Introduction: Facial pain and numbness is a common symptom with a variety of  causes; rarely, it can be an initial sign of the perineural infiltration of malignant tumors.
Description: Here we have reported three challenging cases, all presenting with  pain and numbness of the cheek as the primary symptoms. Upon referral, there were  neither signs of severe illness nor information about previous malignant diseases, while  the diagnostic work-ups revealed additional involvement of the facial nerve in two  of the cases. Surgical removal of the perineural tissue around the infraorbital nerve  revealed perineural invasion by a squamous carcinoma. A more thorough review of  their medical histories revealed that all three of the patients had had previous facial  skin cancer. 
Conclusion: Numbness or pain in the cheek may represent perineural invasion of  a facial cutaneous carcinoma. These cases address the necessity of identifying previous  incidences of skin cancer in the medical history.

• Squamous cell carcinoma

• Skin neoplasm

• Facial pain

• Perineural invasion

• Squamous cell carcinoma

Okholm C, Frendø M, Kiss K, Von Buchwald C (2016) Numbness of the Cheek Caused by Perineural Invasion of the Infraorbital Nerve: A Review of Three Diagnostically Challenging Cases. Ann Otolaryngol Rhinol 3(10): 1137.

Facial pain, paresthesia, and motor deficits are commonly encountered in clinical practice, and can be caused by a variety of diseases [1,2].

The main causes of facial pain are dental problems and sinusitis [3], while other causes include temporomandibular joint disorders, trigeminal neuralgia, migraines, and post-herpetic neuralgia. The variety of causes makes this condition a diagnostic challenge; therefore, care is needed when diagnosing patients presenting with numbness of the face. Rarely, it can be the sole sign of malignancy.

Perineural invasion (PNI) has been observed in less than five percent of patients with cutaneous carcinoma, but the diagnosis is often delayed [1,4]. Here we present three challenging cases presenting with facial pain and numbness. The diagnostic workups revealed that the lesions were caused by the spread of a tumor from previous facial skin cancer.

Case 1

An 86-year-old female was referred to our clinic with a history of six months of numbness and pain in the right cheek, and chronic sinusitis was suspected. The ear, nose, and throat (ENT) examination did not reveal any abnormalities; therefore, a magnetic resonance imaging (MRI) scan was performed, showing a solid process in the right maxillary sinus in relation to the infraorbital nerve Figure (1A).

Figure 1a: Case 1. Coronal CT of the sinuses used for image guidance during endoscopic surgery. A pedunculated tumor attached to the floor of the orbit in the right maxillary sinus is demonstrated.

The tumor was removed via endonasal endoscopic surgery Figure (1B).

Figure 1b: Case 1. The perioperative endoscopic image (see cross hair in Figure 1A) showing a tumor above the viewing wand placed in the right maxillary sinus.

The histology showed a well-differentiated squamous cell carcinoma (SCC) invading the infraorbital nerve and anterior wall of the maxillary sinus. An extensive review of her medical history revealed a welldifferentiated SCC on the right cheek, diagnosed from a biopsy 15 months earlier. The biopsy was not suitable for assessment of margins or spread of cancer cells, however, no perineural invasion was found in the biopsy. The follow-up of the SCC at the dermatologist nine months later was ended due to a negative control biopsy. At the time of her referral to the ENT department, there was no evidence of recurrence of the facial skin cancer upon clinical examination. After sinus surgery, she completed radiation therapy of the right cheek and maxillary sinus. At the clinical control three months after the surgery, there was no sign of recurrence.

Case 2

A 58-year-old male was admitted to the neurological department due to pain, numbness, and minor facial palsy of the right cheek, which had been going on for four months. An MRI showed pathological enlargement of the infraorbital nerve. The patient was referred to the ENT department, and the tissue around the nerve was resected from the right maxillary sinus via the Caldwell-Luc procedure. The histology showed an SCC invading the infraorbital nerve Figure (2).

Figure 2: Case 2. Perineural invasion of the infraorbital nerve visualized by immunohistochemical staining for Cytokeratin 5. Arrows indicate the squamous cell carcinoma. Original magnification x 200.

The patient’s history was discussed at a multidisciplinary meeting. After addressing the patient’s medical history, it became evident that he had been treated five times within the last 12 years for recurrent basal cell carcinoma (BCC) and actinic keratosis in the right temporal area, either by curettage or excision. A positron emission tomography and computed tomography scan (PET/ CT) did not reveal any primary tumor. Subsequently, the patient underwent Caldwell-Luc surgery, where the infraorbital nerve was removed up to the infraorbital foramen, including the bone and mucosal membrane in the maxillary sinus. Due to the nonradical resection, the patient underwent additional radiation therapy. Despite radiation therapy, the symptoms progressed with increased numbness of the right facial side, partial facial palsy, tinnitus, and right hearing loss. A follow-up MRI showed metastasis in the right cerebellopontine angle, which was treated with stereotactic radio surgery. Fifteen months after the referral to the ENT department, the patient became psychotic, and an MRI showed a tumor in the frontal lobe of the brain. He was referred for palliative treatment, and died of advanced cancer 18 months after the onset of symptoms.

Case 3

A 78-year-old male presented to our clinic with severe left facial pain, paresthesia, and hypoesthesia of the left cheek. Prior to the referral, he had been treated for atypical headaches in the neurological department, and evaluated with an MRI scan, PET/CT scan, and lumbar puncture. The MRI showed a process between the hard and soft palate. The patient’s symptoms were discussed at a multidisciplinary meeting where neurosurgeons, otolaryngologist and head and neck oncologists were present. The suspected tumor area in the palate was surgically removed, and the histology showed a benign lesion of fibrous and salivary tissue. Five months later, the patient presented with progressive left sided numbness of all three trigeminal branches, and partial ipsilateral facial nerve paresis. Another MRI showed the progression of the pathological process, extending from the maxillary nerve into the cavernous sinus and medial cranial fossa, and retrograde perineural invasion was suspected. Concurrently, the patient was treated for a recurrent actinic keratosis, later found to be an SCC, on the left side of his nose in the plastic surgery department. A deep submucosal biopsy from the infraorbital nerve showed a moderately differentiated SCC invasion (Figure 3).

Figure 3: Case 3. Neural invasion of the SCC. Arrows indicate the tumor, arrowheads the spindle-shaped nerve cells. H&E staining. Original magnification x 100.

Subsequently, the patient underwent radiation therapy of the skull base and the posterior wall of the maxillary sinus. Currently, six months after radiation therapy, the patient still requires rehabilitation due to several comorbidities

We have presented three cases of hypoesthesia or pain in the cheek caused by the spread of facial skin cancer. In Denmark (population 5.6 million), non-melanoma skin cancer is diagnosed in more than 13,000 patients every year, and the age at diagnosis is usually older than 65 years [5]. It develops on sun-exposed sites, such as the head and neck, and is frequently treated with curettage [6]. It is often considered to be an indolent disease, and might not be mentioned in the patient’s medical history, which can lead to diagnostic challenges and delays in treatment.

In the first case, the patient had had a biopsy-proven SCC in an ulcer on the right cheek; however, the dermatologist ended the follow-up due to a negative follow-up biopsy. A thorough examination of her skin showed no other lesions and the patient did not present with any other symptoms suggestive of a different primary tumor. Yet, the MRI scan showed no connection to the site of her prior skin SCC and no additional abnormalities. However, it is impossible to conclude that the patient did not have a new primary tumor, not detected by our diagnostic work-up. Possibly, the lesion was not adequately removed in the first place. The second patient had multiple recurrences of BCCs and actinic keratosis, mainly treated with curettage; nevertheless, an SCC was found invading the nerve. Despite the thorough diagnostic work-up including two PET-CT scans, we were unable to detect any other primary tumor. Since a new primary tumor was ruled out, we conclude that some of the actinic keratosis, treated only by curettage, must have been SCC.

The possibility of the spread and progression of a lesion diagnosed as pre-cancerous actinic keratosis, as demonstrated by the second and third case presented here, is a well-known complication [7]. Curettage is known to carry a significantly higher risk of recurrence when compared with excision; therefore, it has been suggested that curettage should not be used for recurrent tumors [8]. Fragmented curettage material, in which the relationship to the surrounding stroma has not been properly visualized, is a diagnostic challenge, and can lead to misdiagnoses, such as the under-diagnosis of highly differentiated SCC.

The pathogenesis of PNI has not been fully elucidated. Recent theories suggest that a cleavage plane between the perineurium and the nerve fiber provide a path of lessened mechanical resistance, allowing cancer cells to spread [1]. Furthermore, it has been suggested that some SCCs have a predilection for PNI; those being the highly aggressive tumors leading rapid and invasive growth [9].

PNI occurs in 3–14% of skin SCCs, which is more frequent than in BCCs. The initial symptoms are comprised of pain, numbness, and/or motor deficits. Most frequently, it involves the fifth and seventh cranial nerves [10]. Moreover, PNIs can be classified as either incidental or clinical [1,2]. An incidental PNI refers to the asymptomatic stage, in which only microscopic invasion is present. In one previous review, approximately 60–70% of the patients with PNIs were asymptomatic [1]. The symptomatic stage, when a patient presents with sensory or motor changes, is categorized as a clinical PNI; however, these symptoms can often be misinterpreted, leading to a delay in the diagnosis. A clinical PNI is relevant for prognostication since the local control rate is observed to be only 55 %; furthermore, a clinical PNI exhibits more aggressive behavior, as observed in these three cases [11,12]. Recently, the 7th edition of the American Joint Committee on Cancer staging system for cutaneous skin cancers was updated, determining PNIs to be a high-risk features [13].

The treatment of a PNI depends on the type and location. In one recent study, the best treatment strategy for a clinical PNI was suggested to be surgical resection and adjuvant radiotherapy [14]. In Denmark, a PNI is considered to be a high-risk feature requiring surgical removal with a resection margin of at least six millimeters, and in selected cases, adjuvant radiotherapy [15]

Facial numbness and/or pain are common clinical symptoms, rarely caused by malignancy. However, common cutaneous SCC should be kept in mind, especially for otolaryngologists, when evaluating elderly patients with signs of facial numbness and pain, and a history of skin carcinoma.

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