Revision Transoral Robotic Surgery for Early Stage HPV Positive Oropharyngeal Squamous Cell Carcinoma, it’s Timing and Margins: Past and Present- a Prospective Single Centre Observational Study

Abstract

To review cohort of patients with HPV positive early stage oropharyngeal cancer that underwent revision trans oral robotic surgery for positive or close margin for evidence of residual disease, its impact on survival and discussion about clear margin. This is a prospective observational study. Our TORS revision rate was 20.6%. 91.7% did not need radiotherapy to primary site; mean recurrence free survival is 31 months and no mortality in this cohort due to the primary disease. There is no consensus on what is clear margin. The surgical margins are a surrogate marker for later recurrences or long-term survival and this is what guides our treatment but equally attempts should be made to preserve their function and not increase the morbidity.

Introduction

Transoral Robotic Surgery (TORS) for oropharynx was introduced in 2005. Since then it has been used successfully in oropharyngeal malignancy particularly in T1 & T2 lesions. Weinstein and O’Malley first used the Da Vinci Robot in 2006 for oropharyngeal malignancy and approved by the US Food and drug administration (FDA) in 2009 [1].

Traditionally, oropharyngeal malignancies have been treated with either chemo-radiotherapy or open surgical resection. For early stage cancers Transoral Laser Microsurgery (TLM) [2, 3] or monopolar cautery [4] has been used with good result.

Since the FDA approval and introduction of TORS, treatment of early stage oropharyngeal cancers has been revolutionised and increasing number of hospitals are adopting this technique in the U.K.

Previously, depending on the extent of oropharyngeal cancers, they were either suitable for organ preservation treatments (TLM, Radiotherapy or Chemoradiotherapy) or open resections with free flap reconstruction. Some of these treatments had serious functional side effects and morbidity particularly on their swallow.

The increased understanding of the relationship between the Human Papilloma virus (HPV), causation and prognosis of oropharyngeal squamous cell carcinoma (OPSCC) has influenced how these patients are treated. The patients who have HPV associated OPSCC have better prognosis and need less radical treatment [5]. Currently trials are being run to test this hypothesis and early results are promising (DE-ESCALATE TRIAL, PATHOS, ECOG 3311).

For any surgical treatment to succeed, it is important to ensure that no tumour is left behind and is removed with margins of healthy oropharyngeal tissue. This is however, complicated by the anatomy of oropharynx wherein only limited amount of tissue can be removed particularly in the deep and lateral margin otherwise it will cause perforation of the pharynx or arterial injury. Margin clearance for open approach oropharyngeal surgeries is recommended as 5 mm [6–8].

We have looked into our patient cohort who underwent revision surgery for close or positive margin to check for evidence of residual cancer in revision histology, timing of revision surgery, local recurrence free survival rate and need for any further local treatment.

Materials and Methods

This is a single centre prospective observational study from the University hospital of Derby & Burton NHS trust in the United Kingdom. We prospectively collected data for patients operated between February 2015-January 2021. We use Da Vinci Si robot (Intuitive Surgical Inc., Sunnyvale, Ca).

The inclusion criteria for this study are:

1. Squamous Cell Carcinoma confined to the mucosa of tongue base or in the tonsillar fossa with no involvement of floor of mouth, extrinsic muscles of tongue base, pterygoids and not extending through pharyngeal muscular wall, radiologically. Therefore, T1 and T2 cancers formed the bulk of patients and only one T3 tonsillar cancer was included which remained confined to the tonsillar fossa without involving the muscles of pharynx.

2. HPV positive squamous cell carcinoma

3. Resection margins were reported as either involved or close, histologically

Exclusion criteria:

1. HPV negative tonsil squamous cell carcinoma

2. Advanced T3 and T4 tonsil squamous cell carcinoma with involvement of pharyngeal muscles and or beyond.

The patients were staged according to the American Joint Committee on Cancer TNM 7 staging system to ensure consistency.

Results

A total of 104 patients were operated in this period and 76 patients had malignancy. The most common primary site found in this are arranged in descending order below.

Tonsil- 49.

Tongue base- 9.

Soft palate- 4.

Supraglottis- 1.

Unknown primary-13.

Only patients with oropharyngeal SCC are included in this study. The average age of patients with cancer in our study was 59.8 yrs. The youngest was 40 years and oldest was 78 years. The male patients were more common with the male: female ratio of 2.3:1. In our series tonsillar cancer was more than 5 times common than tongue base carcinoma. The table below shows the distribution of cancer in tongue base and tonsil.

The Tables 1, 2 and 3 below show TNM classification for each oropharyngeal subsite.

Table 1.

Tonsil SCC

	N0	N1	N2a	N2b	N2c	N3
T1	10	2	5	1		1
T2	11	5	4	9
T3		1

Table 2.

Tongue base SCC

	N0	N1	N2a	N2b	N2c	N3
Tx	1
T1		4		2
T2		1	1

Table 3.

Soft Palate

	N0	N1	N2a	N2b	N2c	N3
T1	2	1		1
T2
T3
T4

13 patients underwent revision TORS resection for oropharyngeal malignancies. Hence our revision surgery rate for HPV positive patient oropharyngeal squamous cell carcinoma is 20.6%.

Discussion

We started the TORS service in 2015. Prior to this time, we treated early stage oropharyngeal carcinoma with TLM using a CO2 laser.

76 patients had TORS for malignancies of the upper aero-digestive tract, tonsil being the commonest site for cancer. The resection is tailored to extent and size of tumour removing a cuff of normal tissue, from surgeon’s perspective under magnified view; this does reduce the risk of through defect into neck.

The patients included in this study were predominantly T1 and T2 oropharynx. A T3 patient has also been included because based on size it was localised to the tonsillar fossa with no muscle involvement of the tonsil bed.

The literature has reported wide range of histological margin positivity rate between 4.3%-30% [9, 10]. In our series, this is 19%.

The cohort of revision surgery patients had either close or involved margin. There is no specific guidance about the timing of revision surgery. In our series this was performed 4–6 weeks later to ensure complete resection of any possible remaining cancer tissue. This interval allows the primary site to heal and is relatively easier to distinguish between the cancer tissue and scar tissue. Although, Morisod et al. [10] performed revision surgery between 1–3 weeks following primary surgery, we however feel that it will be difficult to distinguish between granulation tissue and any remnant of cancer if the revision surgery is performed in the early healing phase following primary surgery. Nishimura et al. did the second look surgery between 2–3 months for positive or close margin [11].

A search of the literature at the Pubmed did not find any other study about the timing of revision surgery.

The most common margin involved in tonsil cancer was deep margin.

Three patients with tongue base carcinoma had involved margin and inferior margin was more common. The second patient with involved inferior and lateral margin was close to the midline and hence was referred for radiotherapy to the neck and oropharynx.

The involved margin is further explained in the Table 4 below.

Table 4.

Close/involved margin and revision histology

Tonsil	Margin	Revision histology
T1N1M0	Superior	Fibrous tissue
T1N1M0	Deep and Superior	Fibrous tissue
T2N2bM0	Superior	Fibrous tissue
T1N0M0	0.5 mm from deep margin	Fibrous tissue
T3N0M0	Radial	Fibrous tissue
T2N2bM0	Deep	Fibrous tissue
T2N1M0	Deep anterior	Fibrous tissue
T2N0M0	Deep radial	Fibrous tissue
T2N2bM0	Deep	Fibrous tissue
T2N0M0	Deep	Fibrous tissue
Tongue Base
T1N1M0	Deep	Fibrous tissue
T1N1M0	Inferior & lateral	Squamous cell carcinoma
T1N1M0	Inferior	Fibrous tissue

None of the patients who underwent revision resection from the tonsil had any evidence of cancer in the re-resected tumour bed on histology (Table 4).

There is no specific recommended margin for TORS procedure for the oropharynx but some centres have suggested the same margin as used in open approach surgery for oropharyngeal resection [12] A 5 mm margin of normal tissue is considered as adequate resection for open procedures. This is however impossible to obtain via TORS in patients with tonsillar cancer without routinely extending the deep margin into the neck, causing pharyngeal perforation. The thickness of pharyngeal constrictor radiologically has been measured between 2-3 mm [13]. Therefore, if the tumour involves the lateral most extent of tonsil tissue or capsule or extends into this muscle, then we cannot obtain 5 mm lateral clearance margin without perforating the pharynx. A pharyngeal perforation can increase patient morbidity and will then have to be closed via local flap followed by nasogastric tube feeding. This will also increase the length of their hospital stay, with attending risks. There is no consensus on what is an adequate margin for HPV positive oropharyngeal carcinoma and various articles have reported margins varying from just microscopic clearance to up to 5 mm. Morisod [10] et al. has classified the margin as involved (less than 1 mm), close (between 1 and 3 mm) and clear (more than 3 mm). Lorincz [14] and Kaczmar [15] et al. considered less than 2 mm as involved margin. This variation in the definition of involved and closed margin implies that some centres would subject their patients to further treatment in the form chemo/radiotherapy to the mucosa.

We should also consider mucosal margin retraction post surgery and this has been studied extensively in oral cancer. Mistry [16] et al. reported 22% retraction in the mucosal margin within half an hour after surgery. This can give an impression that the tumour was not excised with adequate recommended margin.

We feel that for carefully selected HPV patients, extensive resection and pharyngeal perforation can be avoided in early stage T1/T2 tonsil cancer and if the primary surgery reveals close/involved margin then this can be re-excised 4–6 weeks later. TORS is a procedure that can be repeated as long as we have good access via oral route to the site. But if we accept narrower margin, this may reduce need for re-excision and additional therapy.

The extent of the primary surgery is guided by the following factors.

1. Size

2. Location in the subsite- more medially located tonsil tumour will allow removal with more than adequate cuff of normal tissue

3. If it involves the capsule and or muscles forming the tonsil bed. This will generally result in close excision margin on histological examination. Therefore, it is of paramount importance to choose the patient carefully pre-operatively to avoid increased post-operative morbidity.

The early indicators and results in this study are promising and the average local recurrence free survival of primary site in this cohort is 31 months. None of the patients have shown recurrence till the date of writing this paper. We continue to follow up these patients in our clinics.

Only one patient with tongue base carcinoma needed post- operative radiotherapy to the primary (8.3%) because it was close to the midline. However, 91.7% of the patients were able to avoid radiotherapy to the primary site.

The national cancer centre network guidelines recommend a margin of 5 mm for oropharyngeal cancer. We realise that our study numbers are small to make any recommendation but in our experience 5 mm resection is not required or even possible in many cases for complete oncological resection in the primary surgery for HPV positive malignancies and also avoided pharyngeal perforation and associated morbidity.

According to Pool [17] et al., a recent survey by the American head and neck society revealed that only 27.7% of surgeons felt less than 5 mm is considered as close margin while 32.3% felt that less than 1 mm should be considered as close in HPV positive patients. 51% of the surgeons who participated in this survey opted for post-operative observation in patients with close margin.

Molony [18] et al. reported in their study that the survival outcome in OPSCC patients with positive margin following surgical resection and post-operative radiotherapy was strongly dependent on p16 status; positive patients had very low risk of recurrence and death.

Conclusion

While it is important to make sure that there is no residual viable cancer tissue left behind, equally attempts should be made to preserve their functions as well. There is no consensus amongst the surgeons about what is close margin in HPV positive patients, but considering the good prognosis of HPV positive patient and the anatomical constraint, less than 1 mm should be considered as close in our experience and more than 1 mm is adequate margin. Revising the involved or close margin has given reassurance to both the surgeon and the patient that no tumour was left behind and adjuvant radiotherapy to the primary site was avoided. The assessment of surgeon’s judgement about tumour resection needs to be considered in deciding further treatment in patients with close margin. This has been studied in glottic carcinoma [19] but needs research in HPV oropharyngeal carcinoma.

Those patients who need further local resection, timing of revision surgery at 4–6 weeks post first resection has not shown to have any adverse outcomes for these patients. There was no other study in literature that studied the effect of timing of revision surgery in the prognosis of HPV positive patients with early stage oropharyngeal carcinoma.

Declarations

Conflicts of interest

There is no conflict of interest and no external funding was needed to support this study.