Primary Salivary Gland Malignancy: A Review on Post-Operative Follow-Up Duration and Radiological Modalities

Follow-up

Studies across SGCs share similar challenges, primarily being heterogeneous histological groups with variable biological behavior. The limited data, largely retrospective study designs, inconsistent integration of radiotherapy, short follow-up duration, and lack of post-operative investigation make it particularly difficult to establish a standard post-operative guideline. Follow-up after initial treatment was designed to identify locoregional recurrence and/or distant metastases. The slow and stealthy nature of these neoplasms mandates a long-term follow-up duration to establish local failure and/or distant metastases.^2,16 The relative risk of frequent recurrence and/or distant metastases depends on the tumor site, size, histology, and staging.^4,5 Shigeishi et al. demonstrated the importance of tumor resection before it increases in size (>4 cm) as delayed tumor resection is associated with higher mortality. This is known as ‘the 4 cm rule’. In a Korean study investigating the treatment outcomes of high-grade SGCs have confirmed that presence of local metastases to regional lymph nodes and distant metastases at presentation were significant of poor survival. On the contrary, early stage high-grade SGCs bare excellent prognosis.¹⁷ This points out the importance of early detection or diagnosis to improve patient’s prognosis. This can be achieved with frequent long duration follow-up plans and the administration of superior imaging modalities. As for the site of the tumor, a non-parotid tumor site was an independent predictor of late recurrence in a 240-patient retrospective analysis.¹⁸ In addition to this, pathological SGC subtypes like AdCC are reported to have frequent nerve invasion, which is associated with high recurrence rate. Clinical stage and facial nerve invasion have been a recurrent predicting factor for developing distant metastases in multiple studies.^18–20 The varied recurrence patterns only mean follow-up duration cannot be limited in turn of improving patient’s prognosis.³

Surgery with or without post-operative radiotherapy remains the cornerstone of treatment for most resectable SGCs.^8,10,12–14 Indications of post-operative RT includes lymph node metastases, perineural invasion, high grade tumors (T3/T4), positive or close margin and distant metastases.²¹ These patients require post-operative RT as they have a higher risk for local failure. In addition, neck dissection is reserved for nodal disease, whereas adjuvant chemotherapy is largely used for palliation.^4,6 In a large retrospective analysis, the collective results have suggested no survival advantage with the use of adjuvant chemoradiotherapy (CRT) versus radiotherapy (RT) alone in resected major SGCs.^17,22 The lack of improved overall survival (OS) has been demonstrated in multiple subset analyses in that study. However in another retrospective, case-controlled study from Moffitt Cancer Centre concluded greater locoregional control and OS with post-operative CRT. The study was greatly limited by small sample size, short follow-up period and imbalance in use of intensity-modulated RT. Amini et al. and Mifsud et al. recently published their results with longer follow-up duration and larger population, demonstrating no statistically significant benefit with CRT in disease-free survival (DFS) and OS.^22,23

In an extensive study on the outcomes of current major SGCs management, post-operative RT only reduced the risk of locoregional recurrence, but not distant metastases.^15,24–27 However, primary tumors of the parotid gland constitute the majority of their study population, despite primary tumors of the submandibular gland representing a significantly higher relative incidence of distant metastases.^28,29 In Pohar et al. where the addition of RT lacks improvement in overall survival but reduces locoregional failure and improves local failure-free survival. Post-operative RT has been described to be an independent predictor of local recurrence.³⁰ Although not focused in this review, the addition of RT also have found improved local control in patients with minor salivary gland tumors.³⁰ Most study emphasizes the DFS and OS based on high-grade tumors, with minimal follow-up duration and the failure to incorporate more low-grade tumors. This underestimates the local failure and distant metastases rates in low-grade tumors. Interestingly, in terms of demographic prognostic factors, this review did not find a sex predilection for survival or failure patterns.^27,28

In a more recent retrospective study by Shabani et al., the average times for locoregional recurrence and distant metastases were approximately 5 and 11 years, respectively. However, their study did not include high-grade tumors. Comparatively, Mimica et al. explored the recurrence of high-grade tumors and showed a median time of 20 months (1.6 years) to diagnose distant metastases after the completion of primary treatment. These data are also reflected in another Korean study focusing on post-treatment outcomes of diverse histologic grade tumors, specifically mucoepidermoid carcinoma (MEC).²⁶ The average time for locoregional recurrence or distant metastases was 21 months (1.8 years). The team followed up the patients more frequently in the first 2 years after the initial treatment and biannually thereafter. The poor prognosis of high-grade tumors emphasizes the need for more aggressive treatment approaches and frequent follow-up in the initial years post treatment. However, high grade tumors that received surgery and post-operative RT are expected to achieve adequate locoregional control in turn reducing distant metastases as concluded by Teo et al. This finding is also apparent in an Indian study producing the most favourable disease-free survival (DFS) and overall survival (OS) at 5 years from the articles reviewed stated in table above.²¹

Our review corroborates that distant metastases can develop years after achieving adequate local control.² The most predominant site of distant metastases is the lung, although metastasis can also be seen in the bone, liver, brain, and skin.¹ Ohta et al. showed that distant metastasis to the lung can occur as late as two decades after initial treatment, using an example case of primary AdCC. It can be argued that the high-grade nature of AdCCs requires a longer follow-up period. Interestingly, although rare, polymorphous adenocarcinoma (PAC), a tumor with low-grade histology with a relatively indolent clinical course and excellent prognosis, has been reported to present with distant metastasis 20 years after initial diagnosis.¹⁰ While no definitive upper limit for follow-up have been established in the literature, our review recommends a minimum standard follow-up duration of 15-20 years for comprehensive monitoring and management of high-grade tumors, ensuring timely intervention should distant metastases arise.

Radiological modalities

The main reason for treatment failure and eventual death is distant metastases in patients with primary SGC.^13,14,24 This further emphasizes the need for a longer follow-up duration and adequate imaging to detect local recurrence and/or distant metastases. The heterogeneous histology and variable biological behavior of SGC impose significant challenges for clinicians. The establishment of uniform post-operative guidelines is dependent on previous studies and scarce data.

Currently, magnetic resonance imaging (MRI) is the investigation of choice for the assessment of deep lobe parotid tumors, patterns of infiltration and imaging of para-pharyngeal spaces while computed tomography (CT) is most effective when bony errosion is suspected.²⁵ The value of functional MRI techniques pre-operatively are being further investigated; whilst few studies have evaluated it as post-operative imaging.^31,32 As discussed, follow-up is in place to detect disease recurrence and/or distant metastasis. One study has recommended MRI for local recurrence and chest computed tomography (CT) for lung metastases to be included as part of follow-up investigations.¹⁴ This recommendation is in accordance with lung being the most common site of distant metastases.^2,3,12 There is no consensus on the benefit of positron emission tomography for assessing local recurrence compared with conventional imaging.¹⁴

The United Kingdom National Multidisciplinary Guidelines agree that despite ultrasound being an accurate imaging modality for local recurrence, a quarterly baseline MRI is required for useful comparison.³ It should also be comprehended that the role of ultrasound is limited to patients with superficial swellings of parotid and submandibular gland.²⁵ The frequency of MRI is then reduced to six monthly from the third to the fifth year post-operatively and then annually thereafter.¹⁴ No follow-up protocols have been established for the detection of abdominal or rare distant metastatic sites.³³ Although rare, distant metastatic sites that are anecdotal mandate higher clinical suspicion for diagnosis.