Leiomyosarcoma of the Nasal Cavity and Paranasal Sinuses: A Case Report and Comprehensive Review of the Literature

Abstract

Sinonasal leiomyosarcoma (LMS) is a rare and aggressive mesenchymal tumor with smooth muscle differentiation. The sinonasal tract is an unusual primary site for LMS, as scant smooth muscle exists in this location, with only 75 cases reported in the English literature including the case presented herein. Sinonasal LMS is considered an aggressive head and neck tumor with significant potential for recurrence and metastasis. Since recurrence is high and the potential for late metastasis exists, lifelong follow-up in these patients would be beneficial, especially among those with previous history of RB.

Introduction

Sinonasal leiomyosarcoma (LMS) is a rare and aggressive mesenchymal tumor with smooth muscle differentiation. LMS is the most common soft tissue sarcoma and accounts for nearly 25% of somatic soft tissue sarcomas [1]. Sinonasal examples are rare and approximately 75 cases have been reported in the English literature, including the case presented herein. We provide this additional case with a comprehensive literature review to characterize the spectrum of clinicopathological features.

Materials and Methods

In addition to our case, published articles of sinonasal LMS in the English literature were identified with PubMed using a combination of the search terms “sinonasal”, “leiomyosarcoma”, “nasal cavity”, “sinus”, “maxillary”, “ethmoid”, “sphenoid”, “nasopharynx”, and retinoblastoma”. Additional articles were noted after reviewing references cited in the relevant reports. All cases of LMS with sufficient details and probable origin in the sinonasal tract and the nasopharynx were included. Cases with suspected origin in the orbit and oral cavity were excluded, though tumor extension from the sinonasal region into these areas were included.

Case Report

A 64-year-old female presented with a 1-month history of left sided nasal congestion and epistaxis with associated facial pain and otalgia. The epistaxis was present for one month with worsening symptoms. Computed Tomography (CT) imaging revealed a 2.2 × 2.0 cm soft tissue mass in the left nasal cavity extending into the maxillary sinus and causing thinning of the orbital floor (Fig. 1). Upon nasal endoscopy, an expansile mass with increased vascularity was identified arising from the left inferior turbinate causing deviation of the nasal septum. Since the mass extended to the basal lamella, a complete resection, including the inferior and middle turbinates, was performed.

Fig. 1.

Radiologic findings showing tumor infiltrating the maxillary sinus and thinning of the orbital floor. A Coronal image. B Axial image

Upon gross examination, a polypoid mass with a rubbery consistency and a white whorled pattern on the cut surface was observed. Microscopic examination revealed a well-circumscribed lesion with overlying intact sinonasal respiratory epithelium. The tumor was composed of spindled and pleomorphic cells organized in intersecting fascicles (Fig. 2A, B). The tumor cells showed centrally located cigar-shaped nuclei with blunt ends, marked nuclear pleomorphism, and high mitotic activity (21 mitoses/10 high-power fields (HPF)) (Fig. 2C, D). Necrosis was not identified. Immunohistochemical stains revealed the tumor cells to be reactive for smooth muscle actin (SMA), muscle specific actin (MSA /HHF35), and desmin (Fig. 3B–D). No reactivity was identified for cytokeratin AE1/AE3 (Fig. 3A), cytokeratin CAM 5.2, epithelial membrane antigen (EMA), SOX10, S100, CD34 and HMB-45. Epstein-Barr virus (EBV)-encoded RNA (EBER) by chromogenic in situ hybridization (CISH) was negative. The morphologic features and immunoprofile supported the diagnosis of sinonasal LMS, Grade 3 by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) Grading System. Post-operative radiation therapy was strongly recommended, but the patient declined further treatment. The patient is presently under close clinical follow-up.

Fig. 2.

Histologic findings of leiomyosarcoma showing. A A subepithelial proliferation without involving the surface epithelium (H&E 4 ×). B Proliferation of spindle cells without involvement of the surface epithelium (H&E 10 ×). C Marked nuclear pleomorphism, hyperchromasia and numerous mitotic figures (H&E 20 ×). D Marked nuclear pleomorphism (H&E 20 ×)

Fig. 3.

Immunohistochemical characteristics of leiomyosarcoma. A Negative cytokeratin AE1/AE3 in the tumor cells with positive expression in the overlying epithelium (10 ×). B Positive desmin expression in the tumor cells (10 ×). C Positive smooth muscle actin (SMA, 10 ×). D Positive muscle specific actin (HHF35, 10 ×)

Discussion

The sinonasal tract is an unusual primary site for LMS, as scant smooth muscle exists in this location. A few potential sources of origin have been described including undifferentiated mesenchyme and smooth muscle from the tunica media of blood vessel walls [2–4]. Derivation from blood vessels is probable, as this is the only source of smooth muscle in the sinonasal tract, and the malignant cells are often found in close association with endothelial cells microscopically [3, 5]. Moreover, compared to the paranasal sinuses, the nasal cavity is more consistently involved in sinonasal LMS. This may be accounted for by the substantial vascular network that supplies this region [3].

In review of the 75 cases of sinonasal LMS, the age range was from 10 to 86 years and the mean age of incidence was 49.1 years (Table 1) [2–45]. Most patients in the first and second decade had a history of retinoblastoma (RB) and radiation therapy (80%); therefore, these cases are likely post-radiation sarcomas [9, 20, 21, 35]. Among 71 cases with gender information, no gender predilection was identified, as 39 cases occurred in males and 32 cases occurred in females. Location was reported in all the cases; some exclusively involved the nasal cavity or the paranasal sinuses, though a combination of both locations was often seen. Forty-five patients (60%) had tumor involvement of the nasal cavity [2–5, 7, 9, 12–14, 17, 19, 24, 25, 28, 29, 31, 33, 38–40, 42–45]. Tumors extending into multiple sinuses were seen in 23 cases (30.7%) [2, 3, 7, 9, 10, 12, 13, 24, 27, 29–31, 33, 38, 39, 42, 44, 45]. Several cases had single sinus involvement, with or without nasal cavity extension. The maxillary sinus was the most common solitary sinus involved with 23 cases (30.6%) identified [3, 4, 6, 8, 9, 11, 14, 21–23, 26, 28, 31–33, 35, 36, 42]. Exclusive involvement of the ethmoid sinus was identified in 9 cases (12%), and involvement of the sphenoid sinus was observed in 5 cases (6.7%) [3, 4, 6, 15, 16, 18–21, 25, 29, 37, 41]. Tumors primarily originating from the nasopharynx were the rarest; only two cases were identified, though a few other cases extended into this region [6, 7, 9, 34].

Table 1.

Clinicopathologic characteristics of sinonasal leiomyosarcomas

Case	Author	Age/Gender	Site	Previous irradiation or chemotherapy	Follow-up
1	Dobben	69/F	Nasopharynx	NS	Recurrence treated with surgery; NR at 1 year
2	Pimpinella and Marquit	56/M	Nasal cavity, sinuses and nasopharynx	NS	Recurrence treated with surgery; NR 4 months later
3	Kawabe et al	60/M	L maxillary sinus	NS	Recurrence treated with radio-chemotherapy; death at 7 months
4	Kawabe et al	52/M	L maxillary sinus	NS	Recurrence treated with curettage and radiotherapy; lung metastasis and death at 1 year
5	Fu and Perzin	18/F	L nasal cavity + sinuses	NS	Multiple recurrences treated with excision and radiotherapy; NR 1 year later
6	Fu and Perzin	37/F	L nasal cavity + sinuses	NS	Multiple recurrences and metastasis to chest wall treated with chemotherapy at 3.5 years
7	Fu and Perzin	36/M	R nasal cavity, sinuses and nasopharynx	NS	NR; death from metastatic liver adenocarcinoma 1.5 years later
8	Fu and Perzin	56/M	L nasal cavity, sinuses and nasopharynx	NS	Multiple recurrences treated with radiotherapy; Death from persistent tumor over 3.5 years later
9	Fu and Perzin	40/F	L nasal cavity + sinuses	"Radium treatments" to both nasal cavities for sinus symptoms	Multiple recurrences treated with surgery and radiotherapy; death from persistent tumor 1 year later
10	Fu and Perzin	45/M	L nasal cavity and maxillary sinus	NS	Persistent tumor; death 1 year later
11	Mindell et al	70/M	L nasal cavity	NS	NR at 2 years
12	Dropkin et al	75/M	Nasal cavity + sinuses	None	NR at 26 months
13	Jakobiec et al	39/M	Paranasal sinuses	None	Exenteration of L ethmoid, maxillary sinus and orbit. Alive with disease 9 months later
14	Kakar et al	31/M	R maxillary sinus	NS	Death after 1 year
15	Kakar et al	55/F	R ethmoid sinus + nasal cavity	NS	Extensive recurrence at 9 months; lost to follow-up afterward
16	Ohashi et al	53/F	Maxillary sinus	NS	NS
17	Josephson et al	87/F	Nasal cavity + sinuses	Radiotherapy for BCC	NR at 3 years; Death from cardiovascular disease at 3 years
18	Kuruvilla et al	22/M	L nasal cavity	None	NR at 15 months
19	Kuruvilla et al	68/F	R nasal cavity	None	NR at 9 years
20	Kuruvilla et al	86/M	R nasal cavity	None	NR at 9 years
21	Kuruvilla et al	72/F	R nasal cavity	None	NR at 20 months
22	Kuruvilla et al	66/M	L nasal cavity + sinuses	None	NR at 58 months; Multiple recurrences later treated with radical surgery and chemotherapy; death at 6 years
23	Kuruvilla et al	51/F	R nasal cavity + maxillary sinus	None	Persistent tumor at 3 months
24	Kuruvilla et al	28/F	R nasal cavity + ethmoid sinus	None	NR at 9 months
25	Kuruvilla et al	43/F	L nasal cavity + sinuses	None	NR at 19 months
26	Kuruvilla et al	60/F	R nasal cavity + ethmoid sinus	None	NR at 19 months
27	Lalwani and Kaplan	66/M	Nasal cavity + sinuses	Radio-chemotherapy	Persistent tumor; palliative radio-chemotherapy; alive with disease several months after diagnosis
28	Martin-Hirsch et al	45/M	R maxillary sinus + nasal cavity	Radiotherapy	Maxillectomy and orbital exenteration after recurrent tumor
29	Sankary et al	32/F	Sphenoid sinus	NS	Persistent tumor with sphenoid sinus resection; death after 1 year
30	Reich et al	74/F	R ethmoid sinus	Radio-chemotherapy for Hodgkin lymphoma, chemotherapy for breast carcinoma	NR at 13 months
31	Lippert et al	44/M	R nasal cavity	NS	Recurrence treated with surgery; NR at 48 months
32	Ikeda et al	43/M	L sphenoid sinus	NS	Partial remission after radiotherapy
33	Kawaura et al	64/M	Ethmoid + nasal cavity	NS	NR at 2 years
34	Rubin et al., Dunkel et al. **	12/NS	Ethmoid sinus	Radiotherapy	NR at 24 months
35	Rubin et al., Dunkel et al. **	23/NS	Sphenoid sinus	Radiotherapy	Alive with disease 148 months later
36	Rubin et al., Dunkel et al. **	32/NS	Ethmoid sinus	Radiotherapy	NR at 6 months
37	Dunkel et al	10/F	R maxillary sinus	Radiotherapy	Persistent tumor treated with radiotherapy; Death at 16 months
38	Dunkel et al	18/NS	L maxillary sinus	Radiotherapy	NR at 29 months
39	Tanaka et al	69/M	R maxillary sinus	NS	Recurrence at 4 months
40	Klippenstein et al	29/M	R maxillary sinus	Radio-chemotherapy	Recurrence after 4 years treated with orbital and maxillary exenteration and radiotherapy; NR after
	Stammberger et al	F	Lateral nasal wall	NS	Death at 21 months from metastatic breast cancer
41	Batra et al	41/F	L nasal cavity + sinuses	NS	NR at 4 months
42	Keck et al	68/F	R ethmoid and nasal cavity	NS	NR at 29 months
43	Sumida et al	77/M	L maxillary sinus	NS	Metastasis to lungs; death at 3 months
44	Fusconi et al	57/F	R ethmoid and maxillary sinus	NS	Recurrence treated with radio-chemotherapy; NR at 48 months
45	Montgomery et al	55/F	Nasal cavity	NS	NS
46	Montgomery et al	34/F	Maxillary sinus	NS	Alive with metastatic disease 24 months later
47	Huang et al	41/M	L nasal cavity	NS	NR at 28 months
48	Huang et al	57/F	L nasal cavity + sinuses	NS	NR at 175 months
49	Huang et al	37/M	L ethmoid sinus + nasal cavity	NS	NR at 24 months
50	Newman et al	40/M	Ethmoid and maxillary sinus	Radiotherapy	NS
51	Prasad et al	27/F	R paranasal sinuses + nasal cavity	NS	Death after 3 days
52	Prasad et al	42/F	L maxillary sinus + nasal cavity	NS	NR at 18 months
53	Sedghizadeh et al	30/M	L maxillary sinus	Radiotherapy	NR after 3 years
54	Ulrich et al	24/M	Nasal cavity + sinuses	Radiotherapy	Alive with disease at 29 months
55	Kuo et al	23/M	Nasopharynx	NS	NS
	Podoj and Šmid	66/F	Ethmoid + lateral nasal wall	NS	NR at 2 years
56	Qureshi et al	15/M	Maxillary sinus	Radiotherapy	Persistent tumor treated with radio-chemotherapy; death at 3 months
57	Chew et al	36/M	L maxillary sinus	NS	NR at 3 years
58	Ramakrishnan et al	77/M	R sphenoid sinus	None	Lost to follow-up
59	Fitzpatrick et al	35/M	Nasal cavity + sinuses	Radiotherapy	Lost to follow-up
60	d'Adesky et al	72/F	L nasal cavity + sinuses	NS	Radiotherapy; NR at 1 year
61	Papoian et al	83/F	R nasal cavity	NS	Recurrence after 4 years treated with surgery and radiotherapy; NR 16 months after
62	Sadashiva et al	53/M	Sphenoid sinus	NS	Lost to follow-up
63	Agaimy et al	77/M	R nasal cavity + maxillary sinus	None	Multiple lung metastasis with resection; alive with disease at 88 months
64	Agaimy et al	48/F	L nasal cavity + sinuses	No	After recurrence and lung metastases, NR at 17 years
65	Agaimy et al	43/F	R nasal cavity	Radiotherapy	Lung metastasis and possible recurrence at 16 months; lost to follow-up
66	Agaimy et al	61/M	Nasal cavity	NS	NS
67	Agaimy et al	28/M	Maxillary sinus	NS	Multiple recurrences over 16 months; lost to follow-up
68	Agaimy et al	26/F	Maxillary sinus	Chemotherapy and stem cell transplant	Lung metastasis at 20 months treated with surgery; NR at 8.2 years
69	Agaimy et al	27/M	Maxillary sinus	Radiotherapy	Local recurrence at 2 years and death shortly after
70	Agaimy et al	66/F	Nasal cavity	No	NR at 6.6 years
71	Agaimy et al	66/M	Maxillary sinus	Radiotherapy for fibrous dysplasia at a young age	Brain extension of tumor; death at 0.5 years
72	Kwok et al	81/M	Nasal cavity	No	NR at 9 months
73	Saadoun et al	84/F	Nasal cavity + sinuses	No	NR at 9 months
74	Ohta et al	49/M	L nasal cavity and sinuses	No	NR at 36 months
75	Current Case	64/F	L nasal cavity + maxillary sinus	No	NR at 1 month

F female, M male, R right, L left, NS not specified, NR no recurrence, GVHD graft versus host disease

**Patients are reported by both authors in separate articles

Clinically, an infiltrative polypoid or pedunculated mass is characteristic of sinonasal LMS [3, 5, 9, 39]. The most common symptom reported was nasal obstruction, followed by epistaxis [3, 11, 25]. Facial pain and ocular signs such as exophthalmos and strabismus have been described as well [3, 9, 11]. CT findings show bulky masses that often demonstrate cystic changes and areas of central necrosis without calcification [31, 37, 40]. The tumor frequently invades surrounding structures, resulting in bony destruction [31]. In the present case, extension into the maxillary sinus and thinning the orbital floor was apparent without invasion into the orbit. While these findings are nonspecific and don’t allow for a definitive diagnosis of LMS on radiology alone, imaging studies are essential for surgical planning and preservation of vital structures such as the orbit [22].

Grossly, the tumor appears as a polypoid or pedunculated mass that exhibit a whorled appearance on the cut surface [3]. Apart from the overlying respiratory epithelium, sinonasal LMS is largely analogous to conventional LMS histologically. The tumor is unencapsulated and infiltrative, with interlacing fascicles of spindle-shaped cells [24]. The nuclei are characteristically “cigar shaped'' with blunt ends and are associated with a fibrillary eosinophilic cytoplasm [24, 37]. Hypercellularity, nuclear pleomorphism, and mitoses are frequently identified and correlate with tumor grade. Grading of extrauterine leiomyosarcoma typically follows the FNCLCC guidelines which consist of three grades based on the degree of mitotic activity, necrosis, and cellular differentiation. This grading system highly correlates with prognosis and can accurately predict tumor-specific distant metastases and mortality [46–48]. The present case fulfills the criteria of a high-grade LMS, showing hypercellularity, pleomorphic and hyperchromatic nuclei, and areas of numerous atypical mitoses within a sparse stroma [11, 37].

In review of the literature, earlier reports (prior to 1990) often used stains in conjunction with histology or ultrastructural studies. Masson’s trichrome stain was most notably used in the identification of these tumors; red cytoplasmic staining of longitudinal fibrils supports compatibility with smooth muscle cells as opposed to blue for collagen fibers [7, 9, 10]. In addition to the latter stain, electron microscopy provides valuable insight into the ultrastructure of LMS. Smooth muscle differentiation is characterized by elongated tumor cells with longitudinal myofibrils and dense bodies, invested by a clear basement membrane material [8, 11, 12]. These methods are not currently used as routine diagnostic tools. In the past couple decades, immunohistochemical stains have emerged as a mainstay for diagnosis. Among prior reports with inclusion of muscle markers, the antibodies for SMA were the most common and were expressed in nearly all cases [3, 6, 14, 16, 18, 22, 25, 26, 28, 29, 32, 33, 35–39, 41, 42, 45]. However, while immunoreactivity for SMA is sensitive for smooth muscle, it lacks specificity. Expression is observed in other cell types, such as myofibroblasts and pericytes, due to the presence of myofilaments [49]. Tumors such as synovial sarcoma, malignant fibrous histiocytoma, fibrosarcoma, fibromatosis, and nodular fasciitis may show reactivity for SMA [32, 38]. As observed in the present case, additional muscle markers, such as MSA and desmin, further support smooth muscle differentiation [3, 6, 14–16, 22, 23, 25, 28, 29, 32, 33, 37, 39, 40, 42, 45]. Moreover, in some studies, h-caldesmon has shown superior smooth muscle distinction in comparison to other muscle markers [50, 51]. In one report, diffuse staining of h-caldesmon was exclusively seen in LMS compared to myofibroblastic tumors [51]. In our review of sinonasal LMS, 6 of 9 cases showed unequivocal expression of h-caldesmon [42]. Inclusion of h-caldesmon in an immunohistochemical panel may seem prudent in conjunction with other muscle markers. Several prior studies also report immunostaining of the cellular proliferation marker MIB-1(Ki-67). Most cases had a proliferation index above 15%, with the highest at 40%, suggesting a role when histologic features are confounding [25, 29, 41, 43]. Few cases in our review showed unusual immunohistochemical findings. In addition to SMA and desmin reactivity, one case of sinonasal LMS showed rare expression of cytokeratin CAM 5.2, EMA, and Bcl-2 [45]. Another two cases showed focal S100 positivity, but the diagnosis of LMS was supported by ultrastructural and immunohistochemical findings [3]. Although we have included these cases in our review, unusual IHC findings should warrant further investigation for cases suspected as LMS, as it is possible that these cases may be reclassified as synovial sarcoma and biphenotypic sinonasal sarcoma (BSNS), respectively. In the present case, we believe sinonasal LMS is the most appropriate diagnosis, as supported by the characteristic histologic features and strong expression of all muscle markers.

Low-grade LMS may be difficult to distinguish from sinonasal leiomyomas, as mild cellular atypia and variable mitotic activity are seen in the former [29]. Apart from lack of atypia and mitotic activity, sinonasal leiomyomas are usually circumscribed and smaller in size [42]. One report describes MIB-1 as a valuable discriminator between LMS and leiomyoma. The proliferation index was considerably higher (≥ 15%) in low-grade LMS compared to leiomyoma (≤ 5%) [29]. Aside from leiomyoma, the differential diagnosis of sinonasal LMS includes several malignant spindle cell tumors such as malignant peripheral nerve sheath tumor (MPNST), undifferentiated spindle cell, synovial sarcoma, and BSNS [3, 38, 42]. MPNST consists of highly cellular fascicles of spindle cells with wavy nuclei and may be distinguished from LMS with variable S100 and SOX10 staining and lack of reactivity to muscle markers [1]. In addition, loss of nuclear expression of H3K27me3 is highly sensitive and specific for MPNST in an appropriate setting [52]. Undifferentiated spindle cell carcinoma lacks features of smooth muscle differentiation such as blunt-ended nuclei and a fascicular growth pattern and may show variable cytokeratin, p60, and p40 reactivity [42, 53]. An in-situ component and negative staining for desmin support its diagnosis as well [42]. Synovial sarcoma may exhibit a monophasic spindle cell pattern that can be confused with LMS, but often expresses cytokeratin positivity, CD99, and Bcl-2, which is rarely identified in LMS [38, 45]. Most importantly, LMS does not harbor rearrangements of the SS18 gene, which are frequently identified in synovial sarcoma [38]. Lastly, BSNS is a recently recognized sarcoma that shows neural and myogenic differentiation. BSNS is characterized by consistent PAX3 rearrangements detected by fluorescence in situ hybridization (FISH) [1, 54]. BSNS also reliably expresses nuclear β-catenin, which is consistently negative in LMS [54].

A previous history of RB is commonly associated with sinonasal LMS. RB is the most common primary ocular malignancy in children and infants [55]. Most patients with the hereditary form of RB have bilateral disease, while unilateral disease is frequently associated with the sporadic type [20]. Genetic studies have established the deletion of the RB-1 gene on chromosome 13 as the responsible event for hereditary RB [20]. In our review, a previous history of retinoblastoma was documented in 14 cases (18.7%) of sinonasal LMS. Of the 14 cases, 4 showed unilateral orbital involvement, while the remainder were bilateral. Although a family history of retinoblastoma was only reported in three cases, it is reasonable to conclude that nearly all bilateral cases are associated with genetic inheritance [21]. Remarkably, two of the three cases with a documented family history occurred in patients with unilateral retinoblastoma. This is unusual, as patients with the germline defect frequently develop mutations in retinal cells of both eyes, resulting in bilateral RB. Individuals with hereditary unilateral RB have been described with an inheritance pattern referred to as low-penetrance retinoblastoma [32].

The occurrence of a secondary malignancy in patients with a history of hereditary retinoblastoma is not exceptional. In one cohort study, 14.3% of patients with hereditary RB developed a secondary tumor, compared to 1.9% patients with non-hereditary RB [56]. In this study, among hereditary RB patients, LMS was the most common secondary tumor identified, followed by osteosarcoma and melanoma [56]. A secondary sarcoma usually occurs between 1 to 4 decades after initial RB treatment, and two-thirds of tumors occur within the field of radiation [20]. While it is evident that radiation is a significant risk and may be involved in the induction of a sarcoma, a significant subset of tumors occurs independently of the head and neck region. Furthermore, as secondary tumors are more common in hereditary RB compared to the sporadic form, a synergistic role between inheritance and radiation therapy is supported [42]. In reported cases, all patients with a previous history of RB were treated with radiotherapy [6, 14, 20, 21, 23, 30, 32, 33, 35, 38, 42]. Prior radiotherapy was identified in 19 cases [6, 9, 12–14, 16, 20, 21, 23, 30, 32, 33, 35, 38, 42]. Aside from RB, other conditions treated with radiation therapy included: unspecified sinus disease, basal cell carcinoma, granulomatosis with polyangiitis, Hodgkin lymphoma, and fibrous dysplasia [9, 12, 13, 16, 42]. Locations for Hodgkin lymphoma and fibrous dysplasia were not specified, so the precise field of radiation is undetermined for these cases [42]. Accordingly, patients with previous head and neck irradiation, irrespective of tumor type, may have an increased risk of developing sinonasal LMS.

Fewer reports have discussed a prior history of chemotherapy and the occurrence of a secondary sarcoma. In reported cases, prior chemotherapy was identified in 4 (5.3%) patients. Only one patient with bilateral RB was treated with chemoradiotherapy. Exposure to chemotherapy, particularly cyclophosphamide, has been associated with development of sinonasal LMS. [16, 24, 40]. A case report describes long-term cyclophosphamide therapy for breast carcinoma in a patient who developed sinonasal LMS 15 years later [16]. The patient, however, also had previous irradiation for Hodgkin lymphoma 40 years prior to development of LMS [16]. Cyclophosphamide has also been implicated in the development of urinary LMS [57]. One report describes development of urinary LMS in two patients 5–21 years after extensive treatment with cyclophosphamide [57]. It is difficult to draw conclusions, however, as few cases with an extensive history of chemotherapy have been described in sinonasal LMS. Further research is needed to clarify the risk of chemotherapeutic agents in the induction of sinonasal LMS.

Radical surgical therapy is the primary treatment modality for sinonasal LMS. Patients were treated with surgical excision and resection in all prior reports whenever feasible, as the tumor has been described as relatively radioresistant [11, 33]. In many cases, clear margins are challenging to attain owing to tumor extension into several paranasal sinuses and the orbit [40]. Few reports describe surgical debulking or partial excision of the tumor when complete resection was impractical, due to tumor involvement of the cranial base or structures such as the cribriform plate [26, 33]. Several of these patients were treated with palliative radiotherapy or chemotherapy which resulted in residual disease or death at follow-up [15, 21, 26, 33, 37]. Predominantly, radiotherapy was used as an adjunct to surgical excision or resection. Of the 74 cases where the treatment regimen was provided, radiotherapy was initially used in 26 (35.1%) cases, and several cases included follow-up with radiotherapy due to persistent or recurrent tumor. Chemotherapy was often used in conjunction with radiotherapy but was largely considered palliative [3, 27]. Nevertheless, it is notable that one report discusses a 50% tumor reduction after neoadjuvant chemotherapy, implying it may have a role in large unresectable tumors [33] (Table 1).

Of 67 cases with follow-up data, recurrence was seen in 20 cases (29.9%) [3, 4, 6–9, 14, 17, 22, 23, 27, 40, 42]. Tumor persistence, without a disease-free interval, was seen in 6 cases (8.8%) [3, 9, 13, 15, 21, 35]. Among 12 patients with a previous history of RB and follow-up data, recurrence of sinonasal LMS was seen in 8 patients (66.7%) [14, 20, 21, 23, 33, 35, 42]. Three of these patients received radiation therapy for progressive and recurrent tumors, and two patients died during treatment [21, 23, 35]. Compared to RB, secondary tumors are more aggressive, and less responsive to radiation therapy [30]. Death from sinonasal LMS was seen in 13 cases (19.4%), ranging from within 1 month after initial treatment to 72 months post-treatment, with a mean of 17 months [3, 4, 6, 8, 9, 15, 21, 26, 31, 35, 42]. Metastasis of sinonasal LMS was seen in 8 cases (11.8%), with a range of 3 months to 156 months, a mean of 41 months, and a median of 22 months [6, 8, 9, 26, 28, 42]. Of 7 cases with the location of metastatic disease specified, 6 were in the lung [8, 26, 42]. One report discusses a patient with no evidence of recurrence at nearly 5 years after the initial surgery, who later died at 6 years due to subsequent recurrence [3]. Despite radical surgeries and adjuvant chemoradiotherapy, extension into crucial anatomical structures facilitates the insidious nature of this tumor.

Sinonasal LMS is an aggressive head and neck tumor with significant potential for recurrence and metastasis. The diagnosis of sinonasal LMS is contingent on histology and immunohistochemistry, as there are several microscopic mimics. Patients with a history of RB and radiotherapy are of particular concern, as the tumor often occurs at an earlier age, and recurrence was observed in most of these individuals. In patients with metastatic disease, a predilection for the lung is seen. Since recurrence is high and the potential for late metastasis exists, life-long follow-up in these patients would be beneficial, especially among those with previous history of RB.

Author Contributions

All authors SSS, BS, EN, MEL and EMD confirm they have meaningfully contributed to the research and read and approved the final manuscript.

Funding

The authors did/did not receive support from any organization for the submitted work nor was there any funding to conduct the study or to assist with manuscript preparation.

Data Availability

It is possible upon reasonable request, deidentified for maintenance of annonymity and compliance with IRB request.

Code Availability

Not applicable.

Declarations

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethical Approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was waived by the Institutional Review Board of the University of Florida.

Consent to Participate

It was received from the patient directly.

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It was obtained from the patient for whom identifying information is uniquely included in this manuscript.