S-100 Immuno-Positive Low Grade Myofibroblastic Sarcoma of Nasal Cavity: A Rare Case Presentation and Review of Literature

Abstract

Introduction

Myofibroblastic neoplasms comprise a spectrum of benign/malignant neoplasms. Only low-grade malignant forms have been reproducibly characterized as a diagnostic entity in the WHO classification. Low grade myofibroblastic sarcoma (LGMFS) confined to the nasal cavity is extremely rare.

Objective

To review previously reported cases of nasal cavity LGMFS and provide a better insight regarding its clinical and immunohistochemical features.

Data synthesis

A review was performed involving two databases (PubMed and Google Scholar). Four cases of nasal cavity LGMFS were included. The lesion showed no gender or nasal-side predilection. All cases underwent wide excision. None showed distant metastasis while half recurred locally. Histologically, mitotic rate ranged from 1 to 3/10 high-power-field (HPF) and none exhibited spontaneous necrosis. Immuno-expression of calponin, smooth muscle actin (SMA) and vimentin were seen in either all four or three-fourth of cases. Diffuse S-100 expression was a unique finding in present case and not reported previously, that caused a diagnostic dilemma with schwannomas.

Conclusion

LGMFS of nasal cavity is extremely rare. A wide resection is the primary treatment of choice. Adjuvant therapies (chemotherapy or radiotherapy) are of uncertain significance. Distant metastasis is rather unusual. Calponin, SMA and vimentin are highly sensitive immuno-markers. Diffuse S-100 expression is a possible finding. Mitotic rate < 6/10 HPF and absence of spontaneous necrosis are characteristic indolent features differentiating from high grade lesions. Trifecta of clinical and morphological features plus immunohistological phenotype, are sufficient for a definitive diagnosis. Electron microscopy is the most definitive confirmation test, however, should be reserved only for equivocal/atypical immunostaining pattern.

Introduction

Low-grade myofibroblastic sarcoma (LGMFS) has been considered a distinct entity by the World health organization classification of tumor [1]. They are defined as an atypical mesenchymal tumor with myofibroblastic proliferation and fibromatosis-like features. They are described in literature under various nomenclatures: myofibrosarcoma (MFS), low-grade myofibroblastic sarcoma, myofibroblastic sarcoma, fibromyxosarcoma, low-grade spindle cell sarcoma consisting of myofibroblasts, sarcoma of myofibroblastic differentiation, myofibroblastic-rich fibrosarcoma, etc. [2]. LGMFS is considered to have a wide anatomical distribution with a predilection for head and neck region [3–7]. LGMFS confined to nasal cavity is extremely rare and only three cases have been previously reported in the same location (Table 1). We report an additional case of LGMFS in the nasal cavity which presented with an atypical immunohistochemical phenotype and also provide a review of previously reported cases of LGMFS in the same location.

Table 1.

Clinicopathologic features of cases with LGMFS in the nasal cavity

Case authors	Year	Country	Age/Sex	Lesion duration	Lesion Size (cm)	Site	Clinical symptoms	Mitotis (10 HPF)	Necrosis	Surgical procedure	Follow up	Outcome
Meng et al (case 1)	2007	China	74/M	NI	3	RNC	Nasal stuffiness and epistaxis	3/10 HPF	No	EECWR- RT (50 Gy)	27 m/o	LR after 9 m/o
Meng et al (case 2)	2007	China	14/M	NI	5	RNC	Nasal stuffiness, copious rhinorrhea & proptosis	2/ 10 HPF	No	EECWR- RT (50 Gy)	16 m/o	LR after 9 m/o
Shapiro et al (case 3)	2012	USA	21/F	NI	0.5	LNC	Nasal discomfort	NI	No	CWR with removal and reconstruction of nasal septum	10 yrs	No recurrence/MT until 10 years
Present case (case 4)	2019	India	28/F	9 m/o	3.8	LNC	Nasal stuffiness and epistaxis	1/10 HPF	No	Coblator- assisted EECWR with removal of middle turbinate and adjacent nasal septum	6 m/o	No recurrence/MT until 6 m/o

F, female; M, male; NI, not informed; RNC, right nasal cavity; LNC, left nasal cavity; EECWR, endoscopic endonasal complete wide resection; RT, radiotherapy; Gy: grays; CWR, complete wide resection; m/o, months; yrs, years; HPF, high power field; LR, local recurrence; MT, malignant transformation

Review of Literature

Case Presentation

A 28-year-old female presented with a history of left nasal stuffiness and intermittent epistaxis since the past nine months. She was otherwise healthy, and reported no history of tobacco or recreational drug abuse. No genetic or syndromic abnormalities were reported within her family. Laboratory reports were inconclusive. An endoscopic endonasal examination showed a firm and lobulated mass in the left middle meatus. Computerized tomography (CT) scan showed an enhancing lesion in the left nasal cavity which caused bowing of nasal septum. Lesion seemed adherent to the middle and inferior turbinate. The lesion did not seem to cause any destruction of surrounding bones and did not extend into adjacent paranasal sinusus (Fig. 1). Magnetic resonance imaging (MRI) revealed a hypo-intense lesion on T1 images and isointense on T2 & STIR images. Posteriorly, the lesion caused occlusion & extension upto the choana (Fig. 2). Intra-operatively, a lobulated lesion is seen in the left nasal cavity adherent to the septum and middle turbinate, blocking the middle meatus and extending posteriorly into the choana (Fig. 3). A coblator-assisted, endonasal endoscopic complete excision of the lesion was done, along with removal of the middle turbinate. Adjacent cartilaginous and bony septum was also removed.

Fig. 1.

Computerized tomography (CT) scan shows an enhancing lesion in the left nasal cavity and causing bowing of the nasal septum

Fig. 2.

T2 weighted magnetic resonance imaging (MRI) shows an iso-intense lesion causing occlusion and extending posteriorly upto the choana

Fig. 3.

A firm and lobulated lesion is seen in left nasal cavity

Histological examination showed a non-encapsulated tumor with sparse lymphoplasmacytic infiltrate which was lined by the respiratory epithelium (pseudo-stratified ciliated columnar epithelium) (Fig. 4a). The tumor was composed of spindle cells arranged in both hypercellular and hypocellular pattern (Fig. 4b). In the hypercellular areas, the spindle cells were arranged in interlacing fascicles (Fig. 4c). In certain areas, herringbone pattern of tumor cells was also noted. The cells were uniform with plump ovoid nuclei and dispersed chromatin, and inconspicuous nucleoli and scanty eosinophilic cytoplasm (Fig. 4d). The mitotic rate of the tumor was 1 MF/10 HPF (1 mitotic figure/ 10 high power field). No spontaneous necrosis was noted.

Fig. 4.

Histological findings. a, Non-encapsulated tumor with sparse lymphoplasmacytic infiltrates (small arrows) and lined by respiratory epithelium (bold arrow) [Hematoxylin and eosin staining; 400X]. b, Tumor composed of spindle cells arranged in both hypercellular (bold triangle) and hypocellular areas (asterisk) [Hematoxylin and eosin staining; 100X]. c, Tumor cells arranged in interlacing fascicles [Hematoxylin and eosin staining; 100X]. d, Herringbone pattern of tumor cells containing plump ovoid nuclei with finely distributed chromatin and small inconspicuous nucleoli, and ill-defined scanty eosinophilic cytoplasm [Hematoxylin and eosin staining; 400X]

The immunohistochemical findings of the present case are summarized in Table 2. The tumor was diffusely immunopositive for S-100 protein (Fig. 5a) with focal immunoreactivity with smooth muscle actin (SMA), calponin, muscle-specific actin (MSA) and transducin-like enhancer of split-1 (TLE-1) (Fig. 5b–e). The tumor is immunonegative for high molecular weight caldesmon (h-caldesmon) (Fig. 5f), desmin, sry-related HMg-Box gene 10 (SOX-10), CD-34, anaplastic lymphoma kinase (ALK-1), smooth muscle heavy chain myosin (SMHC myosin), pancytokeratin (AE-1/AE-3), epithelial membrane antigen (EMA) and STAT-6.

Table 2.

Immunohistochemistry findings of patients with LGMFS

Antibodies	Case 1 (Meng et al.)	Case 2 (Meng et al.)	Case 3 (Shapiro et al.)*	Case 4 (present case)
Calponin	+  +  +  +	+  +  +  +	NP	+  +
SMA	+  +  +  +	+  +  +  +	+	+  +
MSA	NP	NP	NP	+  +
TLE1	NP	NP	NP	+  +
Desmin	–	–	+	–
Vimentin	+  +  +  +	+  +  +  +	+	NP
Fibronectin	+  +  +  +	+  +  +  +	NP	NP
S100	NP	NP	–	+  +  +  +
h-caldesmon	–	–	NP	–**
SOX10	NP	NP	NP	–
CD34	+  +	–	–	–
CD68	–	–	NP	NP
CD99	–	–	NP	NP
Type IV collagen	–	–	NP	NP
Laminin	–	–	NP	NP
ALK1	–	–	NP	–
SMHC myosin	NP	NP	NP	–
EMA	NP	NP	NP	–
Pancytokeratin
(AE1/AE3)	NP	NP	NP	–
STAT6	NP	NP	NP	–

SMA, smooth muscle actin; MSA, muscle specific actin; TLE1,transducin-like enhancer of split-1; h-caldesmon, high molecular weight caldesmon; SOX10, sry-related HMg-Box gene 10; ALK1, anaplastic lymphoma kinase; SMHC myosin, smooth muscle heavy chain myosin; EMA, epithelial membrane antigen.

NP, not performed, +  +  +  + : diffuse positive, +  + : focal positive, + /*: positive staining but no mention about diffuse versus focal positivity, –: negative.

^**negative staining for h-caldesmon except for adjacent blood vessel

Fig. 5.

Immunohistochemical findings. a, Biopsy specimen show diffuse expression of S-100 (400X). b, Biopsy specimen shows a focal immunoreactivity to smooth muscle actin (400X). c, Tumor cell shows a focal expression of calponin (400X). d, Biopsy specimen shows a focal expression of muscle specific actin (400X). e, Section showing tumor cells with focal expression of transducin-like enhancer of split-1 (400X). f, Section showing negative reactivity for high molecular weight caldesmon except for adjacent blood vessel (400X)

Tissues from middle turbinate and nasal septum were negative for malignancy.

Based on the clinical and histological findings, and IHC features, the final diagnosis was of a low grade myofibroblastic sarcoma of the nasal cavity.

Methodology

A review of literature was performed on two different databases (PubMed and Google Scholar). The database was searched for full-length articles and abstracts, using the following Medical Subject Headings (MeSH): “Myofibroblastic sarcoma” AND/OR “Myofibroblastic tumor” AND/OR “Myofibrosarcoma” AND/OR “Myofibroblastic malignancy” AND/OR “Low grade myofibroblastic sarcoma” AND/OR “Myofibroblastic malignancy” AND/OR “Nasal cavity” AND/OR “Nose”. It included cases confined to the nasal cavity. Reports with lesion extending into surrounding structures like paranasal sinuses, oral cavity, orbital region or nasopharynx were excluded. The review included isolated case reports or articles with upto 2 cases of low grade myofibroblastic sarcoma (LGMFS), published only in English language and confined to human subjects. Articles containing > 2 cases of LGMFS or larger case series, were not included. No age, race or demographic filters were applied. Information from the included articles was collected in a predesigned Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) spreadsheet.

Result

A total of four cases were included in the current review (three published cases and one illustrative case). From the included articles clinical, immunohistopathologic, and treatment findings were documented (Table 1 and 2) [6, 7].

The cases were reported from three different countries: China (n = 2), USA (n = 1), and India (n = 1). Out of four included cases, two were males (50%), and two were females. The ages ranged from 14 to 74 years (mean: 34.25).

The lesion involved the left and right nasal cavity in two cases each. Clinically, all four cases presented with either nasal stuffiness or discomfort. Two cases presented with epistaxis, and one case presented with copious rhinorrhea and proptosis.

All four cases underwent complete resection with negative margins, while two cases received post-operative radiotherapy of 50 Gy (case 1 and 2). Two cases underwent resection using conventional endonasal endoscopic approach (case 1 and 2), while coblator assisted endonasal endoscopic resection was performed in our patient. Follow-up duration was mentioned in all four cases, and it ranged from 6 months to 10 years. Case 1 and 2 (Table 1) recurred locally after 9 months of initial surgery and were re-operated. None of the cases showed distant metastasis.

Grossly, the lesion varied in size from 0.5 to 3.8 cm (mean: 3.08 cm) with ill defined margins. Histologically, all four cases showed a non-capsulated tumor with presence of spindle/epitheloid cells arranged in fascicular or storiform pattern. Herringbone pattern of tumor cells was noted in case 4. Cases 1, 2 and 4 showed presence of both hypercellular and hypocellular regions with lymphoplasmacytic infiltrate. Case 3 lacked signs of a significant inflammatory infiltrate. The spindle or epitheloid tumor cells contained wavy tapering nuclei (case 1) or fusiform/round nuclei (case 3) or plump ovoid nuclei (case 4) with ill-defined scanty eosinophilic cytoplasm. Case 1 and 4 showed nuclei with finely distributed chromatin and small inconspicuous nucleoli. Cells with pale multivacuolated cytoplasm were seen in case 3.

The mitotic rates of the tumors ranged from 1 to 3/10 HPF (mean: 2/10 HPF). No information regarding mitotic rate was obtained from case 3. Spontaneous tumor necrosis was absent in all four cases.

The immunohistochemical findings of LGMFs are summarized in Table 2. Cases 1 and 2 were diffusely positive for calponin, vimentin, SMA and fibronectin, while completely negative for desmin, h-caldesmon, type IV collagen, CD99, laminin, ALK1 and CD68. Case 1 showed focal positivity for CD34. Case 3 showed immunopositive to desmin, vimentin and SMA, while negative to S-100 and CD34. Case 4 was diffusely positive for S-100 and focally positive for calponin, SMA, MSA and TLE-1, while immunonegative for desmin, h-caldesmon, SOX-10, CD-34, ALK-1, SMHC myosin, pancytokeratin (AE-1/AE-3), EMA and STAT-6.

Discussion

Myofibroblasts are distinct cell first described in granulation tissue by Gabbiani and colleagues in 1971 [8]. They are modified fibroblasts, which occur in some normal tissues (testicular peritubular stroma and the periodontal ligament), in inflammatory granulation tissue as well in soft tissue of some neoplastic lesions. Myofibroblasts, which share morphological and functional features with fibroblasts and muscle cells, have been reported in various benign and malignant lesions. Myofibroblasts are spindle-shaped, bipolar/tripolar or stellate cells with elongated, tapered, ovoid or wavy nuclei each containing a small nucleolus. The cytoplasm is sparse to moderate in amount with occasionally amphophilic, and there are indistinct cell margins which seem to blend with stroma. Ultra-structurally, the cytoplasm of myofibroblast contains abundant rough endoplasmic reticulum (RER) and peripheral bundles of cytoplasmic filaments with dense foci, termed stress fibers. Other features include a prominent Gogli complexes and collagen secreting granules in Golgi-derived vesicles. Additionally, myofibroblasts shows a presence of fibronexus adhesion complex [9].

The term myofibrosarcoma was first suggested by Ghadially in 1980 [10]. MFS has been classified as low, intermediate and high grade tumor by the modified National Cancer Institute System [11].

Pleomorphic myofibroblastic sarcoma is a high-grade subset of MFS and can be distinguished from low/intermediate grade lesion.

Majority of LGMFS are deep soft-tissue lesions, but may even be located intra-osseous or may be found at a subcutaneous or submucosal site. LGMFS shows a predilection for head and neck. LGMFS confirmed to the nasal cavity is extremely rare, and only four cases have been reported previously from the English medical literature. LGMFS shows a slight higher male predilection. The age of patients with LGMFS ranges from 4–85 years (mean: 40 years), and the tumor size vary between 1.5 and 17 cm [12].

Eyden et al. first described five cases of myofibroblastic sarcomas in 1991 [13]. Mentzel et al. described 18 cases of LGMFS, which form the basis of this entity in 2002 and 2012 version of WHO classification of tumors of soft tissue and bone [1, 14].

LGMFS are slow growing lesion with infiltrative nature and susceptible for local recurrence but rarely metastasize. Factors determining recurrence include tumor size, growth pattern and location, as well histological presence of pleomorphism, cellular atypia, abnormal mitosis and spontaneous necrosis [15].

Histologically, the usual presentation is a cellular fibro-sarcoma like tumor with arrangement of cells in interlacing bundles or broad sheets with occasional focal herringbone arrangement or storiform whorls. The cells are spindle-shaped and uniform with tapered/ plump ovoid nuclei and small nucleoli and scanty or moderate cytoplasm. They show scanty inflammation and a variable amount of collagenous stroma, and occasional presence of osteoclasts- like giant cells [15]. LGMFS are relatively more indolent compared to the high grade lesions and usually shows 5 or less mitosis per 10 high power fields. Spontaneous necrosis and abnormal mitosis are rather absent, and usually noted in high grade lesions [16].

Most of the lesions of LGMFS are SMA immuno-positive half of them focally express desmin. Either or both of these antigens can be expressed resulting in either a SMA-positive/desmin-negative phenotype, as in our case, or a SMA-negative/ desmin-positive phenotype. Calponin is mostly diffusely positive, whereas h-caldesmon is rarely detected with occasional focal expression, as in present case. Diffuse expression of h-caldesmon is seen in leiomyosarcoma. MSA is also expressed in LGMFS. Expression of EMA, cytokeratin, CD-34 and SMHC myosin is unusual and only seen sporadically. Cytokeratin expression is seen in spindle cell carcinoma and is useful in distinguishing from LGMFS. They also display fibronectin, but not laminin or collagen IV [17]. There are rare reports of focal expression of S-100 protein in myofibrosarcoma [13], but diffuse S-100 expression, as in our case, has not been reported/seen previously. Cai et al., in their review of head and neck myofibroblastic sarcoma, showed 17% of cases with a focal expression of S-100. SOX-10 expression is almost always negative. Negative immuno-staining with ALK-1 is helpful in differentiating LGMFS from IMT (inflammatory myofibroblastic tumor) and a positive expression is noted in 30–40% of IMT.

In our case, diffuse immunoreactivity with S-100 protein caused dilemma regarding a probable diagnosis of neurilemmoma. However, a negative reactivity with SOX-10 protein and a positive expression of calponin, SMA and MSA favored a diagnosis of myofibrosarcoma. Additionally, arrangement of spindle cells in interlacing bundles/herringbone pattern and presence of plump ovoid nuclei with inconspicuous nucleoli, and scanty eosinophilic cytoplasm further favored a diagnosis of myofibroblastic sarcoma.

A wide local resection is the primary treatment of choice [15]. Ancillary treatments, such as chemotherapy and radiotherapy, are of uncertain clinical significance. There are no reports of recurrence or metastasis of LGMFS after complete wide excision, either with or without ancillary/adjuvant treatment [18–20]. On the other hand, there are reports of tumor recurrence or metastasis even after administration of ancillary/adjuvant treatment [21]. Although, in our case, the patient underwent wide local resection without any adjuvant therapy, however, there was no recurrence or metastasis until eight months after surgery.

LGMFS must be distinguished from other neoplasms, particularly closely resembling benign myofibroblastic lesions like inflammatory myofibroblastic tumor (IMT), nodular fasciitis, proliferative myositis and fibromatosis, other varients of spindle cell sarcomas like leiomyosarcoma and fibrosarcoma, and from spindle cell carcinoma. The differential diagnosis is usually made based upon clinical and morphological features, combined with histological phenotype and occasionally ultrastructural electromicroscopic features [9, 17].

IMT is a locally aggressive tumor and rarely metastasize. They mostly arise from a retroperitoneal site or the lung, and are occasionally found in a soft tissue or visceral site in the head and neck region. They present as a solitary or multi-centric mass, with a peak incidence in childhood or adolescence [22, 23]. Histologically, there are fasciitis-like fascicular areas and a predominance of chronic inflammatory cells including plasma cells. Atypical cells are occasionally seen but pleomorphism is rare. Negative immuno-staining with ALK-1 is sometimes helpful in differentiating LGMFS from IMT (inflammatory myofibroblastic tumor), as 30–40% of IMT stains positive for ALK-1 [24, 25]. Furthermore, IMT is associated with interleukin-6 linked systemic features like anemia and hypergammaglobulinemia [15].

Nodular fasciitis is a rapidly growing lesion, usually subcutaneous and does not reach a large size. They show a predilection for the head and neck in children, and have been characterized as pseudosarcoma in the past because of its self-limiting nature. They are less cellular and uniform compared to LGMFS, and rarely infiltrate adjacent structure. Fibromatosis is a collagen producing myofibroblastic tumor, has uniform aligned myofibroblasts in a dense collagen stroma, and shows a presence of characteristic blood vessels and mast cells. Fibromatosis lacks nuclear pleomorphism [9, 15, 17].

Leiomyosarcoma typically has alternating fascicles of spindle cells that are less tapered than myofibrosarcoma and shows a diffuse expression of h-caldesmon. Spindle cell carcinoma (SpCC) is highly aggressive tumor and shows a high propensity for distant metastasis. SpCC requires exclusion using a panel of anticytokeratin antibodies [9, 15, 17].

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declarations

Conflict of interest

The authors declare that there is no conflict of interest.

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