A 79-year-old man with a history of radical excision of a left submandibular gland carcinoma ex-pleomorphic adenoma presented with a new 2 cm lump in his left submandibular region which proved to be recurrence on surgical excision. During work up for revision surgery he developed a right VI cranial nerve palsy, which was attributed to his microvascular status having had a history of three previous transient ischemic attacks (TIAs). 6 months later, his palsy had not resolved. MRI revealed new soft tissue by the cavernous segment of the internal carotid artery. The exact source of this was unclear as there was no evidence of local recurrence or nodal disease. A repeat MRI scan 16 months later revealed further growth of abnormal tissue in the cavernous sinus and the primary submandibular location, now involving multiple nerves including branches of cranial nerves IV, V, VI, VII and XII making surgical excision impossible.
- ear, nose and throat/otolaryngology
- head and neck cancer
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Carcinoma ex-pleomorphic adenoma (Ca-ex-PA) is an uncommon diagnosis constituting around 5% of all salivary tumours and around 10% of all salivary malignancies.1 2 Most of these arise from the parotid gland, so Ca-ex-PA arising from the submandibular gland is even more unusual.1–3 Ca-ex-PA is a malignant epithelial and/or myoepithelial tumour derived from a pleomorphic adenoma and often presents clinically as a fast growth in a pre-existing pleomorphic adenoma.4 The histological appearances of Ca-ex-PA vary greatly with different proportions of residual benign pleomorphic adenoma and of a malignant component. The malignant component should be determined histologically; many are high-grade adenocarcinomas. The malignant component may be confined within the gland (intracapsular carcinoma), or may be minimally or widely invasive (figures 1 and 2).4 Ca-ex-Pa is aggressive, although intracapsular and minimally invasive carcinoma are considered to be less so. For those that go on to metastasise, long-term survival is poor.2 5 6 Recurrence of the tumour once excised is also a major predictive factor of poor prognosis.7 Other factors that also predict a poor prognosis include high tumour grade and stage, widely invasive tumours/extraglandular extension and vascular and perineural involvement (figure 3).2 5 6 8 9 The presence of these factors can potentially shorten lifespan from 5–10 years to less than 1 year. As such, early diagnosis of recurrence of these tumours could be very important in a clinical setting.
Diplopia is the medical term for double vision and has a wide range of possible pathologies, from corneal issues and ocular motility problems to severe central nervous or neuromuscular disease.10 The initial approach to the assessment of diplopia should be whether the double vision is present in only one eye (mononocular diplopia; a medial or cortical issue and debatably not true diplopia) or both eyes (binocular diplopia; an ocular motility and/or central problem) by covering each eye independently. Once binocular diplopia has been confirmed, it must be determined if the image pair is separated horizontally or vertically as that helps pinpoint the weak link in the visual pathway.11 If the diplopia is due to an ocular motility issue, once the particular muscle involved is identified a cause can then be determined. This could be due to any of a wide range of diagnoses including central vascular events (transient ischemic attack (TIA) or stroke), myasthaenia gravis, thyroid eye disease, Miller-Fisher syndrome or a brain tumour.11–13 New diplopia is a reason for urgent referral to acute ophthalmology services, especially if symptoms are sudden onset in nature.14
A 79-year-old man presented to ears, nose and throat (ENT) clinic with a lump in his left neck. This was proven to be a pT2, N0, M0 left submandibular Ca-ex-PA and was managed with submandibular gland excision and selective neck node dissection; 18 lymph nodes were removed from levels I, II and III. This was supposed to be followed by postoperative radiotherapy following head and neck multidisciplinary team (MDT) meeting. Unfortunately, he was unable to tolerate the radiotherapy treatment mask and so this was abandoned.
Five months later, he attended the head and neck oncology clinic complaining of a lump in his left neck which was highly suspicious of recurrence. Following MDT discussion MRI neck and fine needle aspiration cytology (FNA) were performed. Cytopathology reported carcinomatous soft tissue, but was unclear as to whether this was a piece of submandibular tissue or metastatic lymph node tissue.
While our patient was being worked up for revision surgery, he was seen in the ophthalmology department complaining of double vision. The history was of sudden onset double vision, which had warranted same day referral to ophthalmology. Visual acuity was good at 6/6 and 6/5-, and on examination a right sixth cranial nerve palsy was noted.
In addition, he also had a relevant history of note of three previous TIAs and Samter’s Triad, having had 11 nasal polypectomies in the past. Given the background and clinical presentation, his diplopia was felt to be more likely due to a microvascular event and he was listed for review by orthoptics 4 weeks later and ophthalmological review in 6 months, although he was also advised to re-contact the ophthalmology department if his symptoms worsened in the interim period.
On ophthalmological review 6 months later the diplopia was no better. In the meantime, after further MDT discussion and counselling with the patient we proceeded to further head and neck surgery (revision submandibular clearance, mandibulotomy, trachesotomy and radial forearm flap) for the submandibular lump, from which he recovered well.
Following surgery and after MDT discussion a further imaging was requested (MRI head) to exclude a space-occupying lesion, and this revealed a new enhancing lesion in the cavernous sinus on the right encasing the carotid artery. Due to its contra-lateral location and lack of any other evidence of local or regional recurrence, there was some doubt as to whether this was Ca-ex-PA metastasis or other possible diagnosis including pathology related to his Samter’s triad (chronic rhinosinusitis and nasal polyps with an increased risk of malignant potential).15–17 Other differential diagnoses included other malignant metastases and primary cavernous sinus tumour.
A further MRI head was requested 4 months later, which showed increased growth of the enhancing cells in the cavernous sinus, and expansion into multiple cranial nerves and through many parts of the skull base. There was also some increased enhancement in a 3 cm2 lump in the submandibular space. These images revealed it was likely the same process affecting both areas. No other primary cause of diplopia was found in our patient and the radiological features of bone erosion were felt to be strongly suspicious of metastasis from our only identified primary lesion (Ca-ex-PA) by the MDT. Unfortunately, due to disease progression we were unable to confirm our clinical suspicion with biopsy.
The initial pathology report from the histology samples sent after the first surgery stated the tumour was a high grade Ca-ex-PA pT2, N0, with no evidence of metastatic tumour in any of the 18 lymph nodes excised. The tumour did however extend >11 mm beyond the gland itself and featured neural and vascular invasion, features associated with increased metastatic and recurrence potential2 5 9; hence postoperative radiotherapy was advised. The pathology report after the revision surgery confirmed that the secondary lump in the neck was indeed recurrent Ca-ex-PA.
Our patient had several MRIs of his neck (figures 4 and 5), monitoring growth of the primary site of the tumour, but it wasn’t until 6 months after he developed the 6th cranial nerve (CNVI) palsy that an MRI of his head was performed, displaying the possible site of metastasis. It also wasn’t until the MRI was viewed by specialist head and neck radiologists at an MDT meeting that the subtle abnormality was identified.
Initial diagnosis of the CNVI palsy was of simple microvascular damage or a TIA. Due to the lack of any metastasis evidenced in the lymph nodes excised and the actual location of the tissue, relation to the cancer was felt to be unlikely. After the MRI showed an area of enhancement in the cavernous sinus, there was some questions as to whether this was a nasopharyngeal or sinus growth due to the diffuse benign growths present from his chronic rhino sinusitis with nasal polyps. However, he was referred to ENT and rhinoscopy did not show changes in keeping with a neoplastic or invasive process.
Due to the tumour location, size and neurovascular involvement, curative treatment intent with surgery or chemo/radiotherapy is not possible with a high risk of side effects. His diplopia was being managed with a patch over his right eye.
Outcome and follow-up
Our patient has been discharged from the care of oral maxillo facial surgery (OMFS) and ENT. Ophthalmology continues to review him; although he was comfortable with his right eye occluded, botox therapy is an option if required. He had been referred to palliative care, and their input may become very important in the near future.
This case in particular highlights the diagnostic difficulty at the overlap of the remits of maxillofacial surgery, ENT and ophthalmology despite multidisciplinary input.
Given the complexity of the structures in the head and neck that can affect diplopia it is understandable about the diagnostic uncertainty in this case. Ischaemia and malignancy are the most common causes in an atraumatic history,12 13 and with our patient’s history of three previous TIAs, ischaemia is certainly feasible. Also, a cavernous sinus lesion is certainly unlikely to have come from a contra-lateral submandibular gland, and most commonly would have come from a malignant sinonasal primary or transformation or even metastases from a separate neoplastic processes in the kidney, stomach, thyroid, lung or breast.18 Samter’s triad is a collection of the symptoms of chronic rhinosinusitis, nasal polyposis and aspirin intolerance. Malignant transformations in nasal polyposis are rare.19–21
To our knowledge this presentation of diplopia from CNVI palsy likely secondary to regional recurrence of submandibular Ca-ex-PA is unique and not published elsewhere in the literature. A similar case was reported in 201022 where there was direct invasion to the cavernous sinus but that was an intraoral tumour of a minor salivary gland and it was into the ipsilateral sinus. Whether our case represents metastasis or local invasion via the path of the carotid artery or one of the nerves in the head and neck is unclear; however, there is some evidence that despite negative lymph nodes on pathological examination, there can be evidence of positive lymph nodes on radiology or micrometastatic disease undetected at time of surgery, so as to whether our patient had truly negative lymph nodes is a point of difficulty.23 This evidence is supported in similar head and neck tumours and shows that traditional intraoperative lymph node sampling is a poor predictor of true nodal disease.24 25 There are also no reported cases in the literature of Ca-ex-PA with node negative necks as well as distant metastases.
The patient also was not able to tolerate postoperative radiotherapy, as he would have undergone as per oncological guidelines,26 which would have decreased his risks of both recurrence and metastasis and should always be recommended to patients fitting the criteria stated in the national head and neck guidelines.
Carcinoma ex-pleomorphic adenoma constitutes ~10% of malignant salivary gland tumours. They arise from benign tumours and have varying degrees of differentiation and aggressive nature.
Postoperative chemo-radiotherapy following surgical resection of such lesions is vitally important to manage micrometastatic disease if it can be tolerated by the patient.
In patients with evidence of tumour recurrence shortly after primary surgery (in our case 5 months) screening for distant metastases is advised before further surgical excision.
Further diagnostic procedures, surgical excision or salvage surgery should only be undertaken after multidisciplinary team discussion.
High index of suspicion should be used through a head and neck multidisciplinary approach for any subsequent symptoms (diplopia) for these patients, even if on the contra-lateral side and multiple confounding benign factors (TIA/polyps) due to their aggressive nature.
Contributors DM analysed the case with case notes, investigations and drafted the case report. ASJF helped with analysis, drafting, interpretation and revisions of the report. SW contributed expert opinion and revisions with specific histopathology scope. JM contributed conception of design of report, revision and final approval of version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Obtained.