identifying SCSCC. In the absence of an epithelial component, immunohistochemistry may be helpful. SCSCC may be positive for epithelial markers, such as cytokeratin AE1/AE3, EMA, p63, p40, and CK5/6, however, only about 70 % of SCSCC react with these epithelial markers [35, 36]. Some SCSCC also express mesenchymal markers, such as CD99, bcl-2, S100 protein, and SMA [35, 37–39]. Interestingly, two tumors in this series of LGFMS were diffusely p63 reactive and one was EMA reactive, further blurring the distinction between mesenchymal and epithelial differentiation. Usually, p63 and/or EMA positivity suggests the diagnosis of SCSCC. Fortunately, it has been recently shown that while half of LGFMS may be p63 reactive, the more specific ΔNp63 isoform of p63 (p40) appears to be consistently negative in LGFMS [40]. Therefore, the immunohistochemical panel should be carefully selected to avoid misinterpretation by including several epithelial and mesenchymal markers.

The presence of alternating loose and pale areas in a spindle cell neoplasm without overt cytologic malignancy would raise the differential diagnosis of peripheral nerve sheath tumors, especially schwannoma and neurofibroma. However, these tumors should exhibit S100 protein and SOX10 staining while LGFMS is consistently non-reactive with S100 protein and SOX10 [10, 41]. Other entities in the differential diagnosis include myofibroblastic tumors and fibromatosis. Myofibroblastic tumors, such as myofibroma or inflammatory myofibroblastic tumor (IMT), will be reactive with actins, while LGFMS is non-reactive. While fibromatosis may show prominent vasculature, the pattern is not that of the vascular arcades seen in LGFMS, and LGFMS will be β-catenin negative, while fibromatosis shows a strong nuclear reaction.

In summary, LGFMS is a low grade sarcoma that may rarely develop in the head and neck. Due to its rarity, a pathologist may not consider LGFMS in the differential diagnosis of spindle cell neoplasms within the head and neck. Awareness of LGFMS and its characteristic histologic features should be considered in the differential diagnosis of a head and neck spindled cell tumors, with MUC4 immunostaining an easy study to help confirm the diagnosis.