Rare case of p16-positive oropharyngeal cancer metastasis to the orbit

Abstract

We describe a case of a man in his 70s who was diagnosed with a p16-positive base of tongue squamous cell carcinoma (SCC) and presented with deteriorating vision and exophthalmos. Imaging revealed medial rectus hypertrophy, and surgery confirmed metastatic p16-positive SCC. Literature reveals that orbital metastasis from any malignancy is a rare occurrence, and even that of p16-positive oropharyngeal SCC has only been reported once in English literature previously. The case highlights the importance of maintaining a wide differential and not being narrowed into a diagnosis or treatment, and given the increasing incidence of human papillomavirus-related cancers, it is important to preserve a high index of suspicion.

Background

Orbital metastases are rare, and the presentation varies depending on the underlying pathology.¹ Often, a diagnosis can be unexpected, despite current screening techniques and definitive treatment.²

Head and neck squamous cell carcinomas (SCC) metastasise through lymphatic channels through the cervical lymph nodes, with haematogenous spread occurring in only 10% of distant metastases.² Human papillomavirus (HPV)-associated head and neck cancer has been increasing in prevalence, and treatment algorithms are still being adjusted as the oncological behaviour appears to be different.³

The most common sites for SCC metastasis from head and neck cancers are the lungs, liver and skin.⁴ Orbital or medial rectus metastasis is rare, and to the best of our knowledge, this is the only reported case in English literature of p16-positive orbital metastasis. The following article will discuss clinical and radiological findings and the surgical management of the case.

Case presentation

A man in his 70s was admitted for a small bowel obstruction due to adhesions. While he was recovering, he acutely began having worsening right eye proptosis and ophthalmoplegia.

His medical history included a T4aN2M0 p16-positive right base of tongue SCC diagnosed in 2021 that was treated with cetuximab and concurrent 70 Gy radiation that had a complete response. The patient completed all treatment in February 2022 and was being closely followed up by the ear, nose and throat (ENT) and radiation oncology departments. His surveillance imaging, which included an MRI and CT-positron emission tomography (PET) done 1-month post-treatment showed complete resolution of his cancer.

He also had a history of stage IV chronic kidney disease, hypercholesterolaemia and hypertension. He was independent in his activities.

During his admission, he was referred to the ophthalmologist and was thought to have antibody-negative thyroid eye disease associated with Graves. He was given pulse methylprednisolone with minimal symptom improvement.

His initial examination by the ophthalmologist showed a Snellen’s vision rating of 6/24 pinholing to 6/15 unaided and 6/30 pinholing to 6/24 in the left and right eyes, respectively. There was visible proptosis, myopic fundi and bilateral nuclear sclerotic nuclear cataract. On examination, there was some gaze limitation on supraduction and infraduction. His conjunctiva was inflamed and injected with a mild chemosis of the inferior eyelid. Intraocular pressures were normal, and colour vision was normal with corneal sensation intact.

With the worsening of the proptosis despite treatment, he was transferred to a tertiary centre with endoscopic sinus, orbital and skull base expertise for consideration of orbital decompression and biopsy. The steroids were withheld prior to the transfer to yield the best results from the biopsy.

Investigations

Thyroid function tests revealed subclinical hyperthyroidism with a reduced thyroid stimulating hormone (TSH) of 0.15 IU/L and a reduced thyroxine (T4) of 6. Antithyroglobulin antibodies, thyroid peroxidase antibodies and TSH receptor antibodies were all negative.

Other biochemical workups, including the hepatitis B and C antibody panels, extractable nuclear antigen, IgG subclasses, c-antineutrophil cytoplasmic antibodies (ANCA) and p-ANCA, were all normal. The antinuclear antibody was mildly elevated at 30.

A CT scan revealed bilateral proptosis, with the right eye worse than the left; however, clinically, the left eye appeared normal. In the right orbit, there was perimuscular intraorbital fat stranding and muscle thickening. There were also associated radiological findings of sinusitis, although flexible nasoendoscopy did not show any mucopus or polyps (figures 1 and 2).

Figure 1.

Axial CT head demonstrating proptosis of the right eye.

Figure 2.

Coronal CT head demonstrating sinusitis with inflamed right extraocular muscles.

An MRI revealed enlargement and thickening of all the extraocular muscles in the right orbit. There was also infraorbital fat induration; the right globe was proptosed and deformed. There was enhancement of the pterygomaxillary fissure bilaterally and extension into the right pterygopalatine fossa. No overt mass was seen (figure 3).

Figure 3.

Axial MRI T1-weighted image with inflammation of the right orbit with no obvious masses.

He also had a routine PET fluorodeoxyglucose (FDG) scan performed as surveillance for his oropharyngeal cancer. There were widespread focal lesions in the skeleton, skeletal muscle and bowel that were already noted in the PET scan 3 months prior, but they have increased in number and extent, which was considered an unusual pattern for metastatic disease and may have been disseminated histiocytosis or widespread granulomatous change. It was important to know there was no ocular avidity.

Differential diagnosis

Thyroid eye disease was initially presumed due to the initial MRI findings of thickening of the extraocular muscles, with the medial rectus being the most affected. There was no discrete mass in any of the imaging performed. The treatment was started for presumed thyroid orbitopathy with 75 mg of prednisolone and consulted by immunology. However, as his proptosis worsened despite the steroids, it was thought another pathology was driving the presentation. Furthermore, given that the pathology was unilateral, the diagnosis of thyroid orbitopathy was less likely.

Orbital pseudotumor was postulated given that there was no response to steroids and there was involvement of the extraocular muscles. However, a tissue diagnosis was required to confirm.

Clinically, due to the scleral injection and chemosis of the inferior eyelid, orbital cellulitis was a consideration. Due to the lack of periorbital oedema and erythema, as well as pain, the diagnosis was less likely. He was also given a course of intravenous antibiotics, which did not improve his symptoms.

Eventually, when the patient was transferred for ENT input on orbital decompression, the thought was that the underlying pathology was due to a potential orbital metastasis. However, there was no occult mass found on imaging, and there was no FDG avid activity on the PET scan, making the diagnosis less likely.

Treatment

He underwent bilateral sinus surgery and right endoscopic orbital decompression. As seen in figure 4, the right lamina papyracea was removed, and periorbital fat was retracted and partially excised to expose the medial rectus muscle. Multiple biopsies were taken from the thickened medial rectus muscle as well as the middle turbinate.

Figure 4.

Endoscopic view of the right medial rectus.

The biopsies returned tissue containing stromal and intravascular deposits of differentiated metastatic squamous cell carcinoma. There was no significant cytoplasmic vacuolisation or nuclear creation. The sample was p16 positive.

Outcome and follow-up

The patient’s case was discussed at the multidisciplinary team meeting for head and neck cancer. It was a joint decision that he would pursue palliative radiotherapy for the right orbit and spinal mets. He was started on pembrolizumab and carboplatin or 5-fluorouracil following the completion of radiation targeted at the orbit. He unfortunately passed away after 80 days following the procedure.

Discussion

Orbital metastasis is a rare presentation that was first described by Horner in 1864.⁵ Other sources of orbital metastasis include renal cell carcinoma,⁶ breast cancer, melanoma⁷ and hepatocellular carcinoma.⁸ With breast cancer being the most prevalent.⁷

Orbitopathies can be a challenging diagnostic dilemma without clear systemic symptoms. A combination of imaging, relevant blood and potential tissue diagnosis will assist in the final diagnosis.⁹ Commonly, as in this case, thyroid eye disease can be misdiagnosed for other orbitopathies. Clinically, the symptoms associated with thyroid-associated eye disease include proptosis, chemosis, restricted eye movements and diplopia.⁹ Radiologically, extraocular muscle enlargement specifically medial and inferior rectus first with sparing of the tendons.¹⁰ Muscle involvement is generally bilateral, with multiple muscle groups involved. If any of these features are atypical of thyroid eye disease, then other conditions should be considered, such as inflammatory, vascular, infectious or neoplastic.

Primary orbital tumours that involve extraocular muscles that can mimic thyroid eye disease are also exceedingly rare. Tumours including hamartomas, granular cell orbital tumours, rhabdomyosarcomas and liposarcomas have been described.¹¹ Metastasis from distant sites can present as individual or multiple masses involving the extraocular muscles, orbital fat, globe or bony orbit, and a majority of patients already have been diagnosed with the primary malignancy at the time of presentation.¹² Symptoms can also mimic orbital cellulitis.

The aforementioned patient did not present with symptoms consistent with systemic Graves or overt hyperthyroidism. Second, although imaging was somewhat congruent with thyroid eye disease, there were no distinct masses found on imaging, and the radiological suggestion was that there was an inflammatory pathology that was occurring. Given the mixed clinical picture and poor response to treatment for presumed thyroid eye disease, the next and immediate step was a tissue diagnosis, and given the medial rectus muscle was the most affected, a decompression and biopsy were opted for. This eventually yielded the results that were required.

Despite the declining rates of smoking and chewing tobacco, there has been a growing incidence of HPV-associated oropharyngeal cancer, which makes up 60%–80% of oropharyngeal cancers.¹³ With a relative paucity of research, new data suggests that HPV status is a strong indicator of prognosis. HPV-related oropharyngeal cancers require more sensitive radiotherapy and experience lower rates of local recurrence.¹⁴ Despite this, both non-HPV-related oropharyngeal cancer and HPV-related cancer have similar rates of metastasis. Treatment protocols and algorithms are being adjusted as this form of cancer appears to behave differently from the traditional form of head and neck squamous cell carcinoma. This case demonstrates that recurrence or metastatic disease may occur differently as well, and further research is needed in this area.¹⁵

The management of orbital metastasis is complex and requires a multidisciplinary approach using a combination of chemotherapy, radiotherapy and occasionally surgery. Given the aggressiveness of the tumour, palliative radiotherapy may be used to achieve symptom control.

Orbital metastasis from an oropharyngeal primary is exceedingly rare. Due to the limited literature on this, it is difficult to categorise the ‘classic’ clinical picture for orbital oropharyngeal cancer metastasis. Further literature can assist in clearly defining both clinical manifestations, management and radiological findings.

Learning points.

• When dealing with a unilateral orbitopathy, it is important to have a broad range of differential diagnoses, including inflammatory, infective and malignant, and to revisit them if the treatment response is suboptimal.

• Tissue sampling can be helpful when there are doubts about the diagnosis.

• With the increasing trend of p16-positive oropharyngeal carcinoma and knowledge about this condition, it is an important differential to consider when managing possible orbital metastasis.

• Having good communication and teamwork with various disciplines, such as ophthalmology, immunology, endocrinology and otolaryngology, is crucial.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.