Aggressive oral granular cell tumor with periorbital involvement: An unusual case.

Granular cell tumor (GCT) of the oral cavity is rare and so is the involvement of the eye, orbit, and ocular adnexa. A 65-year-old male developed a posttraumatic ulceroproliferative mass over his left cheek for the past 1 year. The mass involved the periorbital region with accompanying blood-stained purulent discharge from multiple sinus tracts over this lesion for the past 6 months. Radiographs of the orbit suggested chronic osteomyelitis. The lesion was not responsive to treatment with antibiotics. Enlarged submandibular lymph node demonstrated reactive lymphadenitis on cytological examination. However, computed tomography scan of the paranasal sinus (PNS) revealed possibly a malignant mass extending into the maxillary sinus and left extraconal space. Surprisingly, histopathological examination and immunohistochemistry from a growth involving the left upper retromolar region that extended up to the midline and periorbital region suggested a diagnosis of GCT. This unusual and new presentation of GCT is not well known to the dentists and also to the ophthalmologists. It is imperative to examine anatomically neighboring structures, especially the eye, nasal cavity, PNSs, and oval cavity among other structures in an underlying pathology in either of these sites. Copyright:

INTRODUCTION

Granular cell tumors (GCTs) are rare benign neoplasms that can involve any part of the body but are common in the head-and-neck region.[1] Orbital GCTs constitute about 3% of all GCT's. GCTs of the eye, orbit, and ocular adnexa are rare but have been described in the periorbital skin and eyelids, extraocular muscles, lacrimal sac, ciliary body, conjunctiva, and caruncle.[2] Rarely, GCT involves the oral cavity with an incidence of approximately 1:1,000,000 population per year.[34] The patient developed an unusual presentation of oral GCT involving the periorbital and infraorbital region. GCT is an entity mostly observed by the oral and maxillofacial surgeons and by the otorhinolaryngologists in their clinics. This novel clinical presentation of oral GCT in the form of a periorbital mass with a primary source of origin in the retromolar region is not well known and makes this case interesting to be reported.

CASE REPORT

A 65-year-old male, farmer by occupation, suffered a blunt trauma to his left upper cheek area and leg with the concrete of the roof of a building in Nepal earthquake on April 25, 2015, following which a progressively increasing nodular mass was noticed by him over the left upper cheek. One year later, he presented with pain in this mass. Six months before his presentation, the skin overlying this nodule ulcerated accompanied by blood-stained discharge from multiple overlying sinus tracts, five in number [Figure 1a]. Redness and purulent discharge started in the left eye (LE) at this time. He was a chronic smoker for the past 40 years and reported difficulty in chewing food. At presentation, best-corrected visual acuity (VA) was 6/60 and 6/9 in the right eye (RE) and LE, respectively. RE was left aphakic following a planned intracapsular cataract surgery performed 10 years back during which no intraocular lens (IOL) implantation was done. LE was pseudophakic with a posterior chamber IOL in situ. RE had a divergent squint of 25 prism diopters. LE had epiphora and conjunctival congestion. The fundus examination of both eyes was normal and so was the intraocular pressure. A well-circumscribed mass measuring 35 mm × 30 mm × 40 mm was seen at the left zygomatic area extending from the lateral canthus posteriorly up to 4 mm in front of the tragus. The mass was tender, hard in consistency, immobile, and nonpulsatile with erythema of the surrounding skin. However, temperature overlying the lesion was not raised with the absence of overlying prominent vessels. LE was displaced upward and inward.

Figure 1

Clinical photographs showing ulceroproliferative lesion in the periorbital region at initial presentation (a); intraoral lesion in the maxillary retromolar region (b) and posttreatment photograph showing reduction in the lesion (c)

Hemoglobin was 10.8 g/dl with an erythrocyte sedimentation rate of 51 mm/h. A possibility of a cold abscess with atypical tubercular/actinomycotic maxillary osteomyelitis was presumed as there were multiple sinus tracts over the ulceroproliferative mass with a relatively longer duration of symptoms, an indolent course of the disease apart from an unconvincing history of trauma. However, the possibility of a posttraumatic osteomyelitis with underlying fungal etiology could not be ruled out.

Radiographs of the orbit and paranasal sinus (PNS) showed a homogenous opacity with sclerotic changes in the region of the left maxillary sinus, zygomatic bone with apparent nonvisualization of part of the lateral wall of the orbit, and zygomatic arch due to infective changes suggestive of chronic osteomyelitis with left maxillary sinusitis. The rest of the visualized bones, joint spaces, and nasal septum were normal.

Pus from the sinus grew methicillin-resistant Staphylococcus aureus on culture. Ziehl–Neelsen staining for acid-fast bacillus (AFB) was negative. There was no evidence of a fungal growth on culture studies. Fine-needle aspiration cytology from the enlarged preauricular and submandibular lymph node (LN) demonstrated reactive lymphadenitis.

Further, a proliferative growth was observed by a maxillofacial surgeon in the left upper alveolar retromolar region in relation to the mandible [Figure 1b]. The growth was extending up to the midline and communicating with the external growth. This prompted a computed tomography (CT) scan of PNS that revealed a large ill-defined heterogeneously enhancing soft-tissue infiltrating, bone-eroding mass lesion (85 mm × 70 mm) destroying the entire lateral wall and lateral half of the floor of the orbit with extensions into the maxillary sinus and left extraconal space suggestive of a malignant pathology [Figure 2a-c]. The greater wing of the sphenoid, zygomatic arch, squamous part of the temporal bone, walls of the maxillary sinus, lamina papyracea, coronoid process of the mandible, orbital floor, and inferior orbital fissure were involved [Figure 2a-c]. A diagnostic workup to rule out a focus of malignancy elsewhere in the body was unremarkable. Possibility of left maxillary sinus carcinoma in stage four could not be denied.

Figure 2

Coronal computed tomography showing a left infraorbital mass (a) causing massive bony destruction and involving the left maxillary sinus (b); extraconal space (c)

Intravenous vancomycin administration based on the antibiotic sensitivity testing yielded an insignificant response. Sputum testing for AFB was unremarkable. Topical antibiotics were continued in LE along with daily cleaning of the wound with betadine solution [Figure 1c].

Meanwhile, a histopathological examination (HPE) of the sinus edge biopsy specimen revealed chronic inflammatory cell infiltrate without any granulomas or evidence of malignancy. Biopsy taken from the left retromolar region demonstrated proliferation of large cells with abundant coarsely granular eosinophilic cytoplasm [Figure 3a-c] that stained positive with periodic acid–Schiff [Figure 3b]. Nuclei were hyperchromatic and eccentrically located with inconspicuous nucleoli [Figure 3a-c]. Immunohistochemistry (IHC) revealed CD68 [Figure 4a] and S100 [Figure 4b] positivity in the large cells suggesting a diagnosis of GCT. Neuron-specific enolase (NSE) staining was weakly positive [Figure 4c]. The immunohistochemical staining for p53 [Figure 4d], epithelial membrane antigen, cytokeratins (CKs) and Ki 67 [Figure 4e] was negative. The patient was not inclined for a surgical debulking of the tumor. As the growth had caused extensive local bony destruction and extended into the surrounding structures, an oncology reference was sought and he was advised treatment with radiotherapy. However, the patient was lost to follow-up after that.

Figure 3

Photomicrograph of tissue section from the left retromolar region showing stratified squamous epithelium with pseudoepitheliomatous hyperplasia (a-c – black arrow). The granules were periodic acid–Schiff positive (b); large granular cells with abundant coarse cytoplasm and round nucleus (a-c – blue arrow) (hematoxylin and eosin stain, ×40)

Figure 4

Immunohistochemistry showing CD68 positivity (a, black arrow); S100 positivity (b, black arrow); neuron-specific enolase weak positivity (c, black arrow); negative p53 nuclear staining (d, black arrow); negative Ki 67 nuclear staining (e, black arrow)

DISCUSSION

Not long ago, GCT or granular cell myoblastoma or myoblastic myoma was classified as a mysterious tumor and interpretation with a proper diagnosis was regarded as a matter of opinion.[3] It may occur at any age, though is most common between 40 and 70 years.[3] Women are affected more commonly than men.[4] The etiology of GCT appears to be unknown. The origin is believed to be from the neural crest/Schwann cells. Immunoreactivity of the granular cells to a wide range of antibodies that are targeted to different tissues limits the histological and genetic characterization of the lesions of GCT. GCTs might also be considered as lesions that demonstrate a local metabolic or reactive change rather than being a true neoplasm.

The tongue is the most common structure involved with GCT and is seen in over 60% of oral GCTs. Other structures involved with GCT in the head-and-neck region include the buccal mucosa, hard palate, lips, and gingiva. GCT is a relatively rare entity with only 16 cases reported over a period of 35 years in a single institution department of oral and maxillofacial surgery. The involvement of the retromolar region is even a rare observation. This gives a pointer to the importance of the clinical presentation of a single case that presents to the dentist or an ophthalmic colleague with an unusual presentation that is a diagnostic dilemma for the clinician as in this patient.

The common ocular manifestations in patients presenting with GCT involving the orbit based on a literature review include diplopia, proptosis, ptosis, limitation in ocular motility, dystopia, and/or a deterioration in the VA.[56] Most of the patients have symptoms that persist for a long time before they report to an eye health-care professional. This patient also presented with deterioration in VA and displacement of the eyeball. In cases manifesting a limitation in ocular motility, involvement of the extraocular muscles (seen in 67.5% of GCTs), primarily the inferior rectus muscle (40.7% of cases), must be considered.[7] The differential diagnosis of orbital neoplasms in patients presenting with rectus muscle involvement includes Graves' disease, rhabdomyosarcoma, hypertrophic myositis, lymphoma, or a hemangioma. Final diagnosis in these cases is established by HPE. GCTs are mostly well delineated and discrete, yet some tumors may be infiltrative and may invade the sclera or surround the optic nerve sheath or mold around the globe.[89]

Computed tomography and magnetic resonance imaging (MRI) alone are unable to differentiate GCTs of the orbit from other benign or malignant orbital neoplasms, and therefore, GCTs are diagnosed based on histological examination of the excised specimen.[10] The rarity of orbital GCT itself comes as a diagnostic challenge for the clinicians and radiologists. Computed tomography performed in a case of GCT shows a mass that appears isodense or slightly hyperdense in comparison to the normal brain parenchyma with minimal to strong enhancement after administration of intravenous contrast. The tumor does not show any calcifications. These features were also observed in our patient, however, there was destruction of adjacent bony tissue due to locally aggressive nature of the atypical variant of the tumor. GCT appears isointense to gray matter on T1-weighted image on MRI and hypointense on T2-weighted image.[10] Cases exist in literature where an intraorbital tumor was misdiagnosed as hemangioma based on CT imaging and MRI and was eventually confirmed as GCT on HPE of the excised specimen.[10] Similar was the clinical scenario in this patient where a final diagnosis was established after histopathology and IHC.

HPE suggests that the lesion is well circumscribed without a true encapsulation.[4] The cells appear polygonal and have cytoplasmic granules.[4] Nuclear and cellular pleomorphism is rarely observed and so is the mitotic activity.[4] The presence of pseudoepitheliomatous hyperplasia of the overlying epithelium is characteristic which may be falsely diagnosed as a squamous cell carcinoma if the histopathology specimen is of a smaller size.[4] Immunohistochemically, the tumor cells are positive for S100 and CD68 in 90% and 66.7% of the cases.[411121314] S100 positivity in the granular cells supports the neural origin of this tumor. Positive stain with CD68 (a macrophage marker) is a result of the intracytoplasmic accumulation of phagolysosomes and does not support a histiocytic origin. The biopsy specimen from the retromolar trigone in this patient revealed positive IHC for S100, CD68, and NSE, and based on the Fanburg-Smith criteria, this variant of GCT could be categorized as atypical.[1516] Histological categorization of GCT into malignant, benign, and atypical was assessed by Fanburg Smith criteria that comprised of six criteria's. These include necrosis, vesicular nuclei with large nucleoli, spindling, increased mitotic activity that was defined as more than two mitoses per ten high-power fields at ×200 magnification, high nuclear-to-cytoplasmic ratio, and pleomorphism. Tumors that demonstrated three or more of the abovementioned criteria were considered malignant. If one or two criteria were fulfilled, the lesion was classified as histologically atypical and a lesion was categorized as histologically benign if it demonstrated only focal pleomorphism with nonfulfillment of the above mentioned criteria.[15] The malignant variant of GCT is extremely rare and is responsible for <2% of all the cases.

The histopathological differential diagnosis for oral lesions relevant to the dentists and maxillofacial surgeons in patients presenting with a mass mimicking GCT includes central granular cell odontogenic tumor (CGCOT), granular cell ameloblastoma, and congenital epulis of the newborn. The cells of CGCOT stain negative for the S100 protein on IHC. Granular cell ameloblastoma, a variant of ameloblastoma has CK immunopositive (S100 protein inconclusive immunoreactivity) granular cells replacing the stellate reticulum-like cells. Congenital epulis of the newborn or congenital granular cell epulis is observed in the alveolar ridges. The tumor cells that constitute the granular cell epulis are immunopositive for vimentin and NSE and are negative for CK or S100 protein.[17]

GCTs elsewhere in the body, especially in the extremities, may resemble ossifying fibroma, central giant cell granuloma, aneurysmal bone cyst, hyperparathyroidism, and other giant cell lesions. Most of these lesions have masses of reactive osteoclast type of giant cells. 1%–2% of histologically benign GCTs can metastasize to distant structures mostly through the hematogenous route.[16] The common sites for metastases are the bones, regional LNs, peripheral nerves, the peritoneal cavity, the breast, and the lung.[1116] Treatment consists of conservative excision which may be followed by radiotherapy for residual tumor.[816] For malignant variant of GCT, a local wide excision remains the standard treatment modality, and the role of chemotherapy and radiotherapy remains uncertain. Moreover, most of the malignant GCTs are refractory to chemotherapy, however, administration of pazopanib followed by radiotherapy and wide surgical excision seems beneficial.[18] Pazopanib, an inhibitor of vascular endothelial growth factor receptor-1, -2 and-3, platelet-derived growth factor receptor-α and-β, and c-kit, has shown activity against soft-tissue sarcomas including GCT as seen in a series of two cases suffering from malignant GCT. This drug proved to be safe and an effective therapeutic agent, but further clinical trials are required to establish its therapeutic efficacy.[18] Radical excision may not be observed in all cases, yet recurrences are rare. The clinical presentation in this patient was unusual, and the extensive bony destruction pointed to a presumptive diagnosis of underlying osteomyelitis. Superimposing infections can make the diagnosis difficult that necessitates the need for thorough clinical examination, imaging, and IHC. Oral cavity examination must be a definitive part of clinical and investigative work-up in a patient with atypical clinical presentations to ophthalmology clinics in circumstances that come with a diagnostic dilemma.

CONCLUSION

In this case, an ulceroproliferative lesion in the periorbital region was obvious, and hence, the primary presentation was to an ophthalmologist, yet some patients without any obvious ocular involvement may visit a maxillofacial surgeon for bad oral hygiene, dental caries, inadequate mouth opening, or nonspecific dental complaints. It is during such circumstances that a growth in the oral cavity might come to notice, especially when it is localized in the retromolar region which is possibly lying asymptomatic for a certain period. Moreover, such lesions of GCT that are atypical may have extensive involvement of the surrounding paranasal sinuses and are subsequently diagnosed based on imaging and histopathology. In conclusion, ocular, sinonasal structures are close neighbors of the structures in the oral cavity. Involvement of one structure by a tumor or infection definitely has clinical implications in the other. This necessitates multidisciplinary management approach. GCT is one such entity that is found in these sites and hence makes evaluation of all surrounding structures indispensable.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

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