Squamous cell carcinoma of the tongue with cardiac metastasis on 18F-FDG PET/CT

Abstract Introduction: The most common malignancies metastasizing to the heart are cancers of the lung, breast, mesothelioma, melanoma, leukemia, and lymphoma. Cardiac metastasis from a tongue cancer is a rare finding and only a few cases have been reported previously in the literature. In this case report and literature review, we discuss the main clinical features of patients with cardiac metastases secondary to a tongue cancer and imaging modalities performed, especially the 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Patient concerns: This is a case of a 39-year-old woman who in April 2018 was diagnosed with an invasive well differentiated squamous cell carcinoma of the movable tongue. She underwent a left hemiglossectomy followed by a revision of hemiglossectomy and ipsilateral selective neck lymph nodes dissection levels II to III because of pathological margins. An early inoperable clinical recurrence was diagnosed and she received radiochemotherapy with good clinical and metabolic response. She remained asymptomatic thereafter. Diagnosis: In January 2020, a pre-scheduled 18F-FDG PET/CT showed a diffuse cardiac involvement. In February 2020, a biopsy of the lesion revealed a metastatic squamous cell carcinoma. Interventions: She was deemed to not be a cardiac surgical candidate and treated by palliative chemotherapy: taxol-carboplatin associated with cetuximab then cetuximab alone because of adverse effects. A re-evaluation imaging performed in April 2020 evidenced a progression of the cardiac involvement, which led to switch chemotherapy by immunotherapy with nivolumab. Outcomes: This patient had a very poor prognosis and succumbed to major heart failure 4 months after the diagnosis of cardiac metastasis. Conclusion: In this case report, 18F-FDG PET/CT proved to be useful in detecting cardiac metastasis and changed the therapeutic management of the patient. It suggests that patients with tongue malignancies in a context of poor initial prognosis should be followed-up early by 18F-FDG PET/CT with HFLC diet to facilitate detection of recurrence.


Introduction
Oral cancer is the 6th most common cancer in the world, [1] with 9 out of 10 being oral squamous cell carcinomas (OSCCs). [2,3] The most important risk factors for OSCCs are use of tobacco and the regular drinking of alcoholic beverages. In addition, infection with high-risk human papillomavirus (HPV) genotypes is associated with the aetiopathogenesis of OSCCs. [4] These cancers are rare before age 40, but the frequency in this age group tends to increase. One of the commonest sites of OSCCs is tongue with 25% to 40% of the occurrences. [5] Compared to other OSCCs, metastatic spread of tongue cancer is facilitated by its rich lymphatic network resulting in an adverse impact on prognosis. [5] Secondary involvement of the heart appears to be extremely rare. There are only very few reports of this atypical complication in the literature because patients are often asymptomatic.
We present here the case of a young female diagnosed with squamous cell carcinoma of the tongue which recurrence has been principally revealed by cardiac metastasis.

Case presentation
A 39-year-old woman with a 3 pack-year smoking history was initially diagnosed in April 2018 with an invasive welldifferentiated squamous cell carcinoma of the movable tongue. An initial staging 18 F-Fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) showed an isolated moderately hypermetabolic focus on the left side of the tongue (SUV max 6.2). She underwent a left hemiglossectomy in May 2018 followed by a revision of hemiglossectomy and ipsilateral selective neck lymph nodes dissection levels II to III in October 2018 because of pathological margins. The final histological results were persistent in situ carcinoma in the tongue with complete resection and metastatic carcinoma in one lymph node on the 40 analyzed lymph nodes. Therefore, this tongue carcinoma was finally classified pT2pN1M0 and no adjuvant therapy was undertaken.
Two months later, an early clinical recurrence was diagnosed following severe tongue pain. A restaging 18 F-FDG PET/CT showed an intensely hypermetabolic focus along the left side of the tongue (SUV max 16.6) and a mildly hypermetabolic left retropharyngeal lymph node (SUV max 4.0) with no evidence of distant metastasis. The patient received chemotherapy by taxolcarboplatin then cisplatin followed by external radiochemotherapy from January 2019 to March 2019 with good clinical and metabolic response. She remained asymptomatic thereafter.
In January 2020, a pre-planned 18 F-FDG PET/CT, with High-Fat and Low-Carbohydrate (HFLC) dietary preparation included to explore electrocardiogram (ECG) abnormalities of recent onset, revealed an intensely hypermetabolic myocardial focus (SUV max 7.1) in the basal posterolateral wall of the right ventricle (RV) associated with diffuse and hypermetabolic pericardial thickening (SUV max 5.6) and a low intensity pathologic hypermetabolic left retropharyngeal lymph node (SUV max 2,5) (Figs. 1 A-C and 2A). The ECG showed ST elevation in V3, the inferior (II, III, VF) and right (V3R, V4R) leads with T-wave inversion (Fig. 3). Further diagnostic imaging with transthoracic echocardiography (TTE) and cardiac CT scan were performed. Cardiac CT scan revealed a 4.6 Â 3.5 cm size mass infiltrating the basal posterolateral wall of RV, extended to the right atrium with a thickening of the entire pericardium and a moderate infiltration of the 1st segment of the right coronary artery ( Fig. 2

.B).
To further characterize the lesion, cardiac magnetic resonance imaging (CMR) confirmed the tissular mass infiltrating the basal posterolateral wall of RV extended to the basal posterolateral wall of right atrium (Fig. 2C), a tissue infiltration encasing the ascending aorta and a thickening of the entire pericardium. There was a high pathological enhancement after contrast agent injection and a high signal on diffusion-weighted imaging of this features (Fig. 2D).
Cardiac metastasis secondary to squamous cell carcinoma of the tongue was suspected. Nevertheless, because of the atypical presentation, the patient was referred for a surgical biopsy of the pericardium in February 2020 to eliminate a   www.md-journal.com associated with cetuximab was initiated, then by cetuximab alone because of common side effects due to taxol-carboplatin. Followup TTE evidenced in April 2020 a progression of the cardiac involvement with a metastatic invasion of pulmonary trunk and a compression of the right ventricular outflow tract. A systemic immunotherapy by nivolumab was then introduced but the patient died early in May 2020, after 2 cycles of treatment.

Discussion
Although oral cancers are relatively common with respect to all diagnosed malignancies, very few cases of ante-mortem diagnosed cardiac metastasis of OSCCs have been reported in the literature, possibly because of a lack of systematic whole-body follow-up imaging. In a review of the literature from the year 1985 to October 2019, we found 16 other cases of patients with squamous cell carcinoma of the tongue and cardiac metastasis ( Table 1). Cardiac metastases are far more common than primary cardiac tumors and the most common malignancies spreading to the heart are cancers of the lung, breast, mesothelioma, melanoma, leukemia, and lymphoma. [6] Among head and neck cancers associated with cardiac metastasis at autopsy, tongue cancer is the most frequent primary location, accounting for one-ninth (∼11%) of patients. [7] In a literature review of cardiac metastasis of head and neck cancer detected ante-mortem, Kim et al reported 23 cases of which 12 were tumors of the tongue thus representing a large majority with 52%. [8] The structure of the lymphatic system in the heart may explain the relatively low incidence of cardiac metastases compared with other organs in OSCCs. Cardiac metastases are located, by decreasing order of frequency, to the pericardium, myocardium, epicardium, endocardium, and intracavitary regions. [9] Pericardial effusion has been identified as a direct sign of cardiac metastasis, sometimes presenting as the first manifestation. [6] In this literature review, we observed a pericardial involvement in 29% of patients, a left atrial involvement in one case and a myocardial involvement in most cases. Metastases were located in the right and left ventricles, respectively, in about 60% and 40% of cases. Myocardial involvement is almost exclusively the result of retrograde lymphatic spread through tracheal or bronchomediastinal channels. [6] Table 1 shows an unexpected high proportion of women with squamous cell carcinoma of the tongue (47% of cases), while the overall incidence of OSCCs is twice greater in males than in women [10] and an average of 51 ± 14 years, consistent with other oropharyngeal cancer demographic reports in general. Mean duration between diagnosis of tongue cancer and cardiac metastasis was relatively short at 20 ± 14 months, after exclusion of two patients with extreme intervals of 120 months or more. Although cardiac metastasis usually occurred in patients with advanced stages of the disease, this location was isolated in almost a third of them.
Since symptoms in this location are either absent (6/17 symptomatic cases in our study) or nonspecific, cardiac metastasis is difficult to diagnose and usually detected in the postmortem setting at autopsy. ECG may have a diagnostic value, but generally consists of repolarization abnormalities which are poorly specific. ST segment changes were reported in some patients and the persistence of ST elevation without Q waves has been suggested to be pathognomonic of tumor invasion of the myocardium. [11] When patients were symptomatic or in case of ECG abnormalities, TTE was the most frequent imaging modality used owing to its availability and sensibility for detection of cardiac metastasis. [12] Follow-up CT scan often are done in these patients and may help unmask such rare cardiac involvement. Because of its excellent contrast in soft tissues, CMR was used to characterize the malignant-suspected cardiac masses and the surrounding extension in a few of the reported cases (5/16). In the present literature review and with this case report, 18 F-FDG PET/CT was the initial imaging modality in 24% of the patients revealing cardiac metastasis from a tongue cancer. 18 F-FDG PET/CT can be proposed as an option in the monitoring of SCC of the head and neck for the detection of occult recurrence. [13] Some authors have suggested that 18 F-FDG PET/CT yields good diagnostic performance in long-term surveillance and imparts added value to clinical assessment. [14,15] To improve the diagnostic performance of 18 F-FDG PET/CT and suppress the physiological myocardial uptake, a HFLC diet followed by 12-h fasting must be applied. [16] Table 1 Comparison of characteristics between cases with squamous cell carcinoma of the tongue metastasizing to the heart. Treatment options for patients with cardiac metastasis are limited. Due to the extent of the cardiac involvement, the patient presented here was not eligible for surgical resection. Given the lack of evidence, the role for chemotherapy or radiation remains undetermined. [17] Ferris et al suggested that a PD-L1 expression level of 1% or more tended to be associated with a better overall survival. [18] In this case report, PD-L1 expression was determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, multiplied by 100. The CPS was 9.9. Because of progression of the disease on a platinum chemotherapy, an immunotherapy by nivolumab was finally introduced. Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody approved by the Food and Drug Administration (FDA) and the European Medical Agency (EMA) for the treatment of platinum-resistant recurrent and/or metastatic SCC of the head and neck.

Reference
Metastatic involvement of the heart from tongue cancer is an uncommon finding. The diagnosis is often difficult and delayed, as symptoms and signs are absent or nonspecific. In the patient presented here, 18 F-FDG PET/CT proved to be useful in detecting cardiac metastasis and changed the therapeutic management from potentially curative intent radical salvage therapy to palliative care. 18 F-FDG PET/CT is a highly sensitive technique, which provides the unique advantage of scanning the whole body thus reducing the risk of missing distant metastasis with a high negative predictive value. [14,15] This case report suggests that patients with tongue malignancies in a context of poor initial prognosis should be followed-up by 18 F-FDG PET/CT with HFLC diet to facilitate early detection of recurrence, especially in heart, and guide optimal therapeutic management.