Fibrosarcoma: Origin, differential diagnosis, and report of a case in the mandible.

Fibrosarcoma (FS) is a malignant neoplasm of mesenchymal cells with no specific line of differentiation. Histologically, it mimics the wide spectrum of benign and malignant spindle cell neoplasms creating diagnostic conundrum. Immunohistochemistry plays a crucial role in the diagnosis which relies on various antibodies reacting with different antigens expressed by heterogeneous cells. Thus, there is a need to study the origin of the spindle cells to better comprehend their immunophenotypes that forms cornerstone for final confirmatory diagnosis. This case report describes the case of a 42-year-old male with soft-tissue mass in the mandible. Initial biopsy revealed it a reactive fibrous lesion; however, deeper biopsy confirmed spindle cell malignancy which exhibited immunonegativity to all other markers except vimentin. In addition, this case highlights the origin of various spindle cells with markers expressed during their development. The differential diagnosis of FS from other benign and malignant spindle cell lesions on the basis of clinical, histopathology, and immunohistochemistry is also elaborated. Copyright:

INTRODUCTION

The World Health Organization defined fibrosarcoma (FS) as malignant spindle cell tumor with fascicular architecture and variable collagen matrix production, showing fibroblastic/myofibroblastic differentiation.[1]

FS is uncommon in the head and neck (H and N) region presenting 1% of all the human malignancies. Wadhwan et al. have reported 0.05% of FS in H and N among which 23% FS involve oral cavity.[2] It usually occurs in 20s and early 30s (elsewhere, elder age) with male predilection. Oral FS primarily involves mandibular or maxillary bone, where they usually arise from bone, periosteum, and muscle fascia. The clinical presentation is nonspecific which includes pain, swelling, paraesthesia, ulceration of mucosal tissues, and loosening of the teeth.[3]

Microscopically, FS shows spindle cells with no specific line of differentiation which creates diagnostic conundrum with wide spectrum of spindle cell lesions. Thus, it is prudent to understand the divergent differentiation of spindle cells from their precursors with respective immunoprofile expression.[4]

This case report describes a rare case of FS in a middle-aged male patient with gingival involvement. The novelty of this article also lies in the fact that it highlights the origin of diverse spindle cells from their precursors with their immunoprofile and accordingly heterogeneous neoplasms derived from them. In addition, a thorough review of differential diagnostic approach for FS from other benign and malignant spindle cell neoplasms is contemplated.

CASE REPORT

A 42-year-old non-smoker male reported for the treatment of a slightly painful, slowly progressive, gingival growth on labial surface of mandibular incisors which grew to the present size of about 10 mm × 7 mm in 6 months. Medical and drug history was noncontributory. Regional lymph nodes were not palpable. On intraoral examination, a solitary sessile gingival overgrowth of reddish pink color was observed on the labial aspect of mandibular anterior extending from the distal surface of tooth #32 crossing the midline till distal aspect of tooth # 41 [Figure 1a]. The lesion was firm in consistency, nontender, nonfluctuant and had rounded margins. Pocket depths ranging from 5 to 7 mm, Grade II mobility and horizontal bone loss as seen on intraoral periapical radiograph was noted in mandibular incisors [Figure 1b]. Based on clinical and radiographic findings, a provisionally diagnosis of pyogenic granuloma with localized periodontitis was made. Differential diagnoses of peripheral ossifying fibroma and peripheral giant cell granuloma were considered.

Figure 1

Clinical presentation of the lesion (a) Intraoral picture showing gingival overgrowth on the labial aspect of mandibular anterior (b) Intraoral periapical radiograph showing horizontal bone loss (c) Completely excised tissue. (d) Free gingival grafting performed. (e) Postoperative orthopantomogram

At initial visit, complete oral prophylaxis was done and oral anti-inflammatory drugs with 0.2% chlorhexidine mouth rinse were prescribed. No decrease in the size of the lesion was observed at 1-week follow-up. An incisional biopsy was performed which was suggestive of fibrous hyperplasia. Mandibular anterior teeth were splinted, and the lesion was excised in toto with healthy margins under local anesthesia [Figure 1c]. After root planing of the affected teeth, denuded bone surface was covered with a free soft-tissue graft harvested from the palate [Figure 1d].

The excised lesion was again sent for microscopic examination which revealed parakeratinized stratified squamous epithelium with elongated rete ridges overlying dense fibrocellular stroma. The stroma showed hyperchromatic monomorphic spindled cells with moderate to scanty cytoplasm arranged in fascicles showing herring-bone pattern within the background of moderate amount of collagen. The tumor cells showed nuclear pleomorphism, increased nuclear-cytoplasmic ratio and few atypical mitotic figures. A possibility of malignant spindle cell tumor was considered [Figure 2].

Figure 2

Histopathology of the lesion. (a) Photomicrograph showing highly cellular proliferation within stroma with adjacent hyperplastic surface epithelium (H and E, ×4; black arrow indicate hypercellular stroma) (b) Stroma displayed interlacing fascicles (black arrow) of spindle shaped cells (H and E, ×10) and (c) intersecting fascicles displaying herring bone pattern (H and E, ×20). (black arrow indicates herring bone pattern) (d) The atypical spindle shaped cells showed marked nuclear pleomorphism and mitosis (H and E, ×40) (black arrow indicates mitotic figures)

Immunohistochemical analysis was performed by biotin-streptavidin-peroxidase method. The tumor cells were positive for vimentin but negative for S100, desmin, myogenin, smooth muscle actin, pancytokeratin, and cluster of differentiation (CD99). Ki-67 proliferative index was approximately 15% [Figure 3].

Figure 3

Immunoprofile of the lesion. Tumor cells displayed immunopositivity for vimentin (a), immunonegativity for myogenin (b), desmin (c), Smooth muscle actin (d) and CD99 (e) and Ki67 proliferation index approximately 15% (f)

A diagnosis of FS was made on the basis of histopathological and immunohistochemical findings. The patient underwent wide surgical excision followed by 30 cycles of radiotherapy in 3 months. At 2 years of follow-up, the patient was in the stable condition and no recurrence was observed [Figure 1e].

DISCUSSION

In the past, FS was most frequently diagnosed mesenchymal malignancy attributed to incognizance of other spindle cell malignancies and insufficient diagnostic modalities.[3] However, advanced diagnostic techniques such as immunohistochemistry, electron microscopy and molecular techniques unveiled previously diagnosed FS as other spindle cell malignancies. The present paper is unique as it discusses a rare case of FS along with thorough inculcating thorough insight into origin of spindle cell lesions and their differential diagnosis.

Primary FS in the oral cavity can arise within the bone or in soft tissue. Most FS are soft tissue in origin; however, these soft-tissue lesions can secondarily involve bone which should not be confused with primary intraosseous FS which has its origin primarily from the bone.[5] The latter needs to be differentiated from intraosseous malignancies such as odontogenic sarcomas. No clear evidence exists to ascribe etiology of FS; however, origin of FS in the region of dental extraction and in patients of radiation therapy is reported.[6] No definitive etiological factor was identified in present case.

Oral FS has been reported in literature mostly in adults manifesting clinically and radiographically similar to present case.[345] However, cases have also been reported in the literature in children.[67] Typical presentation is swelling associated with pain and paraesthesia. Radiographically, it shows ill-defined osteolytic lesion indistinguishable from other bone destructive lesions. Our case presented with a lobulated gingival overgrowth in mandibular anterior region associated with bone loss. This bone loss can be attributed to the pressure created from the existing lesion or superimposed on previously existing bone loss due to periodontitis.[8]

Histology of FS is variable exhibiting fascicles of spindle cells with variable collagen production.[1] Histological grading of FS depends on the factors such as mitotic activity, cellularity, cellular differentiation, pleomorphism, extent of necrosis, and amount of collagen matrix production. Federation Nationale de Lutte Center de Cancer (FNLCC) grading system is commonly used for grading sarcomas which includes degree of differentiation, mitosis count, and microscopic tumor necrosis.[9] Low-grade tumors show uniformly arranged distinct fascicles, herring bone pattern, and greater production of collagen matrix, whereas high-grade tumors show highly cellular anaplastic cells with abundant necrosis and mitosis and minimal collagen production.[8] Our case belonged to FNLCC grade 2 (total score 4) based on the presence of herringbone pattern (degree of differentiation score; 2), intermediate cellularity with 10 mitosis/10 high power field (mitosis score 2), and no evidence of necrosis (score 0).

The diagnosis of FS usually requires biopsy from the deeper parts of the lesion because superficial biopsy may lead to erroneous diagnosis of a reactive fibrous lesion owing to collagen production as seen in the present case.[2] The histological differential diagnosis include wide spectrum of benign and malignant spindle cell lesions [Tables 1 and 2].[910] To understand immunophenotypes of spindle cells contributing to heterogeneous tumors, the origin of these cells from their precursors with markers expressed during their development is elaborated in Figure 4.[210] The different antigens expressed by these spindle cells form the cornerstone in segregating this complex group of neoplasms through immunohistochemistry. Therefore, meticulous histopathological examination with immunohistochemistry is needed to ascertain confirmed diagnosis of FS.

Table 1

Benign spindle cell lesions in differential diagnosis of fibrosarcoma in head and neck region

Result	NF	IMT		SFT	Lipoma (spindle cell)
Synonyms	Pseudosarcomatous proliferation	Inflammatory pseudotumor, plasma cell granuloma		Hemangiopericytoma, giant cell angiofibroma	Pleomorphic lipoma
Cell of origin	Fibroblastic/myofibroblastic	Myofibroblasts and fibroblasts		Fibroblastic	Adipocytic
Age	3rd-4th decade (most common in children)	Adults		Adults	Middle age (4th-5th decade peak)
Sex	Male=female	Male > female		Male=female	Male > female (10:1)
Site	Upper extremities > H and N (parotid gland, bony prominences of angle mandible, symphysis, zygoma, skull)	H and N common (larynx, oral cavity, sinonasal, pharynx, salivary glands and trachea)		Nasal cavity	Posterior neck, upper back; face, orbit and oral cavity rare
Clinical	Rapid growth, solitary small (<2-3 cm), painful firm fixed nodule	Larynx: Hoarseness stridor Other sites: Obstruction, epistaxis, headache, dysphagia		Nasal obstruction, epistaxis	Painless subcutaneous mass
Pattern	Poorly circumscribed short fascicles (feathery pattern) (never long fascicles like FS), prominent myxoid matrix (zonal appearance)	Submucosal storiform to fascicular loosely cellular		Haphazard (pattern-less pattern) architecture, variable collagenous background, vessels staghorn to stellate shaped	Well circumscribed, spindle cells with “ropy” collagen fibers, myxoid stromal change
Morphology/cytology	Marked cellularity plump cells, fibrillary cytoplasm, chronic inflammatory cells	Spindle to stellate to epithelioid and/or axonal (spider like) with enlarged round to oval nuclei, abundant fibrillary cytoplasm, inflammatory cells May have ganglionic cells		Spindle cells, MGC may be present	Bland spindle cells, admixed with variable mature adipocytes. MGC (floret appearance) Occasional lipoblasts
Mitosis	P (numerous and typical, never atypical)	P (numerous and typical)		R	R
Necrosis	N	N		R	N
Cytokeratin	N	N/FP (33%-77%)		N	N
Vimentin	P	P (S and D)		P	P
S-100	N	N		N/FP	N (W and O/P)
CD34	N	N		P (S and D)	P (D)
Desmin	Fa/N	P (33%-77%)		N/FP	N
SMA	P	VP (F or D)		N or P (20%)	N
Other diagnostic markers	MSA (HHF-35), calponin	ALK -P (30%-60%)**		STAT-6- specific, CD56+ CD99+, TLE-1;R FP	CD10+, loss of nuclear Rb
Molecular	USP6 locus at 17p13: 90% MYH9-USP6 gene fusion: 65% cases PPP6R3-USP6 fusion	50%-70%- clonal rearrangements at chromosomal band 2p23 that fuse with kinase region of ALK gene		NAB2-STAT-6 gene fusion	16q and 13q deletions
Prognosis	LR rare even with incomplete excision, spontaneous regression in few cases	Surgical resection curative in laryngeal tumors LR; rare ALK +; favorable prognosis		Surgical resection curative Age >55 years, size >15 cm, >4 mitosis >10/HPF and necrosis-poor prognosis	Entirely benign, local excision is curative, LR exceptional
Result	Leiomyoma	Myoepithelioma of salivary glands	Neurofibroma	Schwannoma	Fibromatosis/desmoid tumors
Synonyms	Angioleiomyoma (if prominent vessels)	Myoepithelial cell tumor, myoepithelial adenoma, monomorphic adenoma	Fibroneuroma	Neurilemmoma, peripheral nerve sheath tumor	Aggressive fibromatosis
Cell of origin	Smooth muscle	Myoepithelial cells	Mixed schwann cells, perineural like cells and intraneural fibroblasts	Schwann cells	Fibroblastic/myofibroblastic
Age	Adults	-	Teen and 20 years	30-50 years	OMF region: 5-20 years Elsewhere: 25-35 years
Sex	Male=female	Male=female	Male=female	Male=female	Male=female
Site	Extremely rare in H and N (<1%) H and N sites: Lips, tongue, cheeks, palate, gingiva and mandible; extraordinary rare in sinonasal region	Parotid gland>hard and soft palate	Skin commonest site, oral cavity not rare (tongue and buccal mucosa common intraoral sites), exceptional in sinonasal tract Rare intra-osseous	H and N and flexor area of extremities; intraorally (tongue and floor of mouth) Rare intraosseous within mandible or maxilla	Extremities and retroperitonium, rare in OMF region (10%-15%) Soft tissue of neck most common, maxillary sinus, nasopharynx and oral cavity-rare
Clinical	Polypoid masses	Slow growing painless masses	Nonspecific symptoms- mass, obstruction, epistaxis and pain	Painless, slow growing mass	Destructive infiltrative growth, enlarging painless mass
Pattern	More homogenous intersecting fascicular growth pattern	Nests or cords, occasional ducts and intercellular microcystic spaces	Unencapsulated tumors haphazard or vaguely whorled proliferation intermixed with coarse collagen bundles and mast cells within mucopolysaccharide rich stroma (shredded carrot)	Encapsulated hypercellular Antoni A and hypocellular Antoni B patterns	Poorly circumscribed fascicular arrangement like FS but with variable collagen production, cells separated by collagen
Morphology/cytology	Nuclear palisading, nuclei oval to elongated and cigar shaped without atypia, eosinophilic fibrillar cytoplasm	Single cells or clusters, spindled, epithelioid, plasmacytoid or clear	Ovoid to spindle cells with undulating pointy nuclei (wavy or buckled nuclei) and thin cytoplasmic projections	Spindle cells palisading central verocay bodies, degenerative changes	Uniform spindle cells, minimal atypia, indistinct cytoplasm, fine chromatin
Mitosis	N	N	R	R	R*
Necrosis	N	N	N	N	N
Cytokeratin	N	P	N	N/focal	N
Vimentin	P	P	P	P	P
S-100	N	VP	P (30%-60%)	P (D and S)	FP/N
CD34	N	N	P in perineurium	P2 in Antoni B fibroblasts	N
Desmin	P (D and S)	N	N	N	N/FP
SMA	P	VP (P in spindled cells not in plasmacytoid cells)	N	N	Patchy P
Other diagnostic markers	P63+, GFAP +	GFAP +, calponin +, CK14+, CK7+VP for MSA	NFP + GFAP + SOX10 +	SOX10+, GFAP; FP, but NFP negative	β-catenin# (nuclear)- 70% Calretinin: 75%
Molecular	Angioleiomyomas: 22q11.2 and low level amplification of Xq	-	10% in association with neurofibromatosis Type 1 (NF1 gene on 17q11.2)	-	Mutation in 3p21 (CTNNB1) encoding β-catenin - APC on 5q
Prognosis	Excellent	LR uncommon, rare malignant transformation	5% recurrence rate, malignant transformation is exceptional	Excision associated with 100% cure rate, malignant transformation exceptional	Good, young age and CTNNB1 S45F mutation independent prognostic factor for LR

*Presence of more than one mitosis per high power field would raise the suspicion of fibrosarcoma; #However not very specific for fibromatosis, myxofibrosarcoma, SFT, myofibroma, nodular fasciitis, and hypertrophic scars - positive staining in 25% cases. Immunonegativity to CD34, BCl2 help in distinction from SFT; **Also in subset of MPNST, neuroblastoma and RMS (alveolar variant). NF – Nodular fasciitis; IMT – Inflammatory myofibroblastic tumor; SFT – Solitary fibrous tumor; BFH – Benign fibrous histiocytoma; MN – Multinucleated; OMF – Oral and maxillofacial region; ALK – Anaplastic lymphoma kinase; MSA – Muscle specific actin; H and N – Head and neck region; P – Positive; VP – Variably positive; N – Negative; FP – Focally positive; R: Rarely positive; D – Diffuse positivity; S: Strong positivity; O – Occasional positive; Rb – Retinoblastoma protein; NFP – Neurofilament protein1: Few scattered cells; 2 – Positive in perineurium; ALK-P – Alkaline phosphatase; STAT-6 – Signal transducer and activator of transcription 6; CD – Cluster of differentiation; TLE-1 – Transducin-like enhancer of split 1; Rb – Retinoblastoma protein; GFAP – Glial fibrillary acidic protein; CK – Cytokeratin; NFP – Neurofilament protein; SOX10 – SRY-related HMG-box 10; USP6 – Ubiquitin specific protease 6; P – Short arm of chromosome; MYH9 – Myosin 9-homosapiens; PPP6R3 – Protein phosphatase 6 regulatory subunit 3; NAB2 – NGFI-A binding protein 2; q – long arm of chromosome; PDGFRB – Platelet-derived growth factor receptor beta; CTNNB1 – Catenin beta-1 also call beta catenin; APC – Adenomatous polyposis coli; LR – Local recurrences; RMS – Rhabdomyosarcoma; MPNST – Malignant peripheral nerve sheath tumor; FS – Fibrosarcoma; Fa/N – F implies positivity in few scattered cells and N means negative; S and D – Strong and diffuse positivity; N (Wand/OP): weak and occasional positive; HHF – clone of muscle specific actin antibody; HPF – High power Field

Table 2

Malignant spindle cell lesions in differential diagnosis of fibrosarcoma

Results	Spindle cell SCC	MFH	Myoepithelial carcinoma	MPNST	Synovial sarcoma
Synonyms	Sarcomatoid carcinoma, carcinosarcoma	Undifferentiated pleomorphic sarcoma	Malignant myoepithelioma	Neurofibrosarcoma, malignant neurilemmoma, malignant schwannoma, neurogenic sarcoma	Synovial cell sarcoma, synovioma
Cell of origin	Epithelial cells acquiring mesenchymal properties by EMT	Primitive fibroblastic lineage	Myoepithelial cells (epithelial in origin)	Neuroectodermal in origin, heterogenous population, Schwann cells predominate	Spindle cell with epithelial differentiation
Age	Elderly men	Elderly (peak 7th decade)	Wide range (6th decade)	Adults (mean 5th decade)	Mean age 1st to 4th decade
Sex	Male > female	Male > female	Male=female	MALE=female	Male > female
Site	Upper aerodigestive tract (larynx and oral cavity)	Extremities and retroperitonium, rare in OMF region (sinonasal tract)*	Parotid > submandibular > minor salivary glands	Cranial nerves, with vestibular and vagal most common; 20% in H and N	Large joints and bursae, rare in H and N (1.9%-3.7%)
Clinical	Nearly always pedunculated polypoid mass with surface ulceration, occasionally sessile nodular fungating mass	Painless firm fleshy subcutaneous or submucosal mass, intermediate to slow growth, may arise in bone	Rapidly expanding, painless mass Weight loss can be seen	Painful and/or rapidly enlarging mass with neurological deficits	Palpable, deep-seated swellings with or without pain
Pattern	Biphasic (fascicles of spindle cells with atypical epithelial cells), overlying epithelium - dysplastic or insitu carcinoma	Storiform pattern	Infiltrative growth, nodular to diffuse pattern, tumor cells in nests, sheets or cords	Multiple patterns within same tumor; most common is alternating cellular and myxoid areas (marbled effect) Unencapsulated, irregular fascicular growth, perivascular cuffing, distinct whorls or palisades	Biphasic (with glandular and epithelial cells) and monophasic4 (spindle type, myxoid, calcified) and poorly differentiated4
Morphology/cytology	Spindle cells with prominent atypia	MN bizarre giant cells (intense eosinophilic cytoplasm) containing lipid droplets, siderophages and xanthoma cells	Cells in clusters - epithelioid, plasmacytoid, spindled, or clear or mixed types	Range of morphologies (wavy or buckled appearance, spindle, epithelioid, pleomorphic and small round cell) cartilaginous metaplasia more frequent	Cells with more eosinophilic cytoplasm (cellular cohesion)
Mitosis	Numerous	P	P	Frequent	Commond
Necrosis	VP	P	Uncommon	Frequent	Variabled
Cytokeratin	Pa (70%)	N	P	panCK-N CK8/18- P but CK7 or 19-N	P$ CK7 or 19-Pa
Vimentin	P (S and D nearly 100%)	P*	P	P	P
S-100	N/P (5%)	N	P	Pb (N and C)	N/VP (30%)
CD34	N	N	N/occasional positive	VP	N
Desmin	N	N	N/rare positive7	N/**	N
SMA	N/FP	FP	P	-	Ph
Other diagnostic markers	-	-	GFAP +, calponin +, CK14+, CK7+	SOX10 nuclearc, INI retained, CD56/57%-50% (NS)	TLE-1-95% NY-ESO-1e SYT: P VP: CD56, CD99, BCl2 N: WT1
Molecular	Complex genetic aberrations	Complex genetic aberrations	Chromosome 8 alterations, most frequently found EWSR1 rearrangements (more common in clear cell variants)	Loss of NF1 on 17q11 and TP53 on 17q13, deletion of CDKN2A (INK4A) gene on 9p chromosome	fusion SS18 (also called SYT) with SSX1 SSX2 or SSX4 resulting from t (X; 18)
Prognosis	Poor, 5 years survival 30%, metastasizes early	5 years survival rate: 50%-70%, previous RT; adverse prognosis	Intermediate to high grade tumor, LR; common, mets are uncommon at presentation but may occur at later age	Aggressive tumors. Worse prognosis with >5 cm size, NFI association, >6 mitosis/HPF and incomplete resection, LR: 40%, 2/3rd cases with mets	Depends upon staging, grading, site, resectability, radiation and mets 5 years survival rate: 36%-64%
Results	MFS	LMS	RMS (spindle type)g	Atypical spindle lipomatous tumor	Melanoma (spindle cell type)	FS
Synonyms	Myofibrosarcoma	-	-	Spindle cell liposarcoma
Cell of origin	Myofibroblasts	Smooth muscle cell	Skeletal muscle	Adipocytes	Melanocytes	Fibroblasts
Age	Any age (mean 40 years)	Middle to older adults	Children > adults (peak 1st decade)	Adults	Adults	2nd-6th decade
Sex	-	-	Male=female	-	-	Male > female
Site	Predilection for H and N; tongue preferred site Rare in nasal and PNS Also in gnathic bones	Uterine wall and GIT-commonest sites, oral cavity rare	ERMS7 and ARMS: Common in H and N; Pleomorphic RMS: Extremities	Retroperitonium and limbs, H and N can also be involved	In soft tissue as extension of locally advanced melanoma or as a metastasis	Tremities most common H and N rare-6% primary jaw FS (mandible [posterior] > maxilla)
Clinical	Painless swelling or enlarged mass	Nonspecific; enlarging mass; may or may not be painful	Painless infiltrative mass with rapid growth	Slowly growing mass	Lymph node (axillary or inguinal) with ECS is extremely common presentation; previous medical history is crucial for diagnosis	Swelling, pain, paraesthesia, loose teeth and mucosal ulceration
Pattern	Fasciitis like or fibromatosis like to fibrosarcoma like (fascicles of broad sheets of cells) with our without herringbone or storiform pattern, checkerboard like infiltration of adjacent skeletal muscle key feature	Fascicular pattern typically intersect at right angles	Fascicular spindle cells with rhabdomyoblasts	Well circumscribed, bland spindle cell proliferation reminiscent of neural neoplasm set in fibrous or myxoid background with mature adipocytic proliferation	Peritheliomatous growth	Long fascicles, herringbone pattern (acute angle intersection)
Morphology/cytology	Spindle cells, tapered myofibroblastic nuclei-atypical, hyperchromasia, scanty to moderate cytoplasm, background collagenous or myxoid	Spindle cells-cigar shaped blunt ended with eosinophilic cytoplasm cellular atypia	Spindle cells with elongated nuclei and pale cytoplasm, rhabdomyoblasts-spindled or polygonal with bright eosinophilic cytoplasm	Bland spindle cell or few areas with more atypical spindle cells occasional lipoblasts main diagnostic clue	Either spindled or epitheliomatous morphology	Variably cellular, fusiform cell with centrally placed, hyperchromatic, needle spaced nuclei
Mitosis	P	P	P	R	P	P
Necrosis	P	P	P	N	P	P
Cytokeratin	N	N/P (30%-40%)	N/P in 5%-8%	N	N	N
Vimentin	P	P	P	P	P	P (only vimentin positive in FS-S and D)
S-100	N	N	R (<10%)	VP (40%)	P (S and D)	N/FP
CD34	VP	VP	R	VP	N/Pa	N/FP
Desmin	VP	P	Pg	VP	N/Pa	N/FP
SMA	VPj	P	P (10%)	NR	NR	N/R (FP)
Other diagnostic markers	-	h-caldesmonf	Myogenin (MYF4)g/MyoD1	Loss of nuclear Rb (60%), p16+, MDM2+, CDK4+k	SOX10+i (S and D), HMB45+, melan A+, tyrosinase+ (P in <10% cases)	-
Molecular	Complex genetic aberrations	Complex karyotypes	ERMS: Nonspecific (allelic loss at chromosome 11p15.5, pediatric spindle cell RMS: NCOA2 rearrangement	Chromosome 7 monosomy, RB1 heterozygous deletion	-	-
Prognosis	LR common, mets rare to lungs, soft tissue of bone	Depends mainly on location with sinonasal more aggressive; patient die of widespread LR or distant mets	ERMS: spindle cell variant has 5 years survival rate of 88% and excellent prognosis	12% LR with no potential for systemic spread or mets	Poor prognosis	Highly dependent on histological grade Overall survival: 83% at 10 years for low grade and 34% in high grade

aAtleast one epithelial marker should be positive (cytokeratin, EMA or p63 or p40), although absent in upto 30% cases; bEpithelioid MPNST: Strong nuclear and cytoplasmic, spindle MPNST: Only scattered cells are S100 positive and INI is retained, in high grade tumors it may be negative; cAlso detected in melanocytic lesions but found to be more sensitive and specific than S100 for MPNST; dMonophasic and poorly differentiated synovial sarcoma create diagnostic confusion, biphasic is easily diagnosed. Mitosis and necrosis is frequent in poorly differentiated synovial sarcomas; eRecently reported in 76% of SS cases with strong and diffuse pattern; fH-caldesmon negativein myofibrosarcoma; gSpindle cell variant is a subtype of ERMS, RMS is positive for actin, desmin, myogenin and myoD1.MYF4 staining in ERMS is hetererogenous than in ARMS where it is 100%; hCombination of S100 and actin reactivity would be different from FS which may show focal actin positivity; iS100 and SOX10 strongly and diffusely positive in spindle cell melanoma whereas second line melanocytic markers (HMB45, melan A) are rarely useful as expressed in <10% cases. (Hornick); jTram-track’ subplasmalemmal accentuation; kMDM2 and CDK4 present in both atypical lipomatous tumor and well differentiated liposarcomas but not in benign adipocytic tumors; lPositive in desmoplastic melanoma; *3rd most frequently reported sarcoma in sinonasal tract after rhabdomyosarcoma and fibrosarcoma, by definition, it should only be vimentin positive; **MPNST shows divergent differentiation most often myogenic or osteogenic or chondrogenic or very rarely epithelial, thus expressing markers desmin, myogenin, SATB2. Triton tumor (expressing rhabdomyosarcomatous differentiation; $Atleast focal to patchy epithelial marker positive; AE1/AE3, differential keratin expression (CK7 and CK 9+ unlike in MPNST) and BerEP4 feature not found in FS. SCC – Squamous cell carcinoma; MFH – Malignant fibrous histiocytoma; MFS – Myofibrosarcoma; MPNST – Malignant peripheral nerve sheath tumor; LMS – Leiomyosarcoma; RMS – Rhabdomyosarcoma; ERMS – Embryonal rhabdomyosarcoma; ARMS – Alveolar rhabdomyosarcoma; FS – Fibrosarcoma; MN – Multinucleated; OMF – Oral and maxillofacial region; PNS – Paranasal sinuses; RT – Radiotherapy; EMT – Epithelial mesenchymal transition; P – Positive; VP – Variably positive; N – Negative; F – Focally positive; R – Rarely positive; S and D – Strong and diffuse; LR – Local recurrences; mets – Metastasis; N and C – Nuclear and cytoplasmic; NS – Nonspecific; ECS – Extracapsular spread; NR – Not reported; GFAP – Glial fibrillary acidic protein; CK – Cytokeratins; SOX10 – SRY-related HMG-box 10; INI – Integrase interactor 1; TLE-1 – Transducin-like enhancer of split 1; NY-ESO-1 – New York esophageal squamous cell carcinoma 1; SYT: P – Sugar transporter protein; BCl2 – B-cell lymphoma 2; WT1 – Wilms tumor 1; MYF4 – Myogenin factor 4; MyoD1 – Myoblast determination protein 1; Rb – Retinoblastoma protein; MDM2 – Mouse double minute 2 homolog; CDK4 – Cyclin dependent kinase 4; HMB45 – Human melanoma black 45; NF1 – Neurofilament 1 protein; q – long arm of chromosome; P – Long arm of chromosome; TP53 – Tumor suppressor gene; CDKN2A – Cyclin dependent kinase inhibitor 2A; INK4A – Inhibitors of CDK4, SS18; synovial sarcoma translocation; chromosome 18; SSX – Synovial sarcoma X; NCOA2 – Nuclear receptor coactivator 2; LR – Local recurrences; EMA – Epithelial membrane antigen; H and N – Head and neck region

Figure 4

Divergent differentiation of spindle cells with their immunoprofile and neoplasms derived from them. Most of the spindle cell lesions are predominantly mesenchymal in origin, others are epithelial and neural crest origin (1, 2, 3 orange oval shapes). They undergo differentiation into various phenotypes depending upon various genetic stimuli and growths factors and express different antigens which serve as immunohistochemical markers for final diagnosis. Starting from left to right, mesenchymal stem cell can give rise to fibroblast (has vimentin as intermediate filament protein) through intermediate stages and thus various tumors are originated at these corresponding stages (cell name is written in black and corresponding tumor is written in red immediately below it). Similarly, smooth muscle cells, skeletal muscle cells, and adipocytes can arise from the mesenchymal stem cell and their respective spindle cell neoplasms. Spindle cell squamous cell carcinoma arises from the epithelium, which undergo de-differentiation or EMT and thus express both cytokeratin and vimentin. Myoepithelial cells have immunoprofile similar to smooth muscle and epithelial cells, but they are epithelial in origin. Myofibroblasts show intermediate morphology between smooth muscle and fibroblasts; thereby the immunohistochemical markers. Melanoma arises from melanocytes and schwannoma arises from Schwann cells; both are neural crestal in origin. (orange Oval 3) Thus, both melanoma and schwannoma display S100 immunopositivity. V – Vimentin intermediate filaments; CK – Cytokeratin, MPNST – Malignant peripheral nerve sheath tumor; EMT – Epithelial mesenchymal transition; SMA – Smooth muscle actin, MSA – Muscle specific actin; CK – Cytokeratin; IMT – Inflammatory neurofibroblastic tumor; GFAP – Glial fibrillary acidic protein; SCC – Squam cell carcinoma; PPARg2 – Peroxisome proliferator-activated receptor gamma isoform-2; CD – Cluster of differentiation

The treatment of FS usually is wide local excision using 3 cm safe tumor free margins. The lesion which cannot be completely excised, postoperative radiotherapy is necessitated. In grade 3 FS, adjunctive postoperative chemotherapy is advocated to treat potential microscopic or occult metastasis.[8] Similarly, our case was treated by wide local excision followed by postoperative radiotherapy.

The prognosis depends upon grade of tumor (5 year survival rate varies from 39% to 54.4%) with incomplete excision being the most important cause for local recurrence. Metastasis is rare which occurs exclusively by blood stream most commonly to lungs and rarely to vertebral and skull bones.[2811]

CONCLUSION

FS in the oral mucosa is a rare finding and accurate diagnosis demands biopsy of deeper tissues from the lesion. The final diagnosis relies upon exclusion of other spindle cell lesions mimicking FS through collaboration of clinical, imaging, and conventional histopathological features with appropriate use of immunohistochemical markers. The follow-up of the patient is essential as this tumor has tendency for recurrence and metastasis.

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Conflicts of interest

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