Diagnostic value of intraoperative bone marrow assessment for bone margins in patients with head and neck squamous cell carcinoma: a systematic review and meta-analysis

A clear bone margin is essential for complete resection of the bone-involved tumour, but the evaluation of hard tissue takes time and is impractical intraoperatively. Bone marrow assessment remains controversial. The aim of this study was to investigate the diagnostic value of intraoperative bone marrow assessment for bone margins. PubMed and Web of Science were searched for studies published between 1990 and 2017. A systematic review was conducted. After quality assessment, 10 articles with 11 cohorts and 404 patients were identified. Sensitivity, specificity, and other measures were pooled for meta-analysis; the estimates for intraoperative bone marrow assessment were as follows: sensitivity 0.82 (95% confidence interval (CI) 0.62–0.93), specificity 0.99 (95% CI 0.96–1.00), positive likelihood ratio 109.79 (95% CI 22.99–524.34), negative likelihood ratio 0.18 (95% CI 0.08–0.42), and diagnostic odds ratio 241.82 (95% CI 90.33–647.38). Furthermore, sensitivity and specificity at the summary operating point of the summary receiver operating characteristic curve were 0.82 and 0.99, respectively, and the area under the curve was 0.99. Intraoperative bone marrow assessment was investigated by meta-analysis and shown to have a high level of overall accuracy for the diagnosis of bone margins.     

Matching locating holes in multiple plates to record bone position for accurate reconstruction after segmental mandibulectomy

Segmental defect areas in the mandible can change immediately following osteotomy due to muscular traction, impacting on accurate reconstruction. The purpose of this article is to introduce a new technique based on virtual surgery planning to record the position of the bony parts prior to mandibulectomy, for use in precise mandibular reconstruction after segmental osteotomy. The position information for the bony parts is transferred to a plate with complementary surface contact and locating holes with specific directions and angles. This technique was performed for six patients with segmental defects and the results were compared to those of six previous patients in whom the technique was not utilized. The design of the location holes shortened the average operation time from 406 minutes to 349 minutes (P = 0.033) and decreased the average, maximum, and minimum graft deviation from 1.21 mm to 0.88 mm (P = 0.015), 1.28 mm to 0.99 mm (P = 0.027), and −1.15 mm to −0.77 mm (P = 0.077), respectively. The design of the locating holes in multiple plates shortened the time taken for the bony repositioning step and hence significantly shortened the total operation time. More importantly, it also increased the reconstructive accuracy.     

Ultrasound aids in intraoperative assessment of deep resection margins of squamous cell carcinoma of the tongue

We wanted to find out whether ultrasound (US) can be used to assess the deep resection margins after excision of squamous cell carcinoma (SCC) of the tongue, as intraoperative feedback on their condition might help to prevent them being too close. Resected specimens of cancers of the tongue from 31 patients with SCC of the tongue were suspended in US gel and scanned with a small 5-10 MHz US probe. The tumour was readily visible and US could differentiate it from muscle tissue. The margin of normal tongue musculature surrounding the tumour was measured on the US images, and the minimal resection margin was noted and compared with that reported by the histopathologist. The mean (SD) deep resection margins measured on the US images differed by 1.1 (0.9) mm from those reported by the histopathologist (Pearson’s correlation coefficient: 0.79, p < 0.01). The US measurements took a maximum of five minutes. It is feasible to use US to assess resection specimens of SCC of the tongue as an adjunct to existing strategies (such as frozen section analysis) to help achieve the desired deep surgical margins. The method is easy to incorporate into surgical routine as it does not take long.     

Specimen‐driven intraoperative assessment of resection margins should be standard of care for oral cancer patients

With an incidence of 350.000 new cases per year, cancer of the oral cavity ranks among the 10 most common solid organ cancers. Most of these cancers are squamous cell carcinomas. Five‐year survival is about 50%. It has been shown that clear resection margins (>5 mm healthy tissue surrounding the resected tumor) have a significant positive effect on locoregional control and survival. It is not uncommon that the resection margins of oral tumors are inadequate. However, when providing the surgeon with intraoperative feedback on the resection margin status, it is expected that obtaining adequate resection margins is improved. In this respect, it has been shown that specimen‐driven intraoperative assessment of resection margins is superior to defect‐driven intraoperative assessment of resection margins. In this concise report, it is described how a specimen‐driven approach can increase the rate of adequate resections of oral cavity squamous cell carcinoma as well as that it is discussed how intraoperative assessment can be further improved with regard to the surgical treatment of oral cavity squamous cell carcinoma.     

Factors affecting surgical mortality of oral squamous cell carcinoma resection

Survival rates for oral squamous cell carcinoma (OSCC) has remained stagnant in recent years and improving surgical mortality could be an avenue to enhance outcomes. This systematic review aims to identify the causes of mortalities, determine both the modifiable and non-modifiable factors involved and target a reduction in postoperative 30-day mortality. In May 2019, a comprehensive search of key databases including PubMed, EMBASE, Cochrane Library was conducted. Blinded selection by two researchers identified papers that included participants who received oral squamous cell carcinoma resection and suffered an in-hospital or 30-day mortality. Selection identified two relevant papers that meet the inclusion criteria. One study had one death in its population sample but only had the cause of death described. Another study had an overall surgical mortality rate of 1% in a population of 21,681. Patients with multiple factors had the highest mortality rates; 4.6% in patients >85 years old and have a T4 diagnosis, 3.9% in patients with a Comorbidity Index ≥1 and a T4 diagnosis. These studies did not determine relationships between factors and causes of death. There are significant knowledge gaps in the literature, that can be addressed through further population analysis studies.     

Surgery for maxillary oral squamous cell carcinoma: the effect of surgical resection margins and elective neck dissection on oncological outcomes

Maxillary oral squamous cell carcinoma (OSCC) is uncommon. Surgical resection is challenging due to the anatomy, and the role of elective neck dissection (END) is not well-defined. A retrospective cohort study of patients with maxillary OSCC treated with primary surgery between 2007 and 2019 was conducted. Primary tumours of sinonasal origin with extension into the oral cavity were excluded. Survival analysis was performed using Kaplan–Meier and Cox proportional hazards models. Sixty-seven patients were included; mean follow-up was 55 months. On univariate analysis, clear (≥5 mm) margins were associated with higher disease-free (68% vs 36%, P = 0.019) and overall survival (75% vs 36%, P = 0.004) than close/involved (<5 mm) margins. In clinically node-negative patients, the risk of occult cervical metastasis in tumours with depth of invasion (DOI) ≥ 3 mm and T2–4 tumours was 22% and 25%, respectively. END in these groups was associated with a lower rate of loco-regional recurrence (DOI ≥3 mm subgroup: 5% vs 38%, P = 0.029; T2–4 subgroup: 6% vs 50%, P = 0.028) and longer time to recurrence (DOI ≥3 mm subgroup: 119 months vs 96 months, P = 0.042; T2–4 subgroup: 117 months vs 56 months, P = 0.031) than observation of the neck. On multivariate analysis, close/involved margins were associated with an increased risk of overall mortality (hazard ratio 3.4, 95% confidence interval 1.0–11.3, P = 0.043) and disease recurrence (hazard ratio 2.8, 95% confidence interval 1.1–7.1, P = 0.031). In maxillary OSCC, a ≥ 5 mm histological margin should remain the goal of ablative surgery. END should be considered in tumours with DOI ≥ 3 mm.     

Significance of myofibroblasts in oral squamous cell carcinoma

J Oral Pathol Med (2011) 40 : 201–207 It is now recognized that the tumor microenvironment makes significant contribution to tumor progression. Activated fibroblast endothelial cells, inflammatory cells, and various extra cellular matrix components are parts of this microenvironment. Most of the activated fibroblasts are α‐smooth muscle actin–positive myofibroblast that often represent the majority of tumor stromal cells. Their production of growth factors chemokines and extracellular matrix facilitates tumor growth. Myofibroblast have been demonstrated in close to 50% of oral squamous cell carcinomas. In this review, we highlight the histological distribution of myofibroblast in oral squamous cell and the myofibroblast relation to tumor growth on prognosis.     

Marginal or segmental mandibulectomy: treatment modality selection for oral cancer: a systematic review and meta-analysis

Surgery is the most well established mode of initial definitive treatment for the majority of oral cancers. The most important decision in terms of tumour ablation in oral cancers when the jaws are potentially involved is the management of the mandible. The aim of this study was to explore the differences in survival rate and disease control between patients undergoing marginal mandibulectomy and patients undergoing segmental mandibulectomy using a systematic review and meta-analysis approach. A total of 15 cohort studies, including 1672 participants, were identified. Meta-analysis provided weak evidence in favour of segmental mandibulectomy for local control. Segmental mandibulectomy gave 73% better disease-free survival than marginal mandibulectomy when the marrow was invaded (P = 0.04). The overall survival rate was evaluated, and no statistically significant difference was found between the two different mandibulectomy approaches, although the results showed a trend in favour of segmental mandibulectomy which could increase the overall survival by 23%. Based on these findings regarding the survival rate and efficacy of disease control, this study indicates that a marginal mandibulectomy may be recommended for cases with no invasion or superficial invasion of the mandibular cortex, and a segmental mandibulectomy may be a more reasonable choice for patients with extensive mandibular cortex invasion or medullary invasion.     

Biopsy of the sentinel lymph node in oral squamous cell carcinoma: analysis of error in 100 consecutive cases

UK national guidelines in 2016 recommended that sentinel lymph node biopsy should be offered to patients with early oral cancer (T1-T2 N0) in which the primary site can be reconstructed directly. This study describes the pitfalls that can be avoided in the technique of biopsy to improve outcomes. We retrospectively analysed the data from 100 consecutive patients and recorded any adverse events. Lymphatic drainage of tracer failed in two patients as a result of procedural errors. Two patients with invaded nodes developed recurrence after total neck dissection, one after micrometastases had been diagnosed, and the other as a result of extranodal spread that had led to understaging and therefore undertreatment. Two results would not have been mistakenly classified as clear if all the harvested nodes had been analysed histologically according to the protocol. The disease-specific (96%) and disease-free (92%) survival were better than expected for a group of whom a third had stage 3 disease. If all harvested nodes had been analysed by the correct protocol then two of the three nodes wrongly designated clear would have been detected, two deaths potentially avoided, and the false-negative rate would have fallen from 8.3% to 2.7%. We conclude that minor deviations from protocol can result in a detrimental outcome for the patient.     

The cellular and molecular mechanisms of bone invasion by oral squamous cell carcinoma

Oral squamous cell carcinomas (SCCs) are malignant tumours that frequently invade the mandibular bone and bone invasion is a common clinical problem. Recent studies have revealed that bone resorption by osteoclasts is an important step in the process of bone invasion by oral SCCs. However, the cellular and molecular mechanisms of bone invasion by oral SCCs remain unclear. Oral SCCs invade the mandibular bone through an erosive, mixed or infiltrative pattern that correlates with clinical behaviours. The expressions of interleukin (IL)-6, IL-11, tumour necrosis factor (TNF) α and parathyroid hormone-related protein (PTHrP) were higher in the infiltrative pattern than in the erosive pattern. These cytokines lead to receptor activator of NF-κB ligand (RANKL) expression or osteoprotegerin (OPG) suppression not only in oral SCC cells but also in cancer stromal cells to induce osteoclastogenesis. Taken together, oral SCCs provide a suitable microenvironment for osteoclastogenesis to regulate the balance of RANKL and OPG. In this review, we introduce recent advances in the knowledge of the cellular and molecular mechanisms, by which oral SCC invades mandibular bone based on the recent findings of our lab and others.     

Influence of close resection margins on local recurrence and disease-specific survival in oral and oropharyngeal carcinoma

There is a lack of consistency among published reports in the definition of what constitutes close resection margins (1-5mm) in the surgical treatment of oral and oropharyngeal squamous cell carcinoma (SCC). Our aim was to define what would constitute close resection margins in predicting local recurrence and disease-specific survival. The study comprised 192 previously untreated patients with oral and oropharyngeal SCC who were recruited at the Southern General Hospital, Glasgow, from 2001 to 2007 with a minimum follow-up of 2 years. Resection was the primary treatment and the surgical margins were recorded for all patients. Statistical analyses were aided by the Statistical Package for the Social Sciences, version 15.0, and MedCalc software. The status of the surgical margins was evaluated using a receiver operating characteristic (ROC) curve to define the cut-off point. Cox's proportional hazard model was used to establish predictive factors for local recurrence and disease-specific survival. Of 192 patients, 23 (12%) had involved margins (<1.0mm), 107 (56%) had close margins (1.0-2.0mm (16.1%); 2.1-3.0mm (12%); 3.1-4.0mm (10.4%); 4.1-5.0mm (17.2%), and 62 (32.3%) had clear margins (>5mm). No predictive cut-off point was found that related close surgical margins to local recurrence. However, there was a significant adverse association between surgical margins ≤1.6mm and disease-specific survival. In recommending postoperative adjuvant treatment for oral and oropharyngeal SCC, we suggest that surgical margins within 2mm should be considered as the cut-off. However, other clinical and pathological prognostic factors should also be taken into consideration when recommending further treatment.     

Use of Lugol's iodine in the resection of oral and oropharyngeal squamous cell carcinoma

We evaluated the use of Lugol's iodine in achieving surgical margins free from dysplasia, carcinoma in situ, and invasive carcinoma by an observational study of two series of 50 consecutive patients having resection of oral and oropharyngeal squamous cell carcinoma (SCC) between November 2004 and March 2007.     

Cancer stem cell immunophenotypes in oral squamous cell carcinoma

J Oral Pathol Med (2011) 40 : 135–142 Background: The presence of cancer stem cell (CSC) antigens can be evidenced in some human tumors by phenotypic analysis through immunostaining. This study aims to identify a putative CSC immunophenotype in oral squamous cell carcinoma (OSCC) and determine its influence on prognosis. Methods: The following data were retrieved from 157 patents: age, gender, primary anatomic site, smoking and alcohol intake, recurrence, metastases, histologic classification, treatment, disease‐free survival (DFS), and overall survival (OS). An immunohistochemical study for CD44 and CD24 was performed in a tissue microarray of 157 paraffin blocks of OSCCs. Results: In univariate analysis, the immunostaining pattern showed significant influences in relation to OS for alcohol intake and treatment, as well as for the CD44⁺ and CD44^?/CD24^? immunophenotypes. The multivariate test confirmed these associations. Conclusions: Based on our results, the CD44 immunostaining and the absence of immunoexpression of these two investigated markers can be used in combination with other clinicopathologic information to improve the assessment of prognosis in OSCC.     

Oral squamous cell carcinoma in two siblings with Fanconi anemia after allogeneic bone marrow transplantation

Fanconi Anemia patients are a high risk group for solid and hematologic malignancies. The risk seems to be influenced by age, chronic graft versus host disease and immunosuppressive drug regimens. Reports of oral malignant transformation in Fanconi Anemia after hematopoietic stem cell transplantation (HSCT) are increasing probably because of longer survival rates. This is the report of an 18‐ and her 28‐year old sister who developed a post‐HSCT oral squamous cell carcinoma. There were significant differences regarding time to malignant transformation, marrow donor characteristics and graft versus host disease evolution and treatment. The report reinforce the need for a routine head and neck screening for cancer in this particular syndrome and suggest that familial history should also be considered in Fanconi anemia patients at risk for oral malignancy after HSCT.     

Midkine expression in oral squamous cell carcinoma and leukoplakia

J Oral Pathol Med (2012) 41 : 21–26 Background: Midkine (MK), a 13‐kDa heparin‐binding growth factor, is overexpressed in various human cancers. However, its role in the development and progression of oral cavity squamous cell carcinoma (OCSCC) is still unclear. Thus, the aim of this study was to evaluate the expression of MK in samples of OCSCC, leukoplakia, and healthy oral mucosa (control). Methods: Surgically excised specimens from patients with primary OCSCC (n = 28) were immunostained for MK, Ki‐67, PCNA, p53, bcl‐2, Bax, and CD31. Besides this, MK expression was also investigated in leukoplakia and normal oral mucosa. The relationship of MK⁺ cells with clinical parameters (tumor location, tumor size, lymph node metastasis, and survival) and microscopic parameters (WHO histological grading, intensity of inflammation, proliferation index, apoptosis, and angiogenesis) was also evaluated. Results: The results showed that MK expression was increased in OCSCC in relation to leukoplakia and normal mucosa. Furthermore, MK expression was increased in late‐stage tumors (T3/T4) compared with early‐stage lesions (T1/T2). MK‐positive lesions also showed increased expression of the anti‐apoptotic protein bcl‐2. Conclusion: OCSCC, particularly late‐stage tumors, exhibits increased MK expression, which may be involved in tumor progression via upregulation of anti‐apoptotic genes, as shown by the augmented bcl‐2 positivity in MK‐positive tumors.     

Outcomes of oral squamous cell carcinoma arising from oral epithelial dysplasia: rationale for monitoring premalignant oral lesions in a multidisciplinary clinic

Surveillance of oral epithelial dysplasia results in a number of newly diagnosed cases of oral squamous cell carcinoma (SCC). The clinical stage of oral SCC at diagnosis influences the magnitude of treatment required and the prognosis. We aimed to document the stage, treatment, and outcome of oral SCC that arose in patients who were being monitored for oral epithelial dysplasia in a dedicated multidisciplinary clinic. Those with histologically diagnosed lesions were enrolled on an ethically approved protocol and molecular biomarker study. Details of clinical and pathological TNM, operation, radiotherapy, recurrence, second primary tumour, and prognosis, were recorded in patients whose lesions underwent malignant transformation. Of the 91 patients reviewed (median follow-up 48 months, IQR 18-96), 23 (25%) had malignant transformation. All were presented to the multidisciplinary team with stage 1 disease (cT1N0M0). Of these, 21 were initially treated by wide local excision, 2 required resection of tumour and reconstruction, and 2 required adjuvant radiotherapy. At follow-up 3 had local recurrence, one had regional recurrence, one had metachronous lung cancer, and 5 had second primary oral SCC. There were further diagnoses of oral dysplasia in 5 during follow-up, and it is estimated that 76% of patients will have one or other event in 5 years. Disease-specific survival was 100% and overall survival was 96% (22/23). Median follow-up after diagnosis of oral SCC was 24 months (IQR 11-58). Specialist monitoring of oral epithelial dysplasia by a multidisciplinary team allows oral SCC to be detected at an early stage, and enables largely curative treatment with simple and usually minor surgical intervention. The high incidence of second primary oral SCC in high-risk patients with oral epithelial dysplasia further supports intensive targeted surveillance in this group.