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Background
Cancer of the oral cavity is the sixth most common malignancy in developed countries accounting for 3% of all malignancies. Commonly accepted risk factors include tobacco chewing or smoking and alcohol. In some countries, such as India and the Southeast Asian region, up to 50% of all cancers arise in the oral cavity. In these countries, betel quid consumption also plays an important role. It is well known, however, that many cases of oral cancer develop without prior exposure to the previous agents. In these cases, viruses, diet, or genetic predisposition have been hypothesized to play a role.
OUTLINE
Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Histopathological Features and Variants Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
PATHOGENESIS CHARACTERIZATION BETA-CATENIN
- Abnormal beta-catenin expression in oral cancer with no gene mutation: Correlation with expression of cyclin D1 and epidermal growth factor receptor, Ki-67 labeling index, and clinicopathological features.
Odajima T, Sasaki Y, Tanaka N, Kato-Mori Y, Asanuma H, Ikeda T, Satoh M, Hiratsuka H, Tokino T, Sawada N.
Hum Pathol. 2005 Mar;36(3):234-41. Abstract quote
Summary beta -Catenin not only acts as a regulator of E-cadherin-mediated cell-cell adhesion but also plays an important role in Wnt signaling. To assess the prevalence of Wnt signaling, we examined beta -catenin mutation and its immunohistochemical protein expression in oral cancers. The results were linked with expression of cyclin D1, one of the target genes of Wnt signaling, expression of epidermal growth factor receptor (EGFR) relevant to beta -catenin tyrosine phosphorylation, Ki-67 labeling index, clinicopathological features, and survival.
In the analysis based on membranous expression of beta -catenin, 75 (68.2%) of 110 cases showed a reduced membranous pattern, and the remaining 35 (31.8%) had a preserved membranous pattern similar to that in oral epithelium. In the analysis of another category of beta -catenin expression, a cytoplasmic/nuclear pattern was observed in 21 (19.1%) of the 110 tumors. Most (19/21, 90.5%) of these tumors had a concomitant reduction of membranous expression of beta -catenin. The reduced membranous or cytoplasmic/nuclear pattern of beta -catenin was significantly associated with an invasive growth pattern, EGFR expression, an increased Ki-67 labeling index, and shorter survival but not with cyclin D1 expression. Mutational analyses of beta -catenin were performed for 39 cases, including the 21 tumors with a cytoplasmic/nuclear pattern, but no mutations in the beta -catenin gene exon 3 were detected in these samples.
Our data indicate that altered expression of beta -catenin may play an important role in tumor progression through increased proliferation and invasiveness under EGFR activation. However, mutations of beta -catenin do not appear to be responsible for tumor development and abnormal expression of beta -catenin in oral cancers.COX-2 PATHWAY
Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma.Gallo O, Masini E, Bianchi B, Bruschini L, Paglierani M, Franchi A.
Department of Oto-Neuro-Ophthalmologic Surgery, University of Florence Medical School, Florence, Italy.
Hum Pathol 2002 Jul;33(7):708-14 Abstract quote Prostaglandins play a critical role in tumor development and growth by regulating numerous biologic processes, including tumor angiogenesis, with clear prognostic and therapeutic implications.
The aim of this study was to investigate the prognostic relevance of cyclooxygenase-2 (COX-2) pathway activation in head and neck squamous cell carcinoma (HNSCC). COX-2 activity was analyzed in 52 consecutive patients by assessing protein expression and prostaglandin E(2) (PgE(2)) levels and was then correlated to vascular endothelial growth factor (VEGF) expression and tumor angiogenesis. We evaluated the prognostic impact of these parameters by Kaplan-Meier and Cox survival analysis. COX-2 expression by tumor cells was closely correlated to VEGF expression and to tumor vascularization. According to Kaplan-Meier analysis, patients with COX-2 tumor overexpression and with higher PgE(2) tumor levels had significantly shorter overall survival estimates (P = 0.022 and P = 0.033, respectively). Analogously, patients with more-vascularized tumors had worse survival than those with less-vascularized cancers (P = 0.032). Cox multivariate analysis demonstrated that the most significant prognostic factors were presence of lymph node metastasis, tumor vascularization, COX-2 protein expression, and PgE(2) tumor levels.
This study demonstrates a close correlation between COX-2 pathway, VEGF expression, and tumor angiogenesis in HNSCC. In addition, COX-2 overexpression and higher tumor vascularization appear to predict a shorter survival in patients with head and neck cancer.
EPSTEIN BARR VIRUS
Prevalence of Epstein-Barr virus in oral squamous cell carcinoma, oral lichen planus, and normal oral mucosa.Sand LP, Jalouli J, Larsson PA, Hirsch JM.
Goteborg University, Angelholm Hospital, and Uppsala University Hospital.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002 May;93(5):586-92 Abstract quote Objective. The Epstein-Barr virus (EBV) is associated with both malignant and benign diseases in the head and neck region. In several studies it has also been associated with oral squamous cell carcinoma (OSCC). Oral lichen planus (OLP) is a disease with unknown origin, and viral antigens have been proposed as etiologic agents. Smoking and alcohol habits are known risk factors for oral cancer development. In this study, the prevalence of EBV in OSCC and OLP was investigated, along with the effect of smoking, alcohol use, and age on EBV prevalence.
Study Design. We examined 29 patients with OSCC, 23 with OLP, and 67 with clinically healthy oral mucosa. For EBV DNA analysis, a nested polymerase chain reaction method was used.Results. The overall EBV prevalence in patients with oral disease was 32.1%. Of the OSCC patients, 37.9% were EBV positive; and of the OLP patients, 26.1% were EBV positive. Both percentages were statistically significant compared with that of control patients (7.3%). The difference in EBV prevalence between the smoking control group and the nonsmoking control group was insignificant. Increased age did not enhance EBV prevalence.
Conclusions. This investigation shows that EBV is present in oral diseases such as OSCC and OLP. Smoking, alcohol use, or age does not seem to be a risk factor for EBV infection. The etiologic role of EBV in OSCC and OLP needs to be examined in a prospective follow-up study.
Association of Epstein-Barr virus with oral cancers.Shimakage M, Horii K, Tempaku A, Kakudo K, Shirasaka T, Sasagawa T.
Clinical Research Institute, Osaka National Hospital, Japan.
Hum Pathol 2002 Jun;33(6):608-14 Abstract quote Epstein-Barr virus (EBV) persists in the epithelial cells of oral mucosa and often replicates on them. EBV is known to be a causative agent of nasopharyngeal carcinoma.
We suspect that EBV may be associated with oral cancers, and thus examined EBV expression on 28 tongues and 9 other oral cancers. We also examined 6 metastatic lesions in the lymph nodes. All cancers were squamous cell carcinoma (SCC). We used mRNA in situ hybridization, immunofluorescence staining, reverse transcriptase-polymerase chain reaction (RT-PCR), and polymerase chain reaction (PCR). The mRNA in situ hybridization using a probe comprising the transcripts of the BamHIW fragment of the EBV genome demonstrated EBV mRNA in the majority of tumor cells in all cases of oral cancer, but in none of the normal tissues.
RNA in situ hybridization using an EBER1 probe detected RNAs in 16 out of 24 cancers. Also, mRNA in situ hybridization using a probe of the EBV-determined nuclear antigen-2 (EBNA2) region detected positive signals in 9 out of 12 cancers. Furthermore, EBNA2, latent membrane protein-1 (LMP1) and BZLF1 were detected in these cancers by immunofluorescence staining, but were not detected in any of the epithelial cells of the normal tissues. Four out of 6 metastatic tissues showed stronger fluorescence than that in the primary tissues. RT-PCR analysis also showed EBER1 expression in 1 of the 3 tongue cancers. PCR detected the BamHIW sequence of EBV DNA in all cases, including the normal tissues tested.
These findings indicate that EBV may be involved in neoplastic transformation in oral cancers, such as nasopharyngeal carcinoma.
HEAT SHOCK PROTEINS
From the *Stomatology Department, School of Medicine and Dentistry, University of Santiago de Compostela; daggerDepartment of Pathology, "Gomez Ulla" University and Military Hospital, Madrid; double daggerDepartment of Pathology, University Hospital, Santiago de Compostela; and section signDepartment of Stomatology, University of the Basque Country/EHU, Leioa, Spain
Heat shock proteins (HSPs) play a significant role in cell proliferation, differentiation, and oncogenesis. HSP70 and HSP27 are constitutively and gradually expressed in a broad range of normal tissues and neoplasms, and their expression has been assessed as markers for oral epithelial dysplasia.
The study involved 43 patients with oral leukoplakia (OL): 23 were categorized as nondysplastic and 20 as dysplastic OLs. Immunohistochemistry was carried out with the monoclonal antibodies HSP70 and HSP27. The presence of epithelial dysplasia and its histologic grading was evaluated according to the World Health Organization classification: mild, moderate, and severe squamous epithelial dysplasia. Expression of HSPs within the epithelium was also evaluated. The difference in the percentage of HSP70 positive nuclei in nondysplastic and dysplastic OL reached statistical significance(Equation is included in full-text article.)95% confidence interval = 17.74-43.82; P = 0.000).
None of the 43 specimens analyzed showed positive nuclear immunostaining for anti-HSP27 antibody. No significant difference for HSP27 cytoplasmic expression could be identified between OL with or without epithelial dysplasia(Equation is included in full-text article.)95% confidence interval = 0.44-3.95; P = 0.89). It is concluded that the nuclear HSP70 immunoexpression could be an objective marker for the presence of the epithelial dysplasia in OL.HUMAN PAPILLOMAVIRUS Mod Pathol 2000;13:644-653.
Some of the main viruses include Epstein-Barr virus, human herpes virus 8, human cytomegalovirus, and human papilloma virus (HPV). Recently a study of 53 cases of neoplastic and potentially neoplastic oral lesions were examined for the presence of HPV. A combination of nested polymerase chain reaction (PCR), type-specific PCR, restriction fragment length polymorphism analysis (RFLP), dot blotting, and nonisotopic in situ hybridization (ISH) were utilized to search for the presence of HPV.
Nested PCR found HPV DNA in 91% (48/53) cases and in none of the normal control patients. The positivity was independent of histological findings and smoking history. High risk HPV types (16, 18, and 33), or HPV known to have oncogenic capability, were detected by type specific PCR in 98% (47/48 positive cases). HPV 16 was the predominant type in 71% of infected cases. Based upon these results, high risk HPV may play an important role in oral carcinogenesis.
Number of Patients 29 5 19 16 FIBROBLASTIC GROWTH FACTOR
Immunohistochemical localization of growth factors fibroblast growth factor-1 and fibroblast growth factor-2 and receptors fibroblast growth factor receptor-2 and fibroblast growth factor receptor-3 in normal oral epithelium, epithelial dysplasias, and squamous cell carcinoma.Wakulich C, Jackson-Boeters L, Daley TD, Wysocki GP.
University of Western Ontario.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002 May;93(5):573-9 Abstract quote Objectives. Fibroblast growth factors (FGFs) and their receptors (FGFRs) have been identified in a variety of carcinomas, but there are few studies concerning their presence in oral cancers. The objective of this study was to determine whether FGF-1, FGF-2, and high affinity receptors FGFR2 and FGFR3 are present in the pathogenesis of oral epithelial dysplasias and oral squamous cell carcinoma.
Study Design. Sections from formalin-fixed, paraffin-embedded samples of oral normal mucosa (n = 14), epithelial dysplasia (n = 20), carcinoma in situ (n = 10), and squamous cell carcinoma (n = 12) were tested for cytoplasmic staining by standard in situ immunohistochemistry with antibodies for FGF-1, FGF-2, FGFR2, and FGFR3.
Results. Staining for FGF-1 is decreased or lost in the development of epithelial dysplasia and carcinoma. Staining for FGF-2 showed increased intensity (although not statistically significant) in oral epithelial dysplasias and squamous cell carcinomas and showed a significant increased expression in the upper layers of dysplasias and stratum spinosum-like cells in squamous cell carcinomas. Staining for FGFR2 showed a statistically significant increase in intensity in all layers of epithelial dysplasias and squamous cell carcinomas. Staining for FGFR3 was found in the upper stratum spinosum cells of normal and dysplastic epithelium and well-differentiated squamous cells in squamous cell carcinomas, with a statistically significant increase in staining intensity in dysplastic and carcinomatous tissues.
Conclusions. The loss of FGF-1 is consistent with loss of differentiation in dysplasias and some squamous cell carcinomas. Changes in the localization of FGF-2 and FGFR2 into upper epithelial layers with increasing dysplasia suggest increased mitotic potential of high level cells. The co-localization of FGF-2 and its high affinity receptors in neoplastic tissues suggests an autocrine mechanism of influence on carcinogenesis.
PLAKOPHILINS
Immunohistochemical localization of plakophilins (PKP1, PKP2, PKP3, and p0071) in primary oropharyngeal tumors: Correlation with clinical parameters.Papagerakis S, Shabana AH, Depondt J, Gehanno P, Forest N.
Hum Pathol. 2003 Jun;34(6):565-72. Abstract quote Plakophilins (PKPs) are members of the armadillo multigene family. Armadillo-related proteins function in both cell adhesion and signal transduction, and also play a central role in tumorigenesis.
Here we report the immunohistochemical localization of PKPs in 37 cases of human primary squamous cell carcinoma of the oropharynx lacking overt distant metastases that were followed clinically for 3 years. Immunoreactivity for the PKPs PKP1, PKP2, PKP3, and p0071 (also known as PKP4) was assessed on frozen unfixed sections using a semiquantitative scoring system.
Results were correlated with tumor grade, clinicopathologic parameters, and patient survival. Only p0071 was associated with tumor growth, demonstrating an inverse correlation with tumor size. PKP1 and PKP3 immunoreactivity was inversely correlated with tumor histological grade and was observed only in tumors that did not metastasize. In contrast, strong PKP2 immunoreactivity was observed in 85.7% of metastatic tumors. Interestingly, patients with tumors in which PKP1 and PKP3 immunoreactivity was reduced or absent exhibited local recurrences or metastases, or both, as well as poor survival.
Correlation of the subcellular localization of PKPs with routine histological and clinical parameters suggests that these proteins may serve as useful markers for predicting the clinical outcome of the disease. Although the 4 PKPs displayed different levels and patterns of subcellular distribution in tumors, there was a positive correlation between immunoreactivity for PKP2 and PKP3, as well as for PKP2 and p0071, suggesting possible functional similarities associated with differentiation, tumor growth, and disease prognosis.
Nevertheless, the mechanisms involved in altering the subcellular localization in tumors compared with normal epithelium are unknown, and further investigation is needed to determine whether PKPs are causative factors for oral carcinogenesis or are merely characteristic of the phenotype.
p53
Differential expression of p53 gene family members p63 and p73 in head and neck squamous tumorigenesis.Choi HR, Batsakis JG, Zhan F, Sturgis E, Luna MA, El-Naggar AK.
Departments of Pathology, Biostatistics, and Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
Hum Pathol 2002 Feb;33(2):158-64 Abstract quote p73 and p63 are recently cloned genes that share considerable structural and functional homologies with the p53 tumor suppressor gene. These genes, unlike p53, express multiple mRNA isoforms with variable biologic functions, and their suppressor nature has yet to be confirmed.
To determine the interrelationship between these genes in the tumorigenesis of head and neck squamous carcinoma (HNSC), we performed immunohistochemical analyses of their protein products and compared the data with clinicopathologic parameters in 38 patients. In histologically normal epithelium, p53 and p73 showed similar basal and/or parabasal expression, but that of p53 was weaker and discontinuous. p63 staining was noted in more suprabasal cellular layers and was stronger. In dysplasias, all three markers manifested variable but gradual increase in extent and intensity of cellular expression with histologic progression. In carcinomas, p63 was the most frequently expressed (94.7%), followed by p73 (68.4%) and p53 (52.6%). Significant statistical correlation was noted only between p63 and p73 expressions (P =.04). Although no statistical correlation was found between p53 and p63 or p73, p53-negative tumors overexpressed either p63 or p73. p73 expression was associated with distant metastasis and perineural/vascular invasion.
Our study indicates that (1) p63 and p73 expression may represent an early event in HNSC tumorigenesis, (2) the lack of correlation between p73 or p63 and p53 expression suggests an independent and/or compensatory functional role, (3) p73 expression may play a part in HNSC progression, and (4) p73 and p63 may function as oncogenes in the development of these tumors.
Immunohistochemical p53 Expression Patterns in Sarcomatoid Carcinomas of the Upper Respiratory Tract
M. Ali Ansari-Lari, M.D., Ph.D.; Mohammad O. Hoque, D.D.S., Ph.D.; Joseph Califano, M.D.; William H. Westra, M.D.
Am J Surg Pathol 2002; 26(8):1024-1031 Abstract quote
Sarcomatoid carcinoma of the upper respiratory tract is a phenotypically complex neoplasm that has triggered much thoughtful discussion regarding histogenic origin and morphologic classification. In particular, its putative epithelial lineage and distinction from a pseudosarcomatous reaction are sometimes questioned. Little is known about the genetic alterations underlying sarcomatoid carcinoma. Although about 45% of conventional squamous cell carcinomas of the upper respiratory tract harbor p53 mutations, the p53 status of sarcomatoid carcinomas is not well established.p53 immunohistochemical analysis using the monoclonal antibody D07 was performed on 23 sarcomatoid carcinomas of the upper respiratory tract. Twenty tumors were biphasic, having dual epithelial and spindled components. In four of these biphasic tumors, the epithelial and spindled components were separately analyzed for p53 gene mutations by sequence analysis. p53 immunohistochemistry was also performed on 19 cases of postradiation stromal atypia. Strong and diffuse p53 staining was detected in 18 (78%) of the 23 sarcomatoid carcinomas.
When the spindled component was compared with its corresponding epithelial component, identical patterns of p53 protein expression were noted in 19 (95%) of the 20 biphasic tumors. Weak p53 staining was observed in one (5%) of the 19 cases of postradiation stromal atypia. In the four biphasic tumors evaluated by DNA sequence analysis, p53 status was always the same in the paired epithelial and spindle cell components.
These findings help further dispel the notion that sarcomatoid carcinoma represents a reactive spindle cell proliferation (pseudosarcoma) or a collision between a carcinoma and a sarcoma (collision tumor). Instead, the epithelial and spindled components share a common pathway of tumorigenesis despite their conspicuous divergence at the phenotypic level.
RETINOBLASTOMA (Rb)
- Phenotypic alterations in Rb pathway have more prognostic influence than p53 pathway proteins in oral carcinoma.
Jayasurya R, Sathyan KM, Lakshminarayanan K, Abraham T, Nalinakumari KR, Abraham EK, Nair MK, Kannan S.
1Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.
Mod Pathol. 2005 Aug;18(8):1056-66. Abstract quote
The two well-defined pathways that are shown to be prominently altered in a variety of cancers are the cell cycle regulatory pathways led by either p53 or Rb genes.
The present study is undertaken to find the pathway that is more altered in oral carcinoma at protein level, with special emphasis on its prognostic significance. The expression pattern of key molecules of the Rb and p53 pathways, such as Rb, cyclin D1, CDK4, p16, p53, p21 and Bcl-2 and the proliferative marker PCNA were analysed in 348 oral carcinoma specimens by immunohistochemical technique. The expression index of these molecules and various clinicopathological factors were statistically correlated with treatment end points to assess its prognostic efficacy after following up these patients up to a maximum of 48 months with a median of 23 months. Rb pathway proteins, Rb (P=0.016), cyclin D1 (P=0.0001) and p16 (P=0.012) showed significant association with disease-free survival, and p16 (P=0.041) and cyclin D1 (P=<0.0001) with the overall survival.
Among p53 pathway proteins studied, only p53 expression index showed association with both disease-free survival and overall survival. Multivariate analyses confirmed that the biological variables, cyclin D1 and p16 and the clinical variable, 'stage of disease' were independent predictors of disease-free survival and overall survival. Subgrouping of the patients on the basis of p16 and cyclin D1 expression revealed that the subgroup having downregulation of p16 and overexpression of cyclin D1 exhibited the worst disease-free survival and overall survival compared to the other subgroups.
The present data showed that disabling of the Rb and p53 pathways were frequent events in oral carcinoma. The study also demonstrated that the Rb pathway proteins are comparatively more important than p53 pathway proteins for the prognostication of oral carcinoma patients. The combined evaluation of p16 and cyclin D1 in oral carcinoma could identify a group of patients with the worst survival who might therefore need alternate or more intense treatment strategies.SYNDECAN-1
Induced expression of syndecan-1 in the stroma of head and neck squamous cell carcinoma.Mukunyadzi P, Liu K, Hanna EY, Suen JY, Fan CY.
Department of Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA.
Mod Pathol. 2003 Aug;16(8):796-801 Abstract quote Syndecan-1 (CD138), a cell-surface heparan sulfate proteoglycan, is involved in cell-cell, cell-matrix interaction and growth factor binding. Loss of expression of syndecan-1 in tumor cells leads to decreased intercellular cohesion, increased potential for tumor invasiveness, and metastatic spread. Furthermore, induction of syndecan-1 expression in the tumor stroma has been postulated to promote tumor angiogenesis via its binding to growth factors such as basic fibroblast growth factor. Although syndecan-1 expression within tumor cells has been investigated in head and neck squamous cell carcinoma, stromal expression has not been studied in detail.
We analyzed 38 cases of head and neck squamous cell carcinoma by immunohistochemical staining for syndecan-1 expression within the stroma. The expression of syndecan-1 within tumor cells of various histologic grades of differentiation, squamous cell carcinoma in situ cells, and benign squamous epithelium was also determined. Variable levels of diminished syndecan-1 expression were noted within the dysplastic cells of 9 of 16 (60%) squamous cell carcinoma in situ lesions and in all 38 (100%) invasive squamous cell carcinoma. In general, higher levels of syndecan-1 expression were observed in the well-differentiated tumors, in contrast to significant reduction of expression seen in poorly differentiated tumors. Syndecan-1 expression was observed within the stroma (in fibroblasts) surrounding infiltrating carcinoma cells in 28 of 38 (74%) cases. The intensity of syndecan-1 staining within the stroma showed generally an inverse correlation with the degree of tumor cell differentiation. Syndecan-1 expression was not detected in the stroma beneath normal squamous epithelium or adjacent to areas of squamous cell carcinoma in situ.
We conclude that induced expression of syndecan-1 in the stroma surrounding tumor cells of invasive head and neck squamous cell carcinoma is a frequent event. The increased stromal syndecan-1 expression, coupled with its loss from the surface of carcinoma cells, may contribute to tumor cell invasion and the development of metastases.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES ORGAN OF CHIEVITZ Oral Surg 1979;48:231-236
Normal epithelial structure present in the soft tissue at the angle of the mandible around the buccotemporalis fascia
May be a neuroreceptor
Composed of multiple, sharply circumscribed, basement membrane enclosed clusters of cells in a fibrous stroma associated with small bundles of nerves
Cells have pink to clear cytoplasm resembling squamous cells
No keratin pearls or keratohyaline granules
Stroma surrounding the islands is loose and fibrous and this is surrounded by denser connective tissuePathologist must distinguish this from perineural invasion of a squamous cell carcinoma which often has a desmoplastic stromal host response and the metastatic epithelial cell have cytologic pleomorphism and directly invade the nerve
PSEUDOEPI-THELIOMATOUS HYPERPLASIA
- Distinguishing pseudoepitheliomatous hyperplasia from squamous cell carcinoma in mucosal biopsy specimens from the head and neck.
Zarovnaya E, Black C.
Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
Arch Pathol Lab Med. 2005 Aug;129(8):1032-6. Abstract quote
CONTEXT: The differentiation of pseudoepitheliomatous hyperplasia from invasive squamous cell carcinoma is a difficult and frequently encountered distinction, especially in biopsy specimens from head and neck mucosa. The problem is compounded by inflamed and often poorly oriented tissue sections.
OBJECTIVE: To distinguish pseudoepitheliomatous hyperplasia from invasive squamous cell carcinoma, utilizing a panel of antibodies to various epithelial and stromal elements (p53, matrix metalloproteinase 1, E-cadherin, and collagen IV) that has been shown to be useful in differentiating intestinal adenomas with invasive adenocarcinoma from displaced adenomatous epithelium.
DESIGN: Thirty-three archival specimens (16 squamous cell carcinoma [12 with invasion and 4 with microinvasion] and 17 pseudoepitheliomatous hyperplasia) from head and neck mucosal locations were immunostained and examined by the authors.
RESULTS: We found increased nuclear staining of the invasive tumor cells with p53. There was decreased staining within invasive tumor nests with E-cadherin. There was highly significant increased staining within tumor cells and adjacent stroma with matrix metalloproteinase 1 (P < .001). The only antibody in our panel that did not show a reliable staining pattern was collagen IV. It appeared fragmented in benign inflamed and malignant areas and therefore was not useful.
CONCLUSIONS: p53, matrix metalloproteinase 1, and E-cadherin showed significant staining trends independent of inflammation and suboptimal tissue orientation. Although a properly oriented hematoxylin-eosin-stained section was our gold standard, we found this immunoperoxidase panel useful as a diagnostic adjunct in difficult cases.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS HISTOLOGIC PARAMETERS
- Perineural and vascular invasion in oral cavity squamous carcinoma: increased incidence on re-review of slides and by using immunohistochemical enhancement.
Kurtz KA, Hoffman HT, Zimmerman MB, Robinson RA.
Department of Pathology, the Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City 52242, USA.
Arch Pathol Lab Med. 2005 Mar;129(3):354-9. Abstract quote
CONTEXT: Perineural invasion and vascular invasion may be adverse prognostic factors in patients with oral cavity squamous cell carcinoma. However, the incidence of perineural and vascular invasion varies in the literature, and the use of immunohistochemistry to enhance their detection has not been evaluated in oral cavity squamous cell carcinomas.
OBJECTIVE: To determine if the previously assessed incidence of perineural and vascular invasion in cases of oral cavity squamous cell carcinoma would be increased by re-review of the original routinely hematoxylin-eosin-stained sections as well as review of slides stained immunohistochemically with S100 and CD31 to enhance visualization of nerves and vessels.
DESIGN: Forty cases of oral cavity squamous cell carcinoma in which the status of perineural and vascular invasion had been part of the original pathology report were reviewed. All original routinely stained slides were reviewed as well as S100- and CD31-stained sections of each case's tissue blocks that contained tumor.
RESULTS: Perineural invasion was identified in 30% (12/ 40) of tumors in the original reports, 62% (25/40) of the authors' re-review of the same slides, and 82% (33/40) when cases were stained with S100. Vascular invasion was identified in 30% (12/40) of tumors in the original reports, 35% (14/40) of the authors' re-review of the same slides, and 42% (17/40) when cases were stained with CD31. False-positive and false-negative results were common in the original reports. The number of foci of both types of invasion was related to its discovery in the original reports. Vascular invasion, but not perineural invasion, was significantly associated with death at 5-year follow-up.
CONCLUSIONS: Although careful re-review of routinely stained slides will detect a significant number of cases of perineural and vascular invasion, immunohistochemical enhancement further improves the accuracy of the determination.
- Oral Squamous Cell Carcinoma: Histologic Risk Assessment, but Not Margin Status, Is Strongly Predictive of Local Disease-free and Overall Survival.
Brandwein-Gensler M, Teixeira MS, Lewis CM, Lee B, Rolnitzky L, Hille JJ, Genden E, Urken ML, Wang BY.
From the Departments of *Otolaryngology, daggerPathology, and double daggerBiomathematics, Mount Sinai Medical Center, New York, NY; section signDepartment of Otolaryngology, Massachusetts General Hospital, Boston, MA; and parallelDepartment of Oral Pathology, University of Western Cape, Cape Town, South Africa.
Am J Surg Pathol. 2005 Feb;29(2):167-178. Abstract quote
To analyze the impact of resection margin status and histologic prognosticators on local recurrence (LR) and overall survival (OS) for patients with oral squamous cell carcinoma (OSCC). This study was both retrospective and prospective in design. Cohort 1 refers to the entire group of 292 patients with OSCC. The slides from the earliest resection specimens from Cohort 1 were examined in an exploratory manner for multiple parameters. Cohort 2 refers to a subset of 203 patients, who did not receive any neoadjuvant therapy and had outcome data. Cohort 3 represents a subset of Cohort 2 (n = 168) wherein the histologic resection margin status could be reconfirmed. Cohort 4 refers a subset of 85 patients with tongue/floor of mouth tumors.
Margin status was designated as follows: group 1, clearance of >/=5 mm with intraoperative analysis, no need for supplemental margins (n = 46); group 2, initial margins were measured as <5 mm during intraoperative frozen section; supplemental resection margins were negative on final pathology (n = 73); group 3, the final pathology revealed resection margins <5 mm (n = 30); group 4, the final pathology revealed frankly positive resection margins (n = 19).
The endpoints of LR and OS were queried with respect to T stage, tumor site, margin status, and numerous histologic variables, by Cox regression and Kaplan-Meier survival analyses. Tumor stage (T) was significantly associated with LR (P = 0.028). Kaplan-Meier analysis for stage and for intraoral site was significantly associated with LR for T4 tumors. The increased likelihood of LR was higher for T4 OSCC of the buccal mucosa (75%), sinopalate (50%), and gingiva (100%) compared with mobile tongue (27%), and oropharynx (13%) (P = 0.013). Margin status was not associated with LR or OS (Cohort 3). This was so when all tumors were grouped together and when separate analyses were performed by tumor stage and oral subsite. No significance was demonstrated when margin status was examined for patients with similar treatment (surgery alone or surgery with adjuvant RT). However, the administration of adjuvant RT did significantly increase local disease-free survival (P = 0.0027 and P = 0.001 for T1 and T2 SCC, respectively).
On exploratory analyses of histologic parameters, worst pattern of invasion was significantly associated with LR (P = 0.015) and OS (P < 0.001). Perineural invasion involving large nerves (>1 mm) was associated with LR (P = 0.005) and OS (P = 0.039). Limited lymphocytic response was also significantly associated with LR (P = 0.005) and OS (P = 0.001). When used as covariates in a multivariate Cox regression model, worst pattern of invasion, perineural invasion, and lymphocytic response were significant and independent predictors of both LR and OS, even when adjusting for margin status.
Thus, these factors were used to generate our risk assessment. Our risk assessment classified patients into low-, intermediate-, or high-risk groups, with respect to LR (P = 0.0004) and OS (P < 0.0001). This classification retained significance when examining patients with uniform treatment. In separate analyses for each risk group, we found that administration of adjuvant radiation therapy is associated with increased local disease-free survival for high-risk patients only (P = 0.0296) but not low-risk or intermediate-risk patients. Resection margin status alone is not an independent predictor of LR and cannot be the sole variable in the decision-making process regarding adjuvant radiation therapy.
We suggest that the recommendation for adjuvant radiation therapy be based on, not only traditional factors (inadequate margin, perineural invasion, bone invasion) but also histologic risk assessment. If clinicians want to avoid the debilitation of adjuvant radiation therapy, then a 5-mm margin standard may not be effective in the presence of high-risk score.Does histologic grade have a role in the management of head and neck cancers?
Fortin A, Couture C, Doucet R, Albert M, Allard J, Tetu B.
Department of Radiation Oncology and Department of Pathology, L'Hotel-Dieu de Quebec, Quebec, Canada.
J Clin Oncol 2001 Nov 1;19(21):4107-16 Abstract quote
PURPOSE: High histologic grade is usually associated with a greater propensity to distant metastases (DM). Its role to predict DM in head and neck cancer is not yet defined. The aim of this study is to evaluate the role of histologic grade as an independent predictor of DM and to determine a subgroup of patients who may benefit from systemic chemotherapy.
PATIENTS AND METHODS: This is a retrospective study of 1,266 consecutive patients treated by definitive or postoperative radiotherapy between 1989 and 1997. All patients received at least 50 Gy. All stages and subsites of head/neck were included. DM rates were evaluated by the Kaplan-Meier method with a subsequent Cox analysis.
RESULTS: There is a strong correlation of grade with N stage (P <.000001). The metastases-free survival (MFS) was 98%, 90%, and 72% for grades 1, 2, and 3, respectively (P <.000001). In patients with N0 stage, MFS is always greater than 90%, whatever the grade. In the 222 N1 patients, MFS was more than 90% in grade 1 and 2 but dropped to 75% for grade 3 (P =.001). In patients with N2 and N3, MFS was 91%, 79%, and 59% for grades 1, 2, and 3, respectively (P =.008). The same conclusion is applicable when only patients with neck control are analyzed. In a Cox model, grade was an independent predictor of DM (P =.000001) as well as T stage (P =.003), N stage (P =.000001), and neck failure (P =.0003). Higher grade was also an independent predictor of survival (P =.02).
CONCLUSION: Patients with histologic grade 1 and grade 2 (except N3) are at low risk of DM. Patients with grade 2 and N3 or patients with grade 3 and N1 to N3 have a higher risk of distant metastases and should be considered for systemic treatment.
ONCOGENES
- p63 overexpression associates with poor prognosis in head and neck squamous cell carcinoma.
Lo Muzio L, Santarelli A, Caltabiano R, Rubini C, Pieramici T, Trevisiol L, Carinci F, Leonardi R, De Lillo A, Lanzafame S, Bufo P, Piattelli A.
Hum Pathol. 2005 Feb;36(2):187-94. Abstract quote
Summary p63 belongs to a protein family that includes 2 structurally related proteins, p53 and p73.
The aim of this study was to investigate the biologic role of p63 in oral tumorigenesis and its possible role as prognostic marker in oral cancer. Ninety-four cases of oral squamous cell carcinoma and 10 cases of normal mucosa were analyzed for p63 expression by immunohistochemistry. Normal oral mucosa showed a basal and parabasal expression of p63. Five (5.3%) cases of oral cancer showed less than 10% of positive tumor cells; in 33 (35.1%) cases the positive tumor cells comprised between 10% and less than 30%, in 36 (38.3%) cases the positive tumor cells comprised between 30% and less than 50%, and in 20 (21.3%) cases the positive tumor cells were more than 50%. There was also a statistically significant correlation between p63 expression and tumor differentiation: p63 expression was amplified in poorly differentiated tumors ( P < .05).
When analyzed for prognostic significance, patients with perineural infiltration had poorer survival rates than the group with no perineural infiltration ( P < .05) and patients with increased p63 expression had poorer survival rates than the group with reduced p63 expression ( P < .05). The statistical analysis showed no significant correlation between p63 expression, sex, age, tumor size, staging, recurrence, and metastasis. Cases with diffuse p63 expression were more aggressive and poorly differentiated and related to a poorer prognosis.
These data suggest that p63 expression may be useful to identify cases of oral squamous cell carcinoma with more aggressive and invasive phenotype providing novel diagnostic and prognostic information on individual patient survival with oral cancers.The Clinicopathologic Significance of p53 and p21 Expression in the Surgical Management of Lingual Squamous Cell Carcinoma
Po Wing Yuen, MS, Vivian Chow, MPhil, Joe Choy, MPhil, King Yin Lam, FRCPA, Wai Kuen Ho, FRCS, and William Ignace Wei, FRCS
Am J Clin Pathol 2001;116:240-245 Abstract quote
The aim of the present study was to evaluate the clinicopathologic significance of p53 and p21 expression in lingual squamous cell carcinomas. Immunohistochemical staining was performed with p53 and p21 monoclonal antibodies on surgical specimens from 87 patients who underwent primary surgical treatment for lingual carcinoma between 1976 and 1996.
We found positive expression of p53 in 45 (52%) of 87 cases and of p21 in 49 (56%) of 87 cases. There was no correlation of p53 and p21 expression with cancer stage, T stage, nodal metastasis, and tumor grade. Univariate analysis revealed that p21 expression, tumor stage, T stage, and nodal stage were significant prognostic factors for survival. However, only p21 expression and tumor stage were significant independent prognostic factors for survival in a multivariate Cox regression analysis.
Overexpression of p21 but not p53 has prognostic value for survival in the surgical treatment of lingual carcinomas. The combination of stage with p21 expression is recommended for evaluation of prognosis and for management planning.
TOPOISOMERASE Immunohistochemical study of DNA topoisomerase I, DNA topoisomerase IIalpha, p53, and Ki-67 in oral preneoplastic lesions and oral squamous cell carcinomas.
Hafian H, Venteo L, Sukhanova A, Nabiev I, Lefevre B, Pluot M.
Hum Pathol. 2004 Jun;35(6):745-51. Abstract quote
Human DNA topoisomerase I (topo I) is the molecular target of the camptothecin group of anticancer drugs. Laboratory studies have shown that the cellular response to topo I-targeted drugs depends on the topo I expression and DNA replication rate and the apoptotic pathway activity. In this study, we tested potential indicators of the sensitivity of topo I-targeted drugs in 36 cases of oral squamous cell carcinoma (OSCC).
Formalin-fixed, paraffin-embedded tissue sections were immunostained with monoclonal antibodies against Ki-67, p53, and topo I, and with polyclonal antibodies against DNA topoisomerase II-alpha (topo II-alpha). These markers were also tested in 18 epithelial hyperplastic lesions and 18 mild dysplasias. Immunostaining was quantified by the percentage of stained nuclei in each sample (the labeling index); 200 immunoreactive epithelial nuclei were counted per case for each antibody.
The results support the possibility of using topo II-alpha staining for assessing the proliferative activity. High expression of topo II-alpha and topo I in OSCCs suggests that they may serve as potential indicators of sensitivity to topo I inhibitors. However, the apoptotic pathway assessed by p53 immunostaining was found to be uninformative. Analysis of the relationship between immunohistochemical results and clinical and pathologic parameters (the T and N stages and differentiation) showed that only the differentiation parameter correlated with the topo I expression rate.
Thus, significant increase in the topo I expression in the poorly differentiated OSCCs suggests their higher sensitivity to drug treatment.TREATMENT Lack of survival advantage in patients with advanced squamous cell carcinomas of the oral cavity receiving neoadjuvant chemotherapy prior to local therapy, despite achieving an initial high clinical complete remission rate.
Hill BT, Price LA.
Cellular Chemotherapy Laboratory, Imperial Cancer Research Fund, London, U.K.
Am J Clin Oncol 1994 Feb;17(1):1-5 Abstract quote
Subset analyses have been performed on 50 patients with squamous cell carcinomas of the oral cavity from our earlier series of 208 patients with advanced, previously untreated head and neck tumors (J Clin Oncol 1986;4:1340-7).
Forty patients (80%) responded to two initial courses of Schedule A chemotherapy. Side effects were minimal. After definitive local therapy the final complete remission (CR) rate was 76%. Neither chemotherapy response, nor achievement of final CR was significantly affected by stage, T or N status, sex, or histologic grade. With a median follow-up of 11.6 years, the overall 10-year survival rate was 25%. Multivariate analysis indicated that both age, i.e., < 50 years (p = .004) and achievement of a final CR (p = .002) were significant factors for improved survival. Median survival for all patients was only 21 months and for those in final CR 30 months. These survival figures were all significantly lower than those of similarly treated patients with laryngeal or nasopharyngeal tumors, illustrating that all patients with head and neck tumors achieving a final clinical CR do not automatically have improved survival.
These results emphasize the need for randomized trials, with sufficient numbers to identify optimal treatment strategies for tumors at specific sites within the head and neck region.
Preoperative radiochemotherapy and radical surgery in comparison with radical surgery alone. A prospective, multicentric, randomized DOSAK study of advanced squamous cell carcinoma of the oral cavity and the oropharynx (a 3-year follow-up).
Mohr C, Bohndorf W, Carstens J, Harle F, Hausamen JE, Hirche H, Kimmig H, Kutzner J, Muhling J, Reuther J, et al.
Klinik fur Gesichts- und Kieferchirurgie, Universitatsklinik Essen, Germany.
Int J Oral Maxillofac Surg 1994 Jun;23(3):140-8 Abstract quote
A multicentric, randomized study of squamous cell carcinoma (SCC) of the oral cavity and the oropharynx has been undertaken by DOSAK.
The results after radical surgery alone have been compared with the results of combined preoperative radiochemotherapy followed by radical surgery. Patients with primary (biopsy proven) SCC of the oral cavity or the oropharynx with tumor nodes metastasis (TNM) stages T2-4, N0-3, M0 were included in the study. A total of 141 patients were treated by radical surgery alone, whereas 127 patients were treated by radical surgery preceded by preoperative radiochemotherapy. The preoperative treatment consisted of conventionally fractioned irradiation on the primary and the regional lymph nodes with a total dose of 36 Gy (5 x 2 Gy per week) and low-dose cisplatin chemotherapy with 5 x 12.5 mg cisplatin per m2 of body surface during the first week of treatment. Radical surgery according to the DOSAK definitions (DOSAK, 1982) was performed after a delay of 10-14 days.
During the follow-up period, 28.2% of all patients suffered from locoregional recurrence, and 27.2% of the patients died. The percentages were higher after radical surgery alone for locoregional recurrence (31% and 15.6%) and for death (28% and 18.6%).
The life-table analysis showed improved survival rates of 4.5% after 1 year and 8.3% after 2 years in the group of patients treated with combined therapy. The demonstrated improvement appeared to be significant with the Gehan-Wilcoxon test as well as with the log rank test below a P value of 5%.
Intra-arterial preoperative cytostatic treatment versus preoperative irradiation: A prospective, randomized study of lingual and sublingual carcinomas.
Szabo G, Kreidler J, Hollmann K, Kovacs A, Nemeth G, Nemeth Z, Toth-Bagi Z, Barabas J.
Department of Oral and Maxillofacial Surgery, University of Budapest, Budapest, Hungary.
Cancer 1999 Oct 15;86(8):1381-6 Abstract quote
BACKGROUND: For several decades, both preoperative intra-arterial chemotherapy and preoperative irradiation have been accepted treatments for patients with tumors of the head and neck. Unfortunately, arguments have often been put forward in favor of one or other of the two methods, but without the performance of an objective, randomized investigation. To resolve this situation, the authors have carried out a multicenter, randomized prospective study of selected patients with a view to deciding which method affords better results in complex tumor therapy from the aspects of survival and postoperative quality of life.
METHODS: One hundred thirty-one patients with operable sublingual or lingual squamous cell carcinoma in stages T2NXM0 to T4MXM0 were randomized into 2 groups: 1 group participated in preoperative chemotherapy with cisplatin and epirubicin (total doses: 200 mg cisplatin, 120 mg epirubicin) via the external carotid artery, whereas the other group received preoperative radiation therapy (46 grays). Following subsequent radical surgery, the patients received regular follow-up for 5 years.
RESULTS: By the end of the 5 years, 95 of the 131 patients had conformed to the protocol. Of those 95, 47 had received preoperative chemotherapy and 48 preoperative irradiation. After 5 years, 18 of the 47 patients who received chemotherapy and 15 of the 48 patients who received irradiation were still alive and tumor free. A few more patients had died of recurrence or regional metastasis in the chemotherapy group (23 patients) than in the irradiation group (20 patients). Occurrence of a second carcinoma was 3 times as frequent in the irradiation group (9 patients) as in the chemotherapy group (3 patients). Overall, the survival rates were by-and-large the same for the two groups. Regarding postoperative quality of life, the chemotherapy group presented a more favorable picture.
CONCLUSIONS: The long term survival results subsequent to preoperative intra-arterial chemotherapy or preoperative radiotherapy were practically the same. Regarding postoperative quality of life, patients who underwent intra-arterial chemotherapy appeared to be in a slightly more favorable situation. The authors consider it important to stress these findings, as they are not aware of a similar randomized study of patients with tumors of the oral cavity.
A comparison of radiotherapy or radiochemotherapy with symptomatic treatment alone in patients with advanced head and neck carcinomas.
Carvalho AL, Salvajoli JV, Kowalski LP.
Head and Neck Surgery Department, Centro de Tratamento e Pesquisa, Hospital do Cancer, Sao Paulo, Brazil.
Eur Arch Otorhinolaryngol 2000;257(3):164-7 Abstract quote
The choice of palliative treatment and the prognostic factors in unresectable head and neck cancer cases continue to be controversial.
In the present study we compared the survival rates of untreated stage IV head and neck cancer patients with cases managed prospectively at A.C. Camargo Hospital for Cancer with neoadjuvant chemotherapy, concomitant chemotherapy or radiotherapy alone. Previous results had shown that while the type of treatment did not influence survival rates (P = 0.706), tumor response to treatment (whether complete, partial or none) significantly influenced survival (P = 0.00002). In the present study we compared the survival rates in the groups with untreated patients (who remained untreated until death) with the same demographic and clinical characteristics of patients receiving treatment.
We found that there was a significant difference between the survival rates of the untreated group and those of the treated groups that was independent of the type of treatment performed (P < 0.00001) or the tumor response to treatment (P < 0.0001).
Long-term follow-up on an intensified treatment regimen for advanced resectable head and neck squamous cell carcinomas.
Grecula JC, Schuller DE, Smith R, Rhoades CA, Nag S, Bauer CJ, Agrawal A, Au JL, Young D, Gahbauer RA.
Division of Radiation Oncology, 090 James Cancer Hospital, 300 W. 10th Ave., Columbus, OH 43210, USA.
Cancer Invest 2001;19(2):127-36 Abstract quote
From February 1993 through July 1994, 37 patients with stage III-IV squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx (stage II-IV) were registered to a treatment regimen consisting of preoperative continuous infusion cisplatin (80 mg/m2/80 hours) with hyperfractionated external beam radiotherapy (9.1 Gy/7 fractions of 1.3 Gy BID), surgical resection, intraoperative radiotherapy (7.5 Gy), and postoperative radiotherapy (40 Gy) with concurrent cisplatin (100 mg/m2 x 2 courses).
The objectives of the regimen were to improve patient compliance while also increasing treatment intensity. The purpose of this article is to report the local, regional (nodal), and distant disease control of these patients after an extended time at risk (median 40 months).
Overall compliance (73%), local control at primary site (97%), and regional nodal control (95%) were excellent. The rate of distant metastasis was 19%. Absolute survival at 48 months was 45.9%.
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