Tongue: the unusual site in malignant pleural mesothelioma

Abstract

Malignant mesotheliomas (MMs) are malignancies of the mesothelium, with primary deposits originating in the pleura, peritoneum, pericardium and the tunica vaginalis (ie, testicular). Metastatic spread is commonly reported to affect the liver, adrenal glands, kidney and contralateral lung (in cases of malignant pleural mesothelioma). Metastases to distant sites are uncommon. Spread to the oral cavity in particular is very rare. A total of 23 cases of metastatic spread to the oral cavity have been reported in the literature to date; of those, 9 cases have been to the tongue. Given the rarity of the site of metastasis, the management remains challenging. This case highlights a rare site of metastasis in MM, discusses treatment options available and briefly talks about technical limitations in treating a mobile structure such as the tongue. Good palliative and supportive care is crucial in managing cases where no curative treatment is possible.

Background

Malignant mesotheliomas (MMs) are malignancies of the mesothelium. As they originate from the mesothelium, their primary sites are the pleura, peritoneum, pericardium and the tunica vaginalis (ie, testicular). Of these four sites, the most common primary site is the pleura (accounting for roughly 90%),¹ followed by the peritoneum (reported as 7%–20% of MMs).² MMs originating from the pericardium and testes are rare.³

The most significant risk factor is asbestos exposure, which has been shown to be linked to roughly 70%–80% of cases of MM.⁴ Individuals with germline BRCA1-associated protein 1 (BAP1) mutations have been known to develop malignant pleural mesothelioma without any apparent exposure to asbestos.⁵ There have been several other genetic mutations implicated, with over 50% of the reported mutations that predispose to MM being involved in DNA repair mechanisms.⁶ Finally, simian vacuolating virus 40 has also been suggested to be linked to the development of mesothelioma in animal studies, but as of now this link has not been shown to hold in human epidemiological studies.⁷

Metastatic spread is commonly reported to affect the liver, adrenal glands, kidney and contralateral lung (in cases of malignant pleural mesothelioma).⁸ Metastases to distant sites are uncommon.^{8 9} A total of 23 cases of metastatic spread to the oral cavity have been reported in the literature⁹; of those, 9 cases have been to the tongue.^9–11 This case would be the 10th case reported in the literature to our knowledge.

Histologically, MM can be split into three main subtypes, with variants and much rarer types.¹² Epithelioid type accounts for 50%–70%, and is associated with a better prognosis.¹² On the opposite side of the spectrum is sarcomatoid type, which accounts for 7%–20% of MMs and is associated with the worst prognosis.¹² A biphasic histological subtype is the third major type, which account for roughly 20%–35% of MMs. Other variants include the desmoplastic subtype which looks similar to fibrous pleuritis,¹² with several rarer subtypes also mentioned in the literature.¹² It is necessary to combine immunohistochemical staining to reach a diagnosis of MM as histological slides are not sufficiently specific for mesothelioma.³ Immunohistochemistry patterns are used, as there is no single specific stain for mesothelioma.³

Case presentation

A woman was referred to the local oncology department for consideration of radiotherapy. She had a background of T2 N0 M0 (American Joint Committee on Cancer (AJCC) TNM system 7th edition)¹³ biphasic malignant pleural mesothelioma, which was initially diagnosed in November 2017. She was originally treated with four cycles of carboplatin and pemetrexed chemotherapy as part of the Mesothelioma and Radical Surgery 2 (MARS2) trial,¹⁴ which she completed in March 2018 with stable disease. Unfortunately, she later progressed in early 2020 mainly with skeletal deposits in the shoulder and pelvic muscles, a tongue lesion and right temporal muscle metastases. A subsequent biopsy of the shoulder deposit confirmed metastatic mesothelioma histology. She was rechallenged with carboplatin and pemetrexed in February 2020 and received her final cycle of chemotherapy in May 2020; chemotherapy was then discontinued due to toxicity. She was subsequently referred to her local cancer centre in June 2020 for symptom palliation with radiotherapy.

She had a background medical history of anxiety and depression. Her only regular medication was mirtazapine. She reported allergies to cotrimoxazole, latex, fluarix and orciprenaline.

At presentation to local clinic, she was struggling with pain from the right shoulder skeletal deposit (figure 1), and the tongue deposit (figure 2), but with minimal symptoms from the other sites of metastatic spread. The tongue lesion was reported to have developed in January 2020 and it had slowly grown since then. Although she had a biopsy-proven right shoulder metastatic deposit, it was felt that the tongue deposit should be biopsied for confirmation given the unusual location, prior to local therapy, and so she was referred to the oral and maxillofacial surgery team for review and biopsy.

Figure 1.

One of the shoulder lesions identified as skeletal/subcutaneous metastatic spread.

Figure 2.

Dorsal tongue lesion on oral examination (postbiopsy).

Her tongue biopsy was consistent with features in keeping with metastatic mesothelioma. The CT scan of the head and neck region showed deep tongue involvement by the metastatic lesion (figure 3). It also revealed a further 2.7×1.2 cm enhancing mass which involved the left mylohyoid and the left hyoglossus muscles, with some invasion of the left styloglossus muscle.

Figure 3.

CT neck/thorax slice showing tongue lesion.

Investigations

Blood tests including a full blood count, urea and electrolytes and liver function tests prior to her tongue biopsy were unremarkable.

The CT scan of the head and neck region showed deep tongue involvement by the metastatic lesion. It was reported as a nodular, polypoidal enhancing mass of the left anterior tongue crossing the midline measuring approximately 17×17 mm, with a further large midline component to the mass measuring approximately 2×3 cm which invades the genioglossus muscles and right hyoglossus muscle. The mass extended posteriorly on the right to be closely related to the right retromolar trigone. There was a further 2.7×1.2 cm enhancing mass which involved the left mylohyoid and the left hyoglossus muscles. This mass demonstrated small volume invasion of the left styloglossus muscle.

The tongue biopsy was consistent with features in keeping with metastatic mesothelioma with positive staining for cytokeratin AE1/AE3, CK5 (patchy), CK8, Podoplanin (membranous), EMA (patchy), WT-1 (patchy, nuclear), calretinin (epitheloid component, papillae/lumina) and negative staining for CD15, MNF116, S100, PLAP and CEA.

Differential diagnosis

Essentially, the differential was between a primary benign or malignant aetiology of the head and neck site or metastasis. Given its location it was important to ensure that it was not a squamous cell carcinoma, which is the most common tumour type in the oral cavity,¹⁰ however, it would also be rare as the tumour was on the dorsal surface of the tongue.

As discussed earlier metastatic spread to the tongue is an exceedingly rare event in malignant pleural mesothelioma. However, given the overall clinical picture it was a likely possibility. The diagnosis was confirmed with biopsy and immunohistochemistry.

Other diagnoses which could have been considered would have been a pyogenic granuloma or a granular cell tumour. However, the macroscopic appearance of the lesion was not typical of a pyogenic granuloma. It was also negative for S100 staining.

Treatment

The metastatic right shoulder lesion and lesion on the right temple were treated with palliative radiotherapy (20 Gray over 5 fractions), which greatly eased her symptoms of pain. On follow-up 4 weeks later, she reported grade 3 fatigue (Common Criteria for Adverse Events V.5.0).¹⁵ She was given a 5-day prescription of oral dexamethasone 2 mg once a day to help with these symptoms.

Her case was discussed in the local head and neck multidisciplinary team meeting and different treatment options were considered including surgery under local or general anaesthetic, laser ablation or radiotherapy.

Due to deep tongue involvement, laser ablation and excision were ruled out. Also precluding surgery under local anaesthetic was the patient’s strong gag reflex. General anaesthesia was considered unsuitable due to her frailty and lung disease burden.

Since the patient was reporting only mild discomfort from the tongue metastases and no bleeding, radiotherapy was, therefore, held in reserve should there be deterioration. Although it would have been challenging option due to location of the lesion and difficulty with tongue immobilisation, it was still to be considered given the lack of any other alternatives and keeping in view of the patient’s symptoms.

In addition, it was ensured that she was supported for symptoms management of pain and breathlessness by the community palliative care team.

Outcome and follow-up

The patient was reviewed at 6 weeks following completion of radiotherapy and again at 8 weeks. The option of radiotherapy to the tongue was discussed again but the patient was not keen to proceed and decided to be managed with best supportive care. The purpose of follow-up was to monitor progression and treatment response and also offer supportive care as needed.

Discussion

MM is known to be a highly aggressive cancer with dismal overall 5-year survival rates—6.5% in 2017 in the UK.¹⁶

The standard of treatment for unresectable malignant pleural mesothelioma (which much of the research is based on) revolves around platinum-based chemotherapy (cisplatin/carboplatin) together with pemetrexed, a folate antimetabolite.^{17 18} Radical surgery can be offered if there is a possibility of total resection, however, fewer than 10% of patients are deemed fit for surgical resection.¹⁷ However, overall survival has not been pushed beyond the 2-year mark.⁷ This may in part be due to the fact that there are very few cases in which complete macroscopic and microscopic resection are achieved.⁷ Radiotherapy has been used as both adjuvant and neo-adjuvant treatment, however, usually with palliative intent.¹⁷

The combination of cisplatin and pemetrexed was shown to be superior to cisplatin monotherapy by Vogelzang et al.¹⁸ They demonstrated a 3.3-month survival advantage, and reduced the side effect profile of combination chemotherapy through the use of folate and B₁₂ supplementation (without affecting the survival advantage gained). However, this should be taken in the context of a median overall survival of 13 months in epithelioid variants (the variant with the best prognosis).¹⁸ Standard treatment remained the same for over a decade before the next major breakthrough in the Mesothelioma Avastin Plus Pemetrexed-cisplatin (MAPS) trial by Zalcman et al, who demonstrated an improvement in the overall survival to 18.8 months with the addition of bevacizumab.¹⁹ The side effect profile, however, included much higher rates of hypertension and thromboembolic disease.

Immunotherapy has generated some promising signals in stage I and II trials, but these findings have not been seen in practice.¹⁷ The poor response to immunotherapy is thought to be due to the immunosuppressive environment generated through multiple postulated mechanisms by the tumour microenvironment.²⁰ Despite that, in 2018 the National Comprehensive Cancer Network accepted combined PD-L1 blockade with CTLA-4 inhibition (eg, nivolumab/pembrolizumab+ipilimumab) as salvage therapy.²¹ Very recently, however, the Checkmate 743 trial showed statistically improved overall survival rates with first-line nivolumab and ipilimumab versus standard of care chemotherapy (ie, cisplatin and pemetrexed) in unresectable malignant pleural mesothelioma.²¹ If true, this could represent a new standard of care for patients with unresectable malignant pleural mesothelioma.

Malignant peritoneal mesothelioma is more uncommon than the pleural variant, which is already considered a relatively rare malignancy. As such, many of the findings from malignant pleural mesothelioma have been extrapolated to peritoneal mesothelioma.² Among its features, however, is that it commonly presents with diffuse abdominal disease, rarely metastasising beyond the abdominal cavity.²² The mainstay of treatment is cytoreductive surgery with heated intraperitoneal chemotherapy. Unfortunately, the disease appears to be invariably fatal, either due to abdominal complications secondary to the disease, or due to starvation.²³

Of the 10 published cases of mesothelioma with tongue metastasis, the primary in all but one case was pleural (the other case had peritoneal mesothelioma as a primary).¹¹ Seven of the patients were male, with the remaining three being female. Additionally, the epithelioid subtype was the most common subtype (8 out of 10).¹⁰ In terms of staining with immunohistochemistry, the most commonly reported stains were cytokeratins,¹⁰ however, due to some cases not reporting the outcomes of immunostaining it is difficult to draw any conclusions regarding possible signals from immunohistochemistry. None of these features are out of the ordinary with the characteristics and epidemiology of MM. Management of unusual sites of metastasis such as oral tongue remains a challenge. Every effort should be done to manage these sites with a multidisciplinary team approach and exploring all and every option after diagnostic certainty to provide the patient with the best outcome and minimal morbidity.

Learning points.

• It is imperative to confirm histology of the unusual site of metastasis to exclude common causes.

• Effective symptom palliation and supportive care is crucial in managing cases where no curative treatment is possible.

• A multidisciplinary team approach ensures that a patient benefits from all expertise available.

• Palliative radiotherapy can be considered for symptomatic relief in cases where tongue metastases have developed (although reserved in our case), however, reproducible immobilisation radiotherapy position remains technically challenging.

• This is a rare case that benefits being shared with the wider community for knowledge and experience.