Clinical Relevance of Resection Margins in Patients with Total Laryngectomy or Laryngopharyngectomy.

BACKGROUND: Laryngeal and hypopharyngeal cancer is complex and resection margins are therefore constrained. The aim of this study was to investigate the clinical relevance of resection margins in laryngeal and hypopharyngeal surgery. METHODS: A retrospective cohort study was performed for patients treated with a total laryngectomy (TL) or laryngopharyngectomy (TLP) for laryngeal or hypopharyngeal squamous cell carcinoma (LSCC and HSCC, respectively). Within the groups primary LSCC, recurrent LSCC, primary HSCC, and recurrent HSCC the relationship between the status of the resection margin according to the Royal Collage of Pathology and the recurrence and survival rates were investigated. RESULTS: Positive resection margins were found in 54% for primary LSCC, 29% for recurrent LSCC, 62% for primary HSCC, and 44% for recurrent HSCC. For primary and recurrent LSCC, there was a linear association between total recurrence and narrowing margins (p = 0.007 resp. p = 0.008). Multivariate survival analysis for primary and recurrent LSCC showed a significantly worse disease free and disease-specific survival in case of positive margins compared to clear margins. CONCLUSION: Similar survival rates were recorded for close and clear margins for primary and recurrent LSCC. This may suggest that a margin > 5 mm is not clinically relevant in terms of survival. Therefore, a margin of 1-5 mm should be accepted in certain subsites. Margins < 1 mm are related to significantly worse outcomes and should be avoided.

A New Proposal for Adequate Resection Margins in Larynx and Hypopharynx Tumor Surgery-Are the RCP Guidelines Feasible?

BACKGROUND: Resection margins are an important prognostic factor for patients with head and neck cancer. In general, for head and neck surgery, a margin >5 mm is advised by the Royal College of Pathologists. However, this cannot always be achieved during laryngeal and hypopharyngeal surgery. The aim of this study is to identify the resection surfaces and measure the maximum feasible margins per subsite. The clinical relevance of these maximum feasible resection margins were analyzed in this descriptive anatomical study. METHODS: head and neck surgeons and a pathologist from the Erasmus MC performed a total laryngectomy and laryngopharyngectomy on a head and neck specimen specifically available for research. RESULTS: For a total laryngectomy, resection margins >5 mm were not feasible for the ventral and dorsal resection surface. For a total laryngopharyngectomy, resection margins >5 mm were not feasible for the ventral, dorsal and lateral resection surface. CONCLUSION: Clear resection margins, defined as a margin >5 mm, are not always feasible in laryngeal and hypopharyngeal surgery, due to the anatomy of the larynx and tumor location. However, striving for a maximum feasible margin is still the main goal. We propose a new guideline for maximum feasible but adequate resection margins in larynx and hypopharynx tumor surgery.

A case report of extramedullary plasmocytoma-rare pathology in the larynx.

Extramedullary plasmocytoma is a rare finding. The diagnosis is made by histological and immunohistochemical examination. Hematological evaluation is mandatory to rule out multiple myeloma. Radiotherapy is treatment of choice with good results.

Raman spectroscopy to discriminate laryngeal squamous cell carcinoma from non-cancerous surrounding tissue.

As for many solid cancers, laryngeal cancer is treated surgically, and adequate resection margins are critical for survival. Raman spectroscopy has the capacity to accurately differentiate between cancer and non-cancerous tissue based on their molecular composition, which has been proven in previous work. The aim of this study is to investigate whether Raman spectroscopy can be used to discriminate laryngeal cancer from surrounding non-cancerous tissue. Patients surgically treated for laryngeal cancer were included. Raman mapping experiments were performed ex vivo on resection specimens and correlated to histopathology. Water concentration analysis and CH-stretching region analysis were performed in the high wavenumber range of 2500-4000 cm-1. Thirty-four mapping experiments on 22 resection specimens were used for analysis. Both laryngeal cancer and all non-cancerous tissue structures showed high water concentrations of around 75%. Discriminative information was only found to be present in the CH-stretching region of the Raman spectra of the larynx (discriminative power of 0.87). High wavenumber region Raman spectroscopy can discriminate laryngeal cancer from non-cancerous tissue structures. Contrary to the findings for oral cavity cancer, water concentration is not a discriminating factor for laryngeal cancer.

Intraoperative assessment of resection margins by Raman spectroscopy to guide oral cancer surgery.

Patients with oral cavity cancer are almost always treated with surgery. The goal is to remove the tumor with a margin of more than 5 mm of surrounding healthy tissue. Unfortunately, this is only achieved in about 15% to 26% of cases. Intraoperative assessment of tumor resection margins (IOARM) can dramatically improve surgical results. However, current methods are laborious, subjective, and logistically demanding. This hinders broad adoption of IOARM, to the detriment of patients. Here we present the development and validation of a high-wavenumber Raman spectroscopic technology, for quick and objective intraoperative measurement of resection margins on fresh specimens. It employs a thin fiber-optic needle probe, which is inserted into the tissue, to measure the distance between a resection surface and the tumor. A tissue classification model was developed to discriminate oral cavity squamous cell carcinoma (OCSCC) from healthy oral tissue, with a sensitivity of 0.85 and a specificity of 0.92. The tissue classification model was then used to develop a margin length prediction model, showing a mean difference between margin length predicted by Raman spectroscopy and histopathology of -0.17 mm.

Intraoperative Assessment of Resection Margins in Oral Cavity Cancer: This is the Way.

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.

Is the Depth of Invasion a Marker for Elective Neck Dissection in Early Oral Squamous Cell Carcinoma?

OBJECTIVE: The depth of invasion (DOI) is considered an independent risk factor for occult lymph node metastasis in oral cavity squamous cell carcinoma (OCSCC). It is used to decide whether an elective neck dissection (END) is indicated in the case of a clinically negative neck for early stage carcinoma (pT1/pT2). However, there is no consensus on the cut-off value of the DOI for performing an END. The aim of this study was to determine a cut-off value for clinical decision making on END, by assessing the association of the DOI and the risk of occult lymph node metastasis in early OCSCC. METHODS: A retrospective cohort study was conducted at the Erasmus MC, University Medical Centre Rotterdam, The Netherlands. Patients surgically treated for pT1/pT2 OCSCC between 2006 and 2012 were included. For all cases, the DOI was measured according to the 8th edition of the American Joint Committee on Cancer guideline. Patient characteristics, tumor characteristics (pTN, differentiation grade, perineural invasion, and lymphovascular invasion), treatment modality (END or watchful waiting), and 5-year follow-up (local recurrence, regional recurrence, and distant metastasis) were obtained from patient files. RESULTS: A total of 222 patients were included, 117 pT1 and 105 pT2. Occult lymph node metastasis was found in 39 of the 166 patients who received END. Univariate logistic regression analysis showed DOI to be a significant predictor for occult lymph node metastasis (odds ratio (OR) = 1.3 per mm DOI; 95% CI: 1.1-1.5, p = 0.001). At a DOI of 4.3 mm the risk of occult lymph node metastasis was >20% (all subsites combined). CONCLUSION: The DOI is a significant predictor for occult lymph node metastasis in early stage oral carcinoma. A NPV of 81% was found at a DOI cut-off value of 4 mm. Therefore, an END should be performed if the DOI is >4 mm.

Depth of invasion in early stage oral cavity squamous cell carcinoma: The optimal cut-off value for elective neck dissection.

OBJECTIVES: Depth of invasion (DOI) is the most important predictor for lymph node metastasis (LNM) in early stage (T1-T2) oral cancer. The aim of this study is to validate the cut-off value of 4 mm on which the decision to perform an Elective Neck Dissection (END) is made. MATERIALS AND METHODS: We performed a retrospective study in patients with pathologically proven early stage oral cavity squamous cell carcinoma (OCSCC) without clinical or radiological signs of LNM, who were treated between 2013 and 2018. An END was performed when DOI was ≥ 4 mm and a watchful waiting protocol was applied in patients with DOI < 4 mm. RESULTS: Three hundred patients were included. END was performed in 77% of patients with DOI ≥ 4 mm, of which 36% had occult LNM (pN+). Patients in the watchful waiting group (48%) developed a regional recurrence in 5.2% for DOI < 4 mm and 24.1% for DOI ≥ 4 mm. For DOI ≥ 4 mm, regional recurrence free survival was higher for patients who were treated with END compared to watchful waiting (p = 0.002). A Receiver-Operator-Curve -analysis showed that a DOI cut-off value of 4.0 mm was the optimal threshold for the prediction of occult LNM (95.1% sensitivity, 52.9% specificity). CONCLUSION: A DOI of ≥ 4 mm is an accurate cut-off value for performing an END in early stage OCSCC. END results in higher survival rates and lower regional recurrence rates in patients with DOI ≥ 4 mm.

Intraoperative Assessment of the Resection Specimen Facilitates Achievement of Adequate Margins in Oral Carcinoma.

BACKGROUND: Inadequate resection margins in oral cavity squamous cell carcinoma have an adverse effect on patient outcome. Intraoperative assessment provides immediate feedback enabling the surgeon to achieve adequate resection margins. The goal of this study was to evaluate the value of specimen-driven intraoperative assessment by comparing the margin status in the period before and the period after the introduction of specimen-driven assessment as a standard of care (period 2010-2012 vs period 2013-2017). METHODS: A cohort of patients surgically treated for oral squamous cell carcinoma at the Erasmus MC Cancer Institute, Rotterdam, between 2010-2012 was studied retrospectively and compared to results of a prospectively collected cohort between 2013-2017. The frequency, type and results of intraoperative assessment of resection margins were analyzed. RESULTS: One hundred seventy-four patients were included from 2010-2012, 241 patients were included from 2013-2017. An increase in the frequency of specimen-driven assessment was seen between the two periods, from 5% in 2010-2012 to 34% in 2013-2017. When performing specimen-driven assessment, 16% tumor-positive resection margins were found in 2013-2017, compared to 43% tumor-positive resection margins overall in 2010-2012. We found a significant reduction of inadequate resection margins for specimen-driven intraoperative assessment (p < 0.001). Also, tumor recurrence significantly decreased, and disease-specific survival improved when performing specimen-driven intraoperative assessment. CONCLUSIONS: Specimen-driven intraoperative assessment improves resection margins and consequently, the outcome of oral cancer patients. We advocate this method as standard of care.

Relocation of inadequate resection margins in the wound bed during oral cavity oncological surgery: A feasibility study.

BACKGROUND: Specimen-driven intraoperative assessment of the resection margins provides immediate feedback if an additional excision is needed. However, relocation of an inadequate margin in the wound bed has shown to be difficult. The objective of this study is to assess a reliable method for accurate relocation of inadequate tumor resection margins in the wound bed after intraoperative assessment of the specimen. METHODS: During oral cavity cancer surgery, the surgeon placed numbered tags on both sides of the resection line in a pair-wise manner. After resection, one tag of each pair remained on the specimen and the other tag in the wound bed. Upon detection of an inadequate margin in the specimen, the tags were used to relocate this margin in the wound bed. RESULTS: The method was applied during 80 resections for oral cavity cancer. In 31 resections an inadequate margin was detected, and based on the paired tagging an accurate additional resection was achieved. CONCLUSION: Paired tagging facilitates a reliable relocation of inadequate margins, enabling an accurate additional resection during the initial surgery.

Raman spectroscopy for assessment of bone resection margins in mandibulectomy for oral cavity squamous cell carcinoma.

OBJECTIVES: The aim of this study was to investigate the potential of Raman spectroscopy for detection of oral cavity squamous cell carcinoma (OCSCC) in bone resection surfaces during mandibulectomy. MATERIALS & METHODS: Raman mapping experiments were performed on fresh mandible resection specimens from patients treated with mandibulectomy for OCSCC. A tumour detection algorithm was created based on water concentration and the high-wavenumber range (2800 cm-1-3050 cm-1) of the Raman spectra. RESULTS: Twenty-six ex vivo Raman mapping experiments were performed on 26 fresh mandible resection specimens obtained from 22 patients. The algorithm was applied on an independent test set and showed an accuracy of 95%, a sensitivity of 95%, and a specificity of 87%. CONCLUSION: These results form the basis for further development of a Raman spectroscopy tool as an objective method for intraoperative assessment of bone resection margins.

Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics.

Oncological applications of Raman spectroscopy have been contemplated, pursued, and developed at academic level for at least 25 years. Published studies aim to detect pre-malignant lesions, detect cancer in less invasive stages, reduce the number of unnecessary biopsies and guide surgery towards the complete removal of the tumour with adequate tumour resection margins. This review summarizes actual clinical needs in oncology that can be addressed by spontaneous Raman spectroscopy and it provides an overview over the results that have been published between 2007 and 2017. An analysis is made of the current status of translation of these results into clinical practice. Despite many promising results, most of the applications addressed in scientific studies are still far from clinical adoption and commercialization. The main hurdles are identified, which need to be overcome to ensure that in the near future we will see the first Raman spectroscopy-based solutions being used in routine oncologic diagnostic and surgical procedures.

Water Concentration Analysis by Raman Spectroscopy to Determine the Location of the Tumor Border in Oral Cancer Surgery.

Adequate resection of oral cavity squamous cell carcinoma (OCSCC) means complete tumor removal with a clear margin of more than 5 mm. For OCSCC, 85% of the surgical resections appear inadequate. Raman spectroscopy is an objective and fast tool that can provide real-time information about the molecular composition of tissue and has the potential to provide an objective and fast intraoperative assessment of the entire resection surface. A previous study demonstrated that OCSCC can be discriminated from healthy surrounding tissue based on the higher water concentration in tumor. In this study, we investigated how the water concentration changes across the tumor border toward the healthy surrounding tissue on freshly excised specimens from the oral cavity. Experiments were performed on tissue sections from 20 patients undergoing surgery for OCSCC. A transition from a high to a lower water concentration, from tumor (76% ± 8% of water) toward healthy surrounding tissue (54% ± 24% of water), takes place over a distance of about 4 to 6 mm across the tumor border. This was accompanied by an increase of the heterogeneity of the water concentration in the surrounding healthy tissue. The water concentration distributions between the regions were significantly different (P < 0.0001). This new finding highlights the potential of Raman spectroscopy for objective intraoperative assessment of the resection margins. Cancer Res; 76(20); 5945-53. ©2016 AACR.

Pigmentation in the sentinel node correlates with increased sentinel node tumor burden in melanoma patients.

The prognosis of sentinel node (SN)-positive melanoma patients is predicted by a number of characteristics such as size and site of the metastases in the SN. The pathway and prognosis of strong pigmentation of melanoma metastases in the SN is unclear. The aim of this study is to evaluate the role of pigmentation and growth pattern of metastases in the SN with respect to survival. A total of 389 patients underwent an SN procedure (1997-2011). Ninety-five patients had a positive SN and material from 75 patients was available for review. The median follow-up time was 75 months (range 6-164). Pigmentation was scored from 0 to 2 using the following scale: 0=absent, 1=slight, and 2=strong. Growth pattern was scored as either eccentric (1) or infiltrative (2). SN tumor burden was measured according to the Rotterdam criteria. The primary melanoma had a median Breslow thickness of 2.90 mm (0.8-12.00 mm). Ulceration was present in 34 patients (45.3%). There was a median SN tumor burden of 0.5 mm (0.05-7.00 mm). In a total of 75 patients, 59 patients (79%) had no pigmentation, 13 patients (17%) had slight pigmentation, and three patients (4%) had strong pigmentation in the SN. Because of the small numbers, the classification was modified to either absent 59 (79%) or present 16 (21%) pigmentation, respectively. The SN tumor burden was significantly higher (P=0.031) for patients with pigmentation. Patients with pigmentation had a 5-year melanoma-specific survival (MSS) of 47% and a 10-year MSS of 33%. Patients without pigmentation had a 5-year MSS of 70% and a 10-year MSS of 59% (P=0.06). There was no difference in MSS for patients with an eccentric or an infiltrative growth pattern, nor did it correlate with other prognostic factors. Multivariate analysis for MSS showed five significant factors associated with worse prognosis: male sex (P=0.036), nodular melanoma (P=0.001), truncal site (P=0.0001), SN tumor burden more than 1.0 mm (P=0.022), and positive completion lymph node dissection (P=0.004). The 5-year MSS for SN tumor burden is 94% for 0.1 mm or less, 66% for 0.1-1.0 mm, and 41% for more than >1.0 mm (P<0.001). The 10-year MSS for SN tumor burden is, respectively, 94, 51, and 35% (P<0.001). This preliminary exploratory retrospective study showed that pigmentation within the SN seems to correlate with increased SN tumor burden.