Mast Cell Metabolism: A Viable Therapeutic Target against Intraoral Neurofibroma

Abstract

Neurofibroma being benign in its behavior remains silent in existence and hence can be mistaken for various reactive lesions of the oral cavity such as fibroma, peripheral giant cell granuloma, or peripheral ossifying fibroma. Although it is a well-established fact that mast cells play the utmost significance in the tumorigenesis of such tumors, little is known about their importance in treatment modalities. Hence, we intend to present a case of intraoral neurofibroma emphasizing the significance of mast cells in therapeutic intervention of neurofibromas (NFs) as such tumors can be accompanied by syndromes and hence necessitates the thorough clinical as well as microscopical analysis as well as an adequate therapeutic approach. Our case revealed the presence of mast cells in the stroma which was further confirmed with toluidine blue staining. Infiltration of mast cells is frequently seen in NF; however, its presence is uncommon in other neoplasms. This distinctive feature can be taken as a target of interest in neurofibroma research. Current clinical treatment options for NF are limited to surgical removal and follow-up of the case. Hence, this warrants the need of better understanding of the role of mast cell-based targeted therapy for such cases. The strategies formulated against the tumors associated with neurofibroma cannot be only applied after the encounter with sporadic counterparts, specifically in terms of benign tumors linked to such disorders. The noteworthy significance of tumor microenvironment in tumorigenesis necessitates adequate clinical examination, followed by delineation of the differential diagnosis and therapeutic approach toward such cases.

INTRODUCTION

Neurofibroma is a nerve sheath tumor developing in the peripheral nervous system that can present in different distinct forms such as solitary or neurofibromatosis.[1] Numerous cases have been reported in literature after its first documentation by Bruce[2] in 1954. Most commonly seen on the skin and intraorally on the tongue. Solitary neurofibromas (NF) presents as slow-growing, pedunculated, or sessile nodules resembling various other soft-tissue tumors. Although the intraoral existence of such tumors is rare, their locally aggressive nature, recurrence, and malignant transformation cannot be negated.[3]

Being benign in behavior such tumors remain silent in their existence and hence can be mistaken for various reactive lesions of the oral cavity such as fibroma, peripheral giant cell granuloma, or peripheral ossifying fibroma.[4] Although it is a well-established fact that mast cells play the utmost significance in the tumorigenesis of such tumors, little is known about their importance in treatment modalities. Hence, we intend to present a case of intraoral neurofibroma emphasizing the significance of mast cells in therapeutic intervention of NF as such tumors can be accompanied by syndromes and hence necessitate a thorough clinical as well as microscopical analysis as well as an adequate therapeutic approach.

CASE REPORT

A 70-year-old male patient reported with the chief complaint of flabby tissue in the lower anterior tooth region. Patient was biopsied and treated with informed consent. He started noticing the growth of a flabby soft-tissue mass in the mandibular left anterior teeth region after the extraction wrt 33 [Figure 1]. Initially, it was pinpoint in size. Then increased up to pea size. Progression of growth of the tissue was constant without any aggravating or alleviating factors. Intraoral examination revealed a well-defined, oval, pink nodular swelling in the mandibular anterior teeth region with smooth texture. Provisional diagnosis of fibroma was given based on clinical resemblance. On the basis of clinical evaluation, the differentials of the case could be peripheral giant cell granuloma, peripheral ossifying fibroma, giant cell fibroma, traumatic neuroma, myofibroma, and nodular fasciitis [Table 1].

Figure 1.

Intraoral examination revealing a solitary well-demarcated growth in the lower left alveolus as depicted in the circle

Table 1.

Differential diagnosis on the basis of clinical parameters

Differential diagnosis based on clinical features
Features	PGCG	POF	Giant cell fibroma	Traumatic neuroma	Myofibroma	Nodular fasciitis	Present case
Age	Very young children as well as in dentulous or edentulous elderly persons (4th–6th decade)	Any age (children are more commonly affected)	10–30 years	10–29 years	Can occur at any age (mean age - 26.6 years)	3rd and 5th decade of life	70 years
Gender	Female predominance	Predilection for females (2:1 to 3:2)	No gender predilection exists	Male > female	No gender predilection exists	Predilection for females (2:1 to 3:2)	Female
Site	Always occurs on gingiva or alveolar process (mostly anterior to molars)	Mandible and maxilla are equally affected	Most common site is mandibular gingiva	Typically near the mental foramen or on the alveolar ridge in edentulous areas. Other sites: lips or tongue	Most common in head-and-neck regions, including oral and perioral sites, than in other areas (Intraoral lesions: tongue, lips, and buccal mucosa and Jaw lesions: Generally mandibular lesions)	Mandible and maxilla are equally affected. Location: Lesion develop mostly within subcutaneous tissue overlying the mandible and zygoma and also occur on buccal mucosa, tongue and alveolar mucosa	Mandibular alveolus
Appearance	Presents as sessile or pedunculated vascular, ovoid or fusiform swelling (1–2 cm in diameter). Ulceration is less common	Well-demarcated focal mass on tissue on gingiva	It appears as an asymptomatic sessile or pedunculated nodule that is 1 cm in diameter. Often it has a bosselated or a papillary surface	Appears as a small nodule or swelling of the mucosa. Slow-growing lesion. Seldom reaches a size greater than a centimeter in diameter. Pressure can cause pain	Oral lesions appear as submucosal nodules with a diameter of 0.3–5.0 cm	Usually firm, painless masses but can be painful and tender with a history of rapid growth	Solitary pink nodule on mandibular alveolus without any tenderness

POF: Peripheral ossifying fibroma, PGCG: Peripheral giant cell granuloma

Excisional biopsy was done, followed by gross examination [Figure 2a], and thus, histopathological examination revealed ortokeratinized stratified squamous epithelium with flat epithelial connective tissue interface overlying a fibrocellular connective tissue stroma [Figure 2b]. Tumor mass was well circumscribed with areas of hypercellularity and myxoid appearance. Stroma was composed of dual cell population, one comprising interlacing bundles of elongated cells with wavy, darkly stained nuclei along with few areas of round cells. Cells were intimately associated with wire-like strands of collagen suggestive of shredded carrot appearance [Figure 2c] which is a classic feature of neurofibroma. Focal areas of short fascicle formation were also evident. Mixed inflammatory cell infiltrates chiefly composed of mast cells and lymphocytes were seen admixed in the stroma. Based on microscopical evaluation, various histological differentials were considered [Table 2]. Toluidine blue staining was done [Figure 2d] after gaining ethical clearance from the institution to confirm the presence of mast cells. Hence, the final diagnosis of neurofibroma was given.

Figure 2.

(a) Gross examination depicting excised tumor mass without any areas of necrosis. (b) Photomicrograph depicting stratified epithelium overlying a fibrocellular connective tissue stroma and (*) showing the tumor area in the stroma (H and E, ×4). (c) Photomicrograph depicting shredded carrot appearance of the collagen fiber bundles along with cells showing wavy nuclei depicted by yellow arrows (H and E, ×40). (d) Photomicrograph showing degranulated mast cells in the stroma suggestive of active mast cells as depicted by yellow (Toluidine blue, ×40)

Table 2.

Differential diagnosis on the basis of histological parameters

Nodular fascitis	Neurilemmoma	Traumatic neuroma	Leiomyoma	Present case
The cells are arranged in short, irregular bundles and fascicles and are accompanied by a dense reticulin meshwork and only small amounts of mature birefringent collagen	Tumor is classically described as being composed of two types of tissues Antoni type A: Made up of cells with elongated or spindle-shaped nuclei which are aligned to form a characteristic palisading pattern. Intercellular fibers are arranged in parallel fashion between rows of nuclei. Fibers are arranged in the form of whorls or swirls	Histologic appearance is characteristic and shows a mass of irregular and interlacing neurofibrils and Schwann cells situated in connective tissue stroma scant or predominant	Well-circumscribed tumor constituting of spindle-shaped cells	Tumor mass was well circumscribed with areas of hypercellularity and myxoid appearance
Intermixed with the spindled cells are scattered lymphoid cells and erythrocytes and, in the more central portion of the lesion, a small number of lipid macrophages and multinucleated giant cells	Antoni type B: Does not exhibit this characteristic palisading. Disordered arrangement of cells and fibers with areas of microcysts formation. Verocay body (acellular eosinophilic zone) is also present in this tumor	Proliferating nerve fibers are arranged in the form of small bundles or spread diffusely throughout the tissue	These cells had elongated, blunt-ended nuclei	Stroma was composed of dual cell population, one comprising of interlacing bundles of elongated cells with wavy, darkly stained nuclei along with few areas of round cells
			The fascicles of tumor cells were arranged in whorls and intersecting each other	The classic shredded carrot appearance was also evident
				Focal areas of short fascicle formation were also evident. Mixed inflammatory cell infiltrates chiefly composed of mast cells and lymphocytes were seen admixed in the stroma

DISCUSSION

Neurofibroma being a tumor of nerve sheath, presents itself in varied distinct forms such as cutaneous and plexiform neurofibroma. Furthermore, the nature of NFs is heterogeneous in nature comprising malignant Schwann cells, nonneoplastic fibroblasts, inflammatory cells such as mast cells, and collagen bundles in a shredded carrot pattern.[1]

Our case revealed the presence of mast cells in the stroma which was further confirmed with toluidine blue staining. Infiltration of mast cells is frequently seen in NF; however, its presence is uncommon in other neoplasms. This distinctive feature can be taken as a target of interest in neurofibroma research.[5] Raised local histamine content in NF is indicative of activated mast cells.[6] This makes mast cells a novel target for research in therapeutic strategies for NF.

Various researchers have worked to predict the role of mast cells in the tumor microenvironment of NF and also experimented to know whether mast cell metabolism could be a viable therapeutic target in such tumors [Figure 3].[1]

Figure 3.

Flowchart depicting the role of mast cells in the pathogenesis of neurofibroma

Mast cells are immune effector cells that feature a high content of secretory granules containing multiple types of immunomodulatory molecules, such as histamine. Therefore, therapeutic approaches have attempted to prevent the growth of NF by stabilizing mast cell activity. Riccardi[7] reported the use of antihistamine agent ketotifen (histamine H1-receptor antagonist) to hamper the growth of neurofibroma and to reduce tumor-associated pain and itching.[8] Recently, it has been reported that a patient with NF Type 1 received beneficial responses from long-term ketotifen treatment by showing far fewer cutaneous NF compared with an age-matched control.[9] These clinical findings further suggested that mast cells could play a supportive role in neurofibroma development and mast cell metabolism might be a druggable target.

Although the present case is only depicting intraoral growth, patients with similar scenarios can develop multiple symptoms throughout the body as neurofibroma is often associated with syndromes.

Current clinical treatment options for NF are limited to surgical resection and follow-up of the case. Hence, this warrants the need of better understanding of the role of mast cell-based targeted therapy for such cases. Furthermore, the intent for treating such tumors should be on inhibiting the deregulated pathway and minimization of the symptoms.[10] Hence, this can be hypothesized that there are complex signaling cascades involved in its pathogenesis and their interactions can act as a potential therapeutic target for such cases.

CONCLUSION

Although intraoral NFs comprise only 5.6% of all head-and-neck NFs, since it is a locally aggressive tumor, hence, dentists should always consider it as a differential diagnosis for soft-tissue swellings and should consider consulting a specialist if required.

The strategies formulated against the tumors associated with neurofibroma cannot be only applied after the encounter with sporadic counterparts, specifically in terms of benign tumors linked to such disorders. The noteworthy significance of tumor microenvironment in tumorigenesis along with varied risk factors involvement necessitates adequate clinical examination, followed by delineation of the differential diagnosis and therapeutic approach toward such scenarios.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.