The goal of this protocol is to provide a clear overview of specimen-driven intraoperative assessment of resection margins. It is encouraged to implement this protocol to improve patient care at other institutes.
The goal of head and neck oncological surgery is complete tumor resection with adequate resection margins while preserving acceptable function and appearance. For oral cavity squamous cell carcinoma (OCSCC), different studies showed that only 15%-26% of all resections are adequate. A major reason for the low number of adequate resections is the lack of information during surgery; the margin status is only available after the final histopathologic assessment, days after surgery.
The surgeons and pathologists at the Erasmus MC University Medical Center in Rotterdam started the implementation of specimen-driven intraoperative assessment of resection margins (IOARM) in 2013, which became the standard of care in 2015. This method enables the surgeon to turn an inadequate resection into an adequate resection by performing an additional resection during the initial surgery. Intraoperative assessment is supported by a relocation method procedure that allows accurate identification of inadequate margins (found on the specimen) in the wound bed.
The implementation of this protocol resulted in an improvement of adequate resections from 15%-40%. However, the specimen-driven IOARM is not widely adopted because grossing fresh tissue is counter-intuitive for pathologists. The fear exists that grossing fresh tissue will deteriorate the anatomical orientation, shape, and size of the specimen and therefore will affect the final histopathologic assessment. These possible negative effects are countered by the described protocol. Here, the protocol for specimen-driven IOARM is presented in detail, as performed at the institute.
Every year, around 350,000 new patients are diagnosed worldwide with cancer in the oral cavity; 90% of cases are squamous cell carcinoma1. The mortality rate is 175,000 worldwide per year and the 5-year survival is 50% to 64.8%1,2,3,4.
The primary treatment of oral cavity squamous cell carcinoma (OCSCC) is surgery5. The goal of the surgery is the complete removal of the tumor with adequate margins, according to the Royal College of Pathologists6. Margins >5 mm (clear) are regarded as adequate, whereas margins from 0-5 mm are regarded as inadequate.
Adequate resection margins lead to higher survival and a reduction in local recurrence-rates of OCSCC7,8,9. Tumor resections with inadequate margins result in the need for adjuvant therapy (postoperative radiotherapy and/or chemotherapy). This brings an additional burden for the patient, increasing morbidity and reducing the quality of life10. The resection margin is the only oncological prognostic factor that the surgeon and pathologist can influence.
Recent reports have shown that adequate resections are only achieved in 15%-26% of cases7,8,11. These poor results are caused by the complex anatomy of the oral cavity and the lack of intraoperative guidance. During surgery, the surgeon can only rely on inspection, palpation, and preoperative imaging.
The final margin status follows only several days after the operation. If an inadequate margin is encountered at the final pathologic assessment, a second operation is usually not an option, because the wound bed reconstruction has usually healed by that time. Moreover, a second operation is mostly not effective, because the relocation of the inadequate margin is even more difficult in the postoperative setting.
To overcome the lack of intraoperative information about margin status, specimen-driven intraoperative assessment of resection margins (IOARM) was implemented in 20139. It became the standard of care in the institute in 2015. Described here is the IOARM method in detail to enable colleagues at other institutes to implement this protocol.
This study was approved by the institutional Medical Ethics Committee (MEC-2015-150).
NOTE: All the patient and personnel information in the figures or examples are fictional (i.e., XXXXX and YYYYY).
1. Before surgery
2. During surgery
Figure 1: Illustration of the relocation protocol. (A) Application of tags in a pair-wise manner. (B) Wound bed and specimen both with one tag of each pair. Please click here to view a larger version of this figure.
Figure 2: Example of anatomical template for IOARM. Please click here to view a larger version of this figure.
Figure 3: Illustration of IOARM. (A) Perpendicular incision performed after identification of suspicious region by palpation. (B) The margin is measured. (C) The result of IOARM and the recommendation are recorded. Please click here to view a larger version of this figure.
3. After IOARM – Grossing room (GR), pathology department
NOTE: To preserve the anatomical orientation and shape of the specimen the following steps are performed.
Figure 4: Illustration of the method to preserve the anatomical orientation and shape of tissue sections. (A) Tissue sections are placed on a piece of cork with a line drawn on the cork around the tissue section with a permanent marker. (B) Pins are obliquely placed over the polar ends and another piece of cork is placed over the tissue section. (C) Illustration of a reassembled fresh specimen kept together with pins that puncture the adjacent corks. (D) Illustration of a reassembled fixed specimen kept together with pins that puncture adjacent corks. Please click here to view a larger version of this figure.
4. Grossing of the fixed specimen after IOARM
NOTE: After formalin fixation, the specimen should be grossed preferably by the pathologist/resident/assistant, who performed the IOARM.
CAUTION: Be careful with the needles/pins when removing the specimen from the container.
Figure 5: Illustration of a polar end with the cut surface facing the cork, held against the cork by tilted pins. (A) Fresh specimen. (B) After fixation. (C) The cut surface of the polar end is flat after fixation. Please click here to view a larger version of this figure.
Figure 6: Grossed specimen with the location of the IOARM marked. Corresponding numbers 1-5 refer to tissue sections from left to right. A-E corresponds with tissue sections included for histopathologic evaluation. Note that the remaining piece of tissue that was evaluated by frozen section (FS) is indicated to enable direct comparison with the permanent HE-stained section. Please click here to view a larger version of this figure.
5. The final pathologic assessment – Impact of IOARM on final margin status
Example of IOARM resulting in an adequate resection
The patient presents with a cT2N0M0 SCC of the left side of the tongue with no medical history. The patient undergoes hemiglossectomy supported by IOARM. The specimen is inspected and palpated; the mucosal margins are measured as >5 mm. One area in the submucosal resection surface is suspicious for an inadequate margin, located around tag 5. The submucosal margin is 3-4 mm at tag 5. All the information is recorded on the template and copied to the EPF (Figure 7A).
Figure 7: Examples of two different IOARMs recorded on the anatomical template. (A) IOARM resulting in an adequate resection. (B) IOARM not resulting in an adequate resection. Please click here to view a larger version of this figure.
The surgeon returns to the OR and performs the additional resection. The pathologist verifies the accuracy and dimensions, including the thickness of the additional resection.
The final pathology report shows the presence of moderately differentiated pT2 squamous cell carcinoma on the left side of tongue. The tumor diameter is 2.5 cm and the depth of invasion is 6.0 mm. The worst pattern of invasion (WPOI) is category 3. Perineural invasion (PNI) is not present and the lymphovascular invasion (LVI) is present. The minimal margins (mucosal and submucosal) at the inferior, superior, anterior, and posterior location are 5.8 mm (including additional resection (PA number: XXXXX) of 3 mm thickness), 6.2 mm (including additional resection (PA number: XXXXX) of 3 mm thickness), 5.2 mm, and 5.5 mm, respectively. IOARM is in concordance with final pathology.
Margins (mm) | |||
Location | Based on IOARM | After additional resection | Based on Final pathology |
Inferior | 3-4 | 6-7 | 5.8 |
Superior | 3-4 | 6-7 | 6.2 |
Anterior | >5 | 5.2 | |
Posterior | >5 | 5.5 |
Table 1: Example of resection margins during IOARM resulting in an adequate resection at final pathology, after additional resection.
Example of IOARM not resulting in an adequate resection
The patient presents with a cT1N0M0 SCC of the right side of the tongue with no medical history. The patient underwent a resection supported by IOARM. The surgeon takes the specimen to the pathologist at the pathology department. The mucosa is visually inspected, and the mucosal margins are measured with a transparent ruler, all mucosal margins are >5 mm. The submucosal margins are visually inspected and palpated and all margins seem >5 mm. A suspicious area is found at tag 1 (anterior resection surface) and tag 3 (posterior resection surface). A grossing knife is placed perpendicular to the resection surface from anterior to posterior (tag 1 to tag 3) and an incision is made. The pathologist measures the margin on the cross-section and the margins are >5 mm. All the information is recorded on the template and copied to the EPF (Figure 7B).
The final pathology report shows a well-differentiated pT1 squamous cell carcinoma on the right side of the tongue. The diameter of the tumor is 1.8 cm, and the depth of invasion is 3.8 mm. The worst pattern of invasion (WPOI) is category 2. Perineural invasion (PNI), lymphovascular invasion (LVI), and dysplasia are not present. The minimal margins (mucosal and submucosal) at the inferior, superior, anterior, and posterior locations are 4.0 mm, 6.1 mm, 6.4 mm, and 7.8 mm, respectively. IOARM is not in concordance with final pathology, margin inferior was missed.
Margins (mm) | |||
Location | Based on IOARM | After additional resection | Based on Final pathology |
Inferior | >5 | Not recommended all margins > 5mm | 4.0 |
Superior | >5 | 6.1 | |
Anterior | 6 | 6.4 | |
Posterior | 8 | 7.8 |
Table 2: Example of resection margins during IOARM not resulting in an adequate resection at final pathology.
The goal of surgical treatment of OCSCC patients is the complete removal of the tumor with adequate margins. This is too often not achieved, which inspired to design an adjusted approach to oral cancer surgery with a focus on intraoperative assessment of resection margins. Aside from resection margins, other adverse tumor factors such as the pattern of invasion, perineural invasion, and lymphovascular invasion also affect the local recurrence. However, of all adverse tumor factors, surgeons and pathologists can only influence the resection margins7,8,11.
The specimen-driven IOARM method was implemented in 2013; this was eventually supported by the evidence that specimen-driven IOARM is superior to defect-driven IOARM7,13,14,15,16,17. This resulted in its recommendation by AJCC in 201718. Noteworthy, the specimen-driven IOARM method became the standard of care in the institute in 2015. From 2013 until 2020 the IOARM was performed in 304 cases with a steep increase from 2018.
It is important to realize that developing and implementing an IOARM method involves many personnel (pathologists/surgeons/assistants/trainees/researchers), in order to make it standard of care. Many professionals were involved, during many years, in the development of this protocol, which is actually the strength of the method. The development of this method started in 2013 and reached a consensus in 2015. This was achieved based on the two-weekly meetings during which discussions regarding all the patients treated with surgery, including IOARM, took place. In this way, it was possible to timely adjust and refine the procedure. Besides, the two-weekly meetings enabled prospective data collection, which provides the basis for the performance and follow-up studies9. Moreover, for every case, the team ensured that the final pathology was not compromised due to IOARM. Finally, it is important to realize that this kind of assessment is a dynamic process and will always undergo changes toward improvement.
With the specimen-driven IOARM method, the margins are assessed by inspection, palpation, and perpendicular incisions (grossing). This approach provides an as accurate as possible estimation of margins in millimeters and enables feedback on whether an additional resection is needed and what the dimensions should be. Kubik et al. described several reasons (e.g., additional resection at an incorrect location, the incorrect orientation of the additional resection, incorrect dimensions of the additional resection) for additional resections to be inadequate17. The IOARM is a valuable method but only when accompanied by an as accurate as possible relocation method of inadequate margins to enable the surgeon to perform an adequate additional resection. The spatial relationship between the additional resection and the main specimen is the key factor. Therefore, a simple but elegant relocation method as shown in Figure 1 was developed and described in detail by Van Lanschot et al.12. This method allows the surgeon to perform an additional resection based on the relocation of the inadequate margin defined by the tags in the wound bed. For example, a margin of 2 mm is found between tags 1-2-3, the surgeon performs an additional resection around tags 1-2-3 with a thickness of 4 mm. This relocation method is shown to be effective by the results of Smits et al.9.
This IOARM method is supported by frozen section procedure only if the tumor cannot be distinguished macroscopically from surrounding tissue (e.g., fibrosis of tissue after radiotherapy or scar formation after previous surgery, or salivary gland tissue). Some institutes use another approach, in which frozen sections are taken from the specimen from all quadrants13,19. This method enables a more standardized protocol. However, the comprehensiveness of this method might not be always efficient. Moreover, multiple frozen sections are needed which is costly, time-consuming, and not accessible for all institutes. The described method is more efficient because the region of interest is preselected (i.e., region of suspicious inadequate margin) and is therefore cheaper, faster, and available for every institute. This is in accordance with previous findings that frozen section analysis does not improve the accuracy of specimen-driven IOARM based on grossing in most cases and is not cost-effective20,21,22.
According to the literature >93% of all inadequate margins are found at the submucosal resection margins23. This is in line with the findings of the institute. Mucosal alterations with high-grade dysplasia/CIS are often easy to detect during IOARM, only in a few cases, a frozen section is recommended. Until now in the IOARM cohort, any mucosal positive margins regarding cancer or high-grade dysplasia/CIS have not been encountered.
Even though specimen-driven IOARM significantly improves the rate of adequate resections in OCSCC patients and consequently improves patient outcome7,9,22,21, its wide implementation is lagging. The main cause of this is the fact that the grossing of fresh tissue is counter-intuitive for pathologists. The pathologists are fearful that grossing fresh tissue will deteriorate the anatomical orientation, shape, and size of the specimen, and therefore will affect the final histopathologic assessment24,25. However, the measures prescribed in the protocol prevent these possible negative effects. Since the implementation of this protocol, the anatomical orientation, shape, and size of the specimen have never been altered nor was the final pathologic assessment ever compromised (manuscript in preparation).
Although little additional time is required to perform IOARM, it is clear that no real obstacles exist to implement IOARM, but there must be a willingness to go through a learning curve, regarding the grossing of fresh tissue and identifying inadequate margins. The most important prerequisite is a dedicated and cooperative team of surgeons and pathologists. In this study, an IOARM method for head and neck cancer surgery has been described, that can easily be implemented in every institute and during any other cancer surgery. This protocol significantly improves the rate of adequate resections while concomitantly reducing the need for postoperative radiotherapy and improving the patient outcome. The specimen-driven IOARM method will help surgeons to achieve first-time-right surgery and patients will benefit.
The authors have nothing to disclose.
We thank Bas J. van Brakel and Roxanna Haak for their help in performing IOARM. Klara A. Bouman-Zevenbergen, Ian Overduin, and Silvy L. Sabiran – Singoredjo for their assistance and supportive role in ensuring logistics, equipment, and availability of personnel at the pathology department.
Anatomical templates | https://www.palga.nl/assets/uploads/Protocollen/HoofdHalstumoren.pdf | ||
Anatomical tweezers | |||
Brush | to apply the inc to the tissue | ||
Bucket for formalin fixation | Size of the container depends on the size fo the tissue | ||
Buffered formalin 4% | |||
Camera | |||
Computer | |||
Cork | Thin plates of cork | ||
Ethanol 70% | |||
Examination gloves | |||
Gauze or Paper | That wont leave particles on the specimen | ||
Grossing knife 15cm | |||
Grossing knife 30cm | |||
Grossing tabel | |||
Inc for tissue | 3 or more different colors | ||
Labcoat | |||
Long pins/Sewing pins | |||
Paper | To place the tissue sections on during the grossing | ||
Permanent markers | Different colors (black/blue/red/green) | ||
Relocation tags | Premier Farnell Limited BV, Utrecht, The Netherlands | Numbered froimn 0-9, cut to a size of 5 mm x 7 mm x 2 mm | |
Scalpel | |||
Surgical tweezers | |||
Sutures | Ethicon | Ethilon 3.0 | To suture in the tags |
Tap water | |||
Transparant ruler 30 cm | 2 rulers needed |