Occurrence of Second Oral Potentially Malignant Disorder following Excision of Primary Lesion: A Prospective Study of Cases from a Tertiary Care Centre

BackgroundEarly diagnosis and timely management of potentially malignant oral disorders may prevent malignant transformation and prompt diagnosis of frank malignancies favours better prognosis. The aim of this study was to evaluate the outcome of surgical management of oral potentially malignant disorders of the oral cavity and observe the prevalence of recurrence at the primary site and occurrence of another potentially malignant lesion in these patients. MethodsThe study participants included patients who had undergone clinical oral examination, surgical excision of biopsy-proven cases of dysplastic oral potentially malignant disorders (leukoplakia, erythroplakia, non-healing ulcerative and erosive areas, etc.) who were on routine follow-up as per the standard guidelines. These patients were followed up closely during each monthly follow-up visit for the first year. The patients were then prospectively analysed for any recurrence of lesion. On follow-up visits, detailed clinical oral examination was done to note the prevalence of a new lesion in any oral cavity sub site other than the previous site. If a new lesion was detected, then biopsy followed by surgical excision was followed as per standard guidelines. The follow-up period after the second surgical intervention was 12 months.ResultsFifty patients with potentially malignant oral disorders underwent surgical excision. The majority of the study subjects were males (39/50) and 41 of them were below 65 years of age. Of 50 patients, 13 (26%) had second oral potentially malignant lesion other than the primary site. The rate of recurrence of the lesions at the primary site was 4% (2/50). Of these patients with recurrence, all had malignant transformation (2/2). Also, patients who were initially diagnosed with moderate dysplasia had a higher chance of recurrence. A second lesion at a site different from the primary lesion was seen in 26% of the cases.ConclusionSurgical management of such lesions with one-centimetre oncological margins in all dimensions contrary to the routine five millimetre surgical margins reduces the chance of recurrence.     

口腔粘膜上皮异常增生和鳞癌组织中凋亡蛋白Bax的表达研究

目的 研究凋亡相关蛋白Ｂａｘ在口腔正常粘膜、上皮异常增生和鳞癌组织中表达及意义。方法 采用免疫组化方法检测１０例正常粘膜、１０例单纯性增生上皮、３２例异常增生上皮１９例高分化鳞癌、９例低分化鳞癌石蜡包理样本中Ｂａｘ的表达。结果 正常粘膜中见Ｂａｘ弱表达局限于角化层。上皮单纯增生时Ｂａｘ表达较正常组增强,轻度异常增生时反面较单纯增生下降,随异常增生程度加重,Ｂａｘ明显增加。癌变时Ｂａｘ表达较正常组增     

The clinical relevance of epithelial dysplasia in the surgical margins of tongue and floor of mouth squamous cell carcinoma: an analysis of 37 patients

BACKGROUND: The clinical relevance of the presence of epithelial dysplasia in the margins of surgically removed oral squamous cell carcinoma is still unclear. METHOD: In a retrospective study, the presence of mild or moderate epithelial dysplasia in the surgical margins of tongue and floor of mouth squamous cell carcinoma was examined histologically. Patients with tumor cells within 0.5 cm of the surgical margins were excluded. Also patients with severe dysplasia were excluded, as this is usually regarded as carcinoma in situ. Patients that received postoperative irradiation were also excluded. Only patients who completed a follow-up period of five years were included. All together, a total number of 37 patients fulfilled the inclusion criteria. RESULTS: Epithelial dysplasia was observed in 7 out of the 37 patients. Five of these patients, and two of the 30 patients with no dysplasia, had a local recurrence (P < 0.01). CONCLUSION: The presence of mild or moderate epithelial dysplasia in the margins of surgically removed oral squamous cell carcinoma carries a significant risk for the development of local recurrence. However, it should be noted that this study was of a retrospective nature and that the group of patients with epithelial dysplasia in the surgical margins was rather small. On the other hand, the inclusion criteria were somewhat strict, by limiting the oral subsite to tongue/floor of mouth, by excluding patients in whom tumors cell were found within 0.5 cm of the surgical margins and by excluding patients who received postoperative radiotherapy, amongst others.     

Elevated ras p21 expression in oral premalignant lesions and squamous cell carcinomas in Taiwan

Expression of ras p21 oncoproteins was examined in histological sections of oral squamous cell carcinoma (SCC), epithelial dysplasia, epithelial hyperkeratosis and normal oral mucosa using antibodies to ras p21 with an immunoperoxidase technique. Ras p21-positive staining was found in 47 of 51 (92.2%) cases of oral SCC, 4 of 4 (100%) cases of epithelial dysplasia, 7 of 7 (100%) cases of epithelial hyperkeratosis, and 1 of 6 (16.7%) cases of normal oral mucosa. The positive staining rate of ras p21 in oral SCC, epithelial dysplasia or epithelial hyperkeratosis was significantly higher than that in normal oral mucosa (P<0.05). No correlation was found between ras p21 expression and patient age, tumour location, tumour size, clinical staging or histological differentiation of SCC. However, a significant positive correlation was found between ras p21 expression and patients' sex (P<0.05) or regional lymph node status (P<0.05). A significant positive correlation was also discovered between ras p21 expression and patients' smoking habits (P<0.01), as well as daily or total betel quid (BQ) consumption (P<0.05). Of the 47 immunostain-positive SCC patients, specimens from 6 patients were also obtained after chemotherapy, when ras p21 expression was found to be reduced. These results indicate that ras p21 over expression may play an important role in the initiation and progression of oral SCCs in patients who are smokers and BQ chewers.     

Genomic analysis to assess disease progression and recurrence in patients with oral squamous cell carcinoma: – a preliminary study

We studied the progression from dysplasia to invasive carcinoma and subsequent second primaries or locoregional recurrences in 11 patients with recurrent squamous cell carcinoma (SCC). Between one and six samples were sequenced/patient. DNA samples were prepared, and libraries multiplexed to between 40 and 80 samples/lane of an Illumina HiSeq 3000 and sequenced with 2 × 100 bp paired end sequencing. Copy number data were generated by CNAnorm (Bioconductor package). Samples of recurrent SCC showed unique patterns of descent when compared with earlier samples from the primary tumour, and three main patterns emerged. In four patients there was convincing evidence that the later lesion was descended directly from cells from the first, and in a further four there were no detectable genomic events between the two lesions. Three patients had some shared events between the early and later lesions, but although there were enough differences to deduce that the two lesions had a shared ancestor, they were not directly descended from each other. We present the patients’ characteristics in detail, including the overall survival in each group. There was a distinct genomic pattern after a second episode of SCC in all the groups. A larger study that uses similar methods and a longer duration could provide reliable conclusions with respect to survival. With the use of new techniques, genomic data can be available to clinical teams during the planning of treatment.     

Current thinking in management of the neck (including contralateral neck) in ipsilateral recurrent or second primary oral squamous cell carcinoma

Metastasis to the neck in patients with oral squamous cell carcinoma (SCC) has a huge impact on long-term survival and prognosis, and its incidence varies. Due consideration therefore should be given to management of the neck in each individual case. The pathways in patients with primary oral SCC are well-established, but there is a paucity of published papers on management of the neck in those with ipsilateral recurrent or second primary oral SCC whose necks have previously been operated on with or without radiotherapy or chemoradiotherapy, or treated with radiotherapy or chemoradiotherapy alone. These patients may be under treated because of failure to stage the most likely drainage site, and are likely to have a worse outcome if there is macroscopic recurrence in the neck after independent treatment of the recurrent or second primary tumour. Based on the current review, we think there is a need for a multicentre, collaborative, retrospective review of the outcomes of patients with ipsilateral second primaries or recurrent oral SCC in the previously treated neck. Our recommendations include consideration of positron emission tomography-computed tomography in all patients with recurrent or second primary oral SCC (if “hot” – neck dissection, if “cold” - sentinel node biopsy); consideration of sentinel node biopsy in all patients with recurrent or second primary oral SCC who have previously had treatment to the neck; and finally, consideration of definitive management of the sentinel biopsy zone or region if the node is invaded.     

Incidence,timing, presentation,treatment, and outcomes of second primary head and neck squamous cell carcinoma after oral cancer

After their initial presentation of oral squamous cell carcinoma (SCC), patients have a lifelong risk of developing another new SCC of the head and neck. The aim of this study was to establish second primary rates, baseline characteristics (site, clinical or pathological stage, and smoking and alcohol history), timing, presentation, treatment, and outcomes. From the regional unit we analysed records of patients treated with curative intent for their first oral cancer between 2002 and 2007 inclusive. All patients had had at least 10 years of follow up either to death or the end of 2017. A total of 347 patients had been treated with curative intent, and of them, 29 had a second primary at a median (IQR) of 52 (30-79) months after the index operation. The incidence of developing a second primary tumour within two years was 1.7% (95% CI: 0.7% to 3.7%), within five years was 4.9% (95% CI: 2.9% to 7.7%), and within 10 years was 7.8% (95% CI: 5.1% to 11.1%). Early stage of first cancer was the only significant factor (p = 0.001) for development of a second primary within 10 years, reflecting survivorship. Most second primaries (21 patients) were staged as early, and by visual inspection. Most (n = 20) were within the oral cavity, one of which overlapped the oropharynx; eight others were in the oropharynx, and one in the larynx. Most patients (n = 22) were treated by operation with curative intent. Three were treated palliatively. Patients need to be aware of the risk of a second primary and, as most are in the mouth or oropharynx, there is a role for surveillance by primary dental care practitioners.     

Prognostic value of hypercalcaemia and leucocytosis in resected oral squamous cell carcinoma

Hypercalcaemia and leucocytosis are common in our patients with progressive oral squamous cell carcinoma (SCC). However, the precise incidence, prognostic value, and correlation with the condition of the tumour remain obscure. A total of 618 patients with oral SCC who were treated primarily between 2007 and 2012 and had serum calcium concentrations and white blood cell count (WCC) measured postoperatively were included in the study. Primary TNM stage, pathological features, and the presence of locoregional recurrence or distant metastasis after comprehensive surgical treatment were recorded. The incidence of hypercalcaemia was 9.1% and that of leucocytosis 7.2%. Hypercalcaemia correlated significantly with size of primary tumour (T status), nodal involvement (N status), TNM stage, perineural invasion, lymphovascular permeation, and recurrence or metastasis of disease. Leucocytosis, however, correlated only with T status, lymphovascular permeation, and recurrence or metastasis. In multivariate analysis of survival, recurrence, metastasis, hypercalcaemia, and leucocytosis were strong independent prognostic factors. Median survival was low if the patient had hypercalcaemia or leucocytosis (179 (range 3–73) days if the patient had distant metastasis, and 43 (range 3–102) days if the patient had locoregional recurrence). The incidence of hypercalcaemia and leucocytosis was high during the course of the disease, and both conditions have an adverse impact on survival from oral SCC. Periodic evaluation of serum calcium concentrations and WCC should be routine during the postoperative period.     

Outpatient follow-up appointments for patients having curative treatment for cancer of the head and neck: are the current arrangements in need of change?

Although there are recommendations, there is little evidence about the rationale for the frequency and duration of review appointments for patients with cancer of the head and neck. We have recorded the pattern of follow-up in a tertiary cancer centre and its association with survival and recurrent disease. We used clinical letters and a prospectively maintained database to obtain details on 297 patients who were treated curatively for squamous cell carcinoma (SCC) of the oral cavity between 2005 and 2008. Mean (SD) age was 63 (12) years and 58% (n = 171) were male. Most patients were seen about 6 times in year one, 3 times in year 2, twice in year 3, twice in year 4, once or twice in year 5, and once yearly beyond year 5. Fewer clinics were scheduled for and attended by patients over 75 years of age, those with overall clinical grades 0-1, and those treated by operation alone in contrast to those who also had adjuvant radiotherapy. Patients were usually seen about 15 times over the 5 years. Taking into account the stage of the tumour and overall mortality, the number and timing of follow-up visits is adequate for the needs of patients with stage II-IV disease. Those with stage I disease may be considered for discharge after the third year if they are told about the risk factors, and signs and symptoms of recurrent disease, and surveillance in primary care.     

Long-term quality of life measured by the University of Washington QoL questionnaire (version 4) in patients with oral cancer treated with or without reconstruction with a microvascular free flap

We used the University of Washington Quality of Life (UW-QoL) questionnaire (version 4) to assess the long-term quality of life (QoL) of patients with oral squamous cell carcinoma treated with or without reconstruction with a microvascular free flap, and all patients with T2–T4 oral squamous cell carcinoma (SCC) treated in this way were eligible for the study. A total of 139 patients’ personal details, medical history, and QoL scores were collected and analysed. The mean (SD) overall QoL score was 73.09 (14.8) for patients with T2–T4 oral SCC. The mean (SD) global QoL scores of patients who had had reconstructions was 75.68 (13.85) and of patients who had not 71.00 (15.34) (t = 1.864, df = 137, p = 0.064). Univariate and multivariate analyses indicated that site of tumour, T stage, and the need for postoperative radiotherapy had significant effects on the global QoL scores. Among patients with T2 oral SCC there was no significant difference between patients who did and did not have reconstructions. However, there were significant differences among patients with T3/T4 SCC in scores for appearance, recreation, mood, anxiety, chewing, swallowing, and speech depending on whether they did or did not have reconstructions. There were significant differences in the domains recreation, chewing, speech, and taste, depending on the primary site of the tumour. We conclude that reconstruction with a microvascular free flap had a beneficial effect on the treatment of SCC and improved the QoL of patients with oral SCC.     

Recurrence patterns of oral leukoplakia after curative surgical resection: important factors that predict the risk of recurrence and malignancy

J Oral Pathol Med (2012) 41 : 682–688 Background: Oral leukoplakia can be treated using a variety of treatment procedures; however, the lesions recur in many cases irrespective of the treatment procedure used. The rate of recurrence was from 7.7% to 38.1%. This study aims to identify the important factors that can lower the risk of recurrence of oral leukoplakia treated by curative surgical resection. Methods: The clinical records of 52 patients with oral leukoplakia (53 lesions) who underwent curative surgical resection between 2004 and 2009 were retrospectively analyzed for the rate of recurrence, clinical outcome, epithelial dysplasia, lesion location, and resection margins. Results: The recurrence rate following curative surgical resection was 15.1%, with the most common site being the gingiva. Malignant transformation occurred in a single patient (1.9%). Minimal resection margins (<3 mm) were observed in many patients with recurrent disease, and recurrence was more likely in cases with positive margins (epithelial abnormalities at the resection margins) than in those with negative margins. There was no significant association between recurrence and the degree of epithelial dysplasia. Conclusions: Our data suggest that surgical resection of oral leukoplakia is curative only if all areas of epithelial abnormalities are identified and resected. Moreover, an adequate resection margin may reduce the risk of recurrence.     

Immunohistochemical evaluation of hedgehog signalling in epithelial/mesenchymal interactions in squamous cell carcinoma transformation: a pilot study

Precancerous lesions have been studied because of their carcinogenic potential and their association with squamous cell carcinoma (SCC) has been reported. In the tumour microenvironment, the processes of angiogenesis and tissue remodelling are regulated by a family of proteins (Hedgehog) described as being able to modulate epithelial/mesenchymal interactions. The objective of this study was to perform a comparative study of precancerous lesions and SCCs by immunohistochemistry for the presence of Sonic, Gli2, SMO and Patched proteins, members of the Hedgehog pathway. Sixteen cases diagnosed as actinic cheilitis associated with SCC were compared to normal oral mucosa. The sections were subjected to immunohistochemistry and the positively stained cells were counted by morphometric analysis. There was a significant progressive increase in expression of all proteins of the Hedgehog pathway, both in the epithelium and in the connective tissue, when sections of normal mucosa, dysplasia and carcinoma were compared (P < 0.05). Thus, one may suggest that the Hedgehog pathway in tumour transformation influences SCC, and more studies should be conducted to expand the understanding of the role of these proteins in neoplastic transformation.     

Sites of recurrence in oral and oropharyngeal cancers according to the treatment approach

OBJECTIVE: The purpose of this study is to evaluate the rates and the sites of tumour recurrence in patients with oral and oropharyngeal carcinomas. DESIGN: This is a retrospective study of a series of cases treated in a single institution. PATIENTS AND METHODS: A series of 2067 patients with oral and oropharyngeal squamous carcinoma, treated from 1954 to 1998 were analysed. The treatment approach was: surgery, 624 cases (30.2%); radiotherapy alone, 729 cases (35.3%); radiotherapy and surgery, 552 cases (26.7%) and radiotherapy and chemotherapy, 162 cases (7.8%). MAIN OUTCOME MEASURES: Tumour recurrence was observed in 1079 patients (52.2%): 561 cases of local recurrences (27.1%); 168 neck recurrences (8.1%); 252 locoregional recurrences (12.2%); 59, distant metastasis (2.9%) and 39 (1.9%), combination of distant metastasis with local, neck or locoregional recurrence. RESULTS: The rates of recurrence varied significantly according to the treatment performed. Oral cavity cancer patients undergoing radiotherapy alone or in combination with chemotherapy presented the highest rates of neck recurrences (22.5 and 40.0%, respectively) for clinical stage (CS) I/II and of local (41.2 and 30.1%) and locoregional (21.7 and 31.1%) recurrences for CS III/IV; yet, for CS III/IV, surgery without neck dissection was associated with the highest rates of neck recurrences (20.7%), but no differences were observed in the rates of local or locoregional recurrences for CS I/II patients. For oropharynx cancer patients with CS I/II there was no difference in the rate of locoregional failures according to the treatment. However, patients with CS III/IV undergoing radiotherapy present a highest rate of local (42.3%) and locoregional (28.8%) failures. CONCLUSION: The results suggest that surgery should be the first option for initial clinical stage oral and oropharyngeal cancers. For advanced cases independently of the site of the tumour, surgery and postoperative radiotherapy should be the standard of care because it is associated with the lowest rates of locoregional recurrence.     

Increase in placental glutathione S-transferase in human oral epithelial dysplastic lesions and squamous cell carcinomas

This study investigated the immunohistochemical expression of human placental glutathione S-transferase (GST-φ) in the epithelium of oral premalignant and malignant lesions. Epithelial lining of normal oral mucosa, hyperplastic lesions and oral epithelium exhibiting mild dysplasia showed weak to moderate GST-φ staining. Moderate epithelial dysplasia revealed an increased antibody content while severe dysplasia. carcinoma- in-situ (CIS) and squamous cell carcinoma (SCC) demonstrated markedly increased antibody binding. The GST-φ staining was evident mainly in the cytoplasm. Severe dysplasia. CIS and SCC were also characterized by areas of cells with intensive nuclear GST-φ staining. These findings support the hypothesis that GST-φ plays a role in human oral carcinogenesis and may be used as a tumor marker for human oral premalignant and malignant lesions.     

CD44 variant 6 (CD44v6) expression as a progression marker in benign, premalignant and malignant oral epithelial tissues

The change in the expression pattern of CD44 variant 6 (CD44v6) protein in benign, premalignant, and malignant (SCC) oral epithelial lesions was studied immunohistochemically and compared with the pattern in normal mucosa in order to examine whether this gene can serve as a progression marker in patients with SCC. The principal finding is that CD44v6 expression was clearly downregulated in most cases of severe premalignant lesions as well as in most of the SCCs. The staining pattern and intensity varied according to the degree of dysplasia and to the degree of differentiation of the SCCs. Premalignant severe epithelial dysplasia cases with early features of invasion, not yet developed into SCC, showed distinctly downregulated expression of CD44v6 protein whereas hyperplastic and benign epithelial lesions (papilloma) expressed positive staining patterns comparable to those of the normal counterparts. The authors conclude that alteration in CD44v6 may occur as an early event in primary oral SCC development, as well as in premalignant severe epithelial dysplasia. It can thus, be used as a molecular progression marker when screening for oral cancer.     

Clinical evaluation of Lugol's iodine staining in the treatment of stage I-II squamous cell carcinoma of the tongue

Oral squamous cell carcinoma (OSCC) is often surrounded by epithelial dysplasia; leaving it unresected can result in local recurrence. Staining with Lugol's iodine solution detects epithelial dysplasia in oral mucosa, but whether it decreases local recurrence after OSCC surgery is unknown. This study investigated local recurrence rates in patients with early tongue cancer who underwent surgery using Lugol's staining. 93 patients with T1-2N0 tongue SCC underwent partial glossectomy using Lugol's staining during surgery. Resection was performed at least 5 mm from the margin of the unstained area. Patients were investigated retrospectively for local recurrence status. Postoperative histology revealed negative surgical margins for SCC or epithelial dysplasia in 81 patients, close margins for SCC in 5, positive margins for mild epithelial dysplasia in 6, and a positive margin for SCC in one. Those with a positive or a close margin for SCC underwent additional resection 2-4 weeks after surgery; one was proved histologically to have residual SCC. No patients developed local recurrence, but 2 died of neck metastasis and 2 of distant metastasis. The 5-year disease specific survival rate was 93.8%. Lugol's staining during surgery can reduce local recurrence and improve survival in patients with early tongue SCC.     

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.     

Gene expression analysis by oligonucleotide microarray in oral leukoplakia

Background:  Oral leukoplakias (LP) are the most frequent types of oral pre-cancerous lesions, but there is no accurate assessment of this malignant transformation or even genetic diagnosis of the oral epithelial dysplasia. We need to identify the new genetic diagnosis system of the epithelial dysplasia.
Methods:  Oligonucleotide microarray was used to analyze expression patterns of 29 952 genes in 10 LP patients. We compared the different gene expressions between mild dysplasia cases and severe dysplasia cases.
Results:  Ninety-six genes expressed differentially were selected as candidates for up-regulated in severe dysplasia. Subsequently, we further selected 16 genes with highest differentially expression. By hierarchical clustering analysis, the 10 cases were divided mild dysplasia from severe dysplasia.
Conclusions:  The 16 genes are suggested as biomarker gene sets of efficacy and quickly recognized in the development of oral epithelial dysplasia.     

Collagen XVIII modulation is altered during progression of oral dysplasia and carcinoma

Background:  Collagen XVIII is a ubiquitous basement membrane (BM) component and a precursor of endostatin.
Methods:  Using immunohistochemistry and in situ hybridization, we studied the expression and localization of collagen XVIII in different stages of normal oral wound healing, epithelial dysplasia and squamous cell carcinoma (SCC).
Results:  In mild epithelial dysplasias collagen XVIII appeared as a continuous signal in the BM, whereas in severe epithelial dysplasias and in the invasive areas of oral SCCs collagen XVIII was absent. In situ hybridization showed that collagen XVIII mRNA expression did not decrease in severe dysplasia or oral carcinoma samples when compared with the mild dysplasias.
Conclusions:  The results indicate that the absence of collagen XVIII protein in severe oral dysplasias is related to the processing of the protein rather than to changes in mRNA expression.