Proliferative verrucous leukoplakia and its related lesions

Proliferative verrucous leukoplakia (PVL) is a unique type of clinical oral leukoplakia. Enigmatic in etiology, PVL behaves in a far more aggressive fashion than other forms of leukoplakia. Its aggressiveness relates not only to a high recurrence rate, but more so to a very high level of and relentless progression from a localized simple keratosis to extensive oral disease and squamous carcinomas of verrucous, or conventional squamous cell type. Diagnosis is often late in the protracted course of PVL with the disease in an advanced stage when it is especially refractory to treatment. Within the histologic spectrum that is seen in PVL, usually as a function of time, are: (1) verrucous hyperplasia (VH), a histologically defined lesion; (2) varying degrees of dysplasia; and (3) three forms of squamous cell carcinoma: verrucous, conventional and, according to some, papillary squamous cell carcinoma. Each of these are discussed both within and outside the context of PVL. VH is a forerunner of verrucous carcinoma and the transition is so consistent that the hyperplasia, once diagnosed, should be treated like verrucous carcinoma. VH is not only an oral lesion; it can occur in the upper airway (sinonasal tract and larynx) where it is not usually found within a maternal soil of PVL. Papillary squamous cell carcinoma has been a loosely defined neoplasm, more often considered a verrucal type of malignancy. It nonetheless is a distinct clinicopathologic entity, separate from verrucous carcinoma and without a predilection for the oral cavity or an association with PVL.     

Squamous papilloma of the urinary tract is unrelated to condyloma acuminata

BACKGROUND: To the authors' knowledge, there is no previous report of squamous papilloma of the urinary tract. It is uncertain whether there is a correlation between squamous papilloma, condyloma acuminatum, and verrucous carcinoma. METHODS: The authors evaluated the clinical and pathologic features of squamous papilloma (5 of the bladder, 2 of the urethra), condyloma acuminatum (3 cases), and verrucous carcinoma (3 cases) of the urinary bladder and performed human papillomavirus (HPV) DNA in situ hybridization studies to determine whether HPV was a common feature shared by these lesions. In addition, DNA ploidy evaluation by image cytometry and p53 immunohistochemical staining were performed. RESULTS: Squamous papilloma of the urinary tract occurred in elderly women and followed a benign clinical course with infrequent recurrence. All squamous papillomas were HPV DNA negative and DNA diploid with no or minimal p53 nuclear accumulation. Condyloma acuminata of the bladder contained HPV DNA, increased p53 protein expression, and aneuploid DNA content. All three cases of condyloma acuminata were associated with coexistent condylomata of the external genitalia, and two required pelvic exenteration for uncontrolled expansile growth. Verrucous carcinoma of the bladder occurred in elderly patients. All three cases of verrucous carcinoma were negative for HPV DNA and DNA aneuploid, and they exhibited consistent p53 expression. CONCLUSIONS: These data indicate that squamous papilloma is a distinct entity not related to condyloma or verrucous carcinoma. These lesions are benign, HPV DNA negative, DNA diploid, and they lack p53 overaccumulation.     

Radiotherapy and verrucous carcinoma of the oral cavity. A study of 107 cases.

One hundred and seven cases of oral verrucous carcinoma treated primarily with radiotherapy at Kasturba Hospital, Manipal, India between 1977 and 1987 were analysed concerning location within the oral cavity, clinical extent, and effectiveness of radiotherapy. The most common site was the buccal mucosa followed by the buccogingival sulcus. Only 13.2% of the patients presented with T1 or T2 tumours and 32.7% had clinically negative nodes. Biopsy had to be repeated more than once in 22 patients to get confirmation of invasive carcinoma. The 5-year survival rate was 35% for stage III and 26% for stage IV. The treatment results with radiotherapy were comparable with those for ordinary squamous cell carcinoma of the oral cavity. It is felt that the treatment policy for verrucous carcinoma can be the same as for ordinary squamous cell carcinoma. In order to prevent delay in diagnosis and treatment, proper cooperation between the treating oncologist and the pathologist is essential.     

Comparison of flow cytometric DNA content in the primary tumor and in the corresponding lymph-node metastasis of patients with squamous cells carcinomas of the head and neck

The clonal DNA content of the cell populations of primary tumors and corresponding lymph node metastases was analysed by DNA flow cytometry in 48 patients with squamous cell carcinoma of the oral cavity. Three primary tumors were diploid, two associated with diploid metastases, one showing an aneuploid cell line in the secondary lesion. Fourty-five cases were aneuploid in both the primary tumors and in the synchronous metastases, all characterized by nearly identical DNA indices of the corresponding primary and secondary lesions. With few exceptions, aneuploidy formation appears to take place prior to dissemination of metastatic cells.     

Flow cytometric DNA ploidy analysis of squamous cell carcinoma of the oral cavity. Comparison with clinical staging and histologic grading

The clonal DNA content of tumor biopsy specimens of 110 patients with primary and untreated squamous cell carcinoma of the oral cavity was determined by flow cytometric study. The ploidy status was compared with tumor size and histologic grading. Thirty tumors (27.3%) were diploid; in 80 cases (72.7%) cell lines with abnormal DNA content were detected. The portion of aneuploid tumors increased with decreasing degree of histologic differentiation (P less than 0.001) from G1 (38.1%) to G2 (76.6%) and G3 (92.0%). Only one of 13 T1 carcinomas (7.6%) showed abnormal clonal DNA content, but 76.9% of T2 and 90.6% T3 tumors (P less than 0.001) did. The emergence of aneuploid clones obviously represents a marker of malignancy progression in oral carcinoma.     

Oral verrucous carcinoma. Treatment with radiotherapy

Fifty-two cases of oral verrucous carcinoma treated with radiotherapy at the Regional Cancer Centre, Trivandrum, Kerala, India in 1982 were evaluated to determine the distribution within the oral cavity, clinical extent, and effectiveness of radiotherapy in controlling the disease. The most common site was the buccal mucosa. Fifty percent of the patients had clinically negative regional lymph nodes and 33% were in earlier stages (T1, T2, N0, and M0). The overall 3-year no evidence of disease (NED) survival rate was 44%. The 3-year NED survival rate with radium implant was 86%. We cannot comment on anaplastic transformation after radiotherapy because our treatment failures have not been subjected for biopsy concerning this matter. Because the results are comparable with those of well-differentiated squamous cell carcinoma, we think that the treatment policies advocated for oral squamous cell carcinoma are also applicable to oral verrucous carcinoma.     

Analysis of ploidy status in progression of head and neck cancers by DNA image cytometry

Eight cases of leukoplakia, 25 lingual cancers, 15 cancers of the floor of the oral cavity, 11 pharyngeal cancers and 14 lymph nodes with squamous cell cancer metastases were stained using the Feulgen method to evaluate the ploidy status and ploidy related parameters. All leukoplakias were euploid. Percentage of aneuploid cancers correlated with the grade of tumours. Significant differences between tumours with 3 different locations were not found. Metastatic carcinoma cells in lymph nodes had significantly more cells in S-phase as compared to primary tumours.     

Pathological and clinical analysis of 102 cases of lip carcinoma

102 cases (103 tumors) of lip carcinoma treated by surgery are analyzed. There were 37 (35.9%) verrucous carcinoma and 66 (64.1%) squamous cell carcinoma which included grade I 29 cases, grade II 21, grade III 14 and grade IV 2. Of the 66 squamous cell carcinomas, six lesions co-existing with verrucous carcinoma were derived from the latter. This fact demonstrated that anaplastic transformation of verrucous carcinoma could occur in patients without radiotherapy. This study suggests that the enlarged neck lymph nodes need not be dissected prophylactically for patients with squamous cell carcinoma grade I and grade II, and with verrucous carcinoma. The management of the cervical nodes still suffices if they enlarge after the primary lesion has been removed. But radical dissection of neck lymph nodes should be performed promptly for patients with squamous cell carcinoma grade III and grade IV.     

Verruciform xanthoma of the penis in a young male masquerading as squamous cell carcinoma: Case Report

Verruciform xanthoma (VX) is a relatively rare benign lesion of unknown etiology with a predilection for oral mucosa. Penis is an uncommon location and to date only 17 cases of VX of penis have been reported. The lesion assumes importance as it can be easily mistaken for verrucous carcinoma or squamous cell carcinoma. We present herein a case of penile VX in a 25-year-old man who was referred to our institute with a histopathologic diagnosis of squamous cell carcinoma reported elsewhere. On microscopy the lesion demonstrated florid verruciform hyperplasia of the epidermis with hyperkeratosis, parakeratosis and acanthosis. There was a dense infiltrate of foam cells in the papillary dermis (a hallmark of VX), which were positive for CD68 and negative for S-100 protein. We present this case to highlight the significance of recognizing VX in extra oral location. An awareness of this entity is crucial to prevent misdiagnosis and halt inappropriate therapeutic intervention. Keywords: penis, squamous cell carcinoma, verruciform xanthoma, verrucous carcinoma.     

Lectin binding to oral squamous carcinoma

Ten benign epithelial hyperplasias, ten invasive squamous carcinomas, and one each of verrucous carcinoma and carcinoma in situ of the oral mucosa were examined immunoenzymatically using biotinylated lectins and avidin-biotin-peroxidase complex to localize glycoconjugates in the epithelial cells. All of the lectins intercellularly bind to benign and malignant epithelial cells. Also, lectins bind to the cytoplasm of the basal cells and all layers of carcinoma in situ. Verrucous carcinoma shows a similar binding as does the benign epithelial hyperplasia. However, in invasive squamous carcinoma some nests and individual invasive cells show intense cytoplasmic binding and a loss of cell surface binding to lectins, especially with Con A, and may be a marker for invasive potential of squamous carcinoma.     

Diagnostic Biomarkers in Oral Verrucous Carcinoma: A Systematic Review

Oral verrucous carcinoma (OVC), a low-grade variant of oral squamous cell carcinoma (OSCC), is most frequently seen in the oral cavity. No clear etiology has been found for this lesion, but human papilloma virus, chewing betel nuts, and ultraviolet radiation are suggested as probable causes. Differential diagnosis of OVC is challenging for oral pathologists. The aim of this study was to review the molecular-based approaches for differential diagnosis of OVC. An electronic search was conducted in Medline and Scopus from January 2004 to July 2015 limited to English language publications. Published papers on verrucous carcinoma (VC) were found according to the inclusion and exclusion criteria and analyzed qualitatively. Data extraction were performed according to PRISMA statement. A total of 423 articles were reviewed; out of which, 26 articles completely fulfilled the inclusion criteria. Most of the included studies investigated proliferative and apoptotic biomarkers such as p53 and Ki67. No definite conclusion was drawn for cytoskeletal biomarkers due to variability of factors and lack of significant expression. However, it seems that cytokeratin10 (CK 10) can be useful for differentiation of OVC and benign squamous lesions. Among cell surface and extracellular matrix biomarkers tissue biomarkers, matrix metalloproteinase (MMP)-2, ?9, CD31 and CD68 seem to be useful for differentiation of OVC and OSCC and glucose transporter-1 (GLUT-1) can help in differentiation of OVC from oral epithelial dysplasia. Differences among OVC, OSCC and normal epithelium in expression profiles of the investigated biomarkers help in their differential diagnosis; although, clinicohistopathological similarities among verrucous hyperplasia, noninvasive OVC and invasive well-differentiated OSCC make the diagnosis difficult. Further studies are required to better differentiate these oral lesions.     

Progression of diploid tumor cells in aneuploid head and neck squamous cell carcinomas

The development of aneuploid clones from diploid progenitor cells is a regular characteristic of head and neck squamous cell carcinoma progression. While the significance of aneuploidy formation for the acquisition of invasive and metastatic behavior is well documented, little is known about the contribution of diploid tumor cells after aneuploid clones have emerged. To distinguish diploid cells of epithelial origin from benign cellular components, we applied multiparameter flow cytometry of DNA content and cytokeratin (CK) expression to 36 primary tumors. Twenty-seven carcinomas accommodated aneuploid cell lines that stained positive for CK. All diploid cell populations obtained from aneuploid carcinomas contained CK-positive subpopulations as did all of nine tumors that consisted exclusively of diploid cells. The proportions of CK-positive diploid cells ranged between 6% and 80%, independent of whether they were achieved from entirely diploid or from aneuploid carcinomas. CK-gated diploid and aneuploid cell populations showed largely identical S-phase fractions. These results emphasize that diploid tumor cells regularly persist after the development of aneuploid clones and significantly contribute to local tumor progression. Despite the presence of diploid epithelial cells in aneuploid primary tumors, exclusively the aneuploid clones of eight corresponding lymph node metastases were CK-positive. This provides further evidence of a largely reduced metastatic potential of diploid tumor cells.     

Real-time quantitative PCR demonstrates low prevalence of human papillomavirus type 16 in premalignant and malignant lesions of the oral cavity.

PURPOSE: Human papillomavirus (HPV) type-16 has been associated with invasive squamous cell carcinoma of the head and neck. This study examines the role of HPV-16 in the progression of oral head and neck cancer by determining the quantity of HPV-16 DNA in premalignant and malignant lesions, using real-time quantitative PCR, to more accurately determine the role of HPV-16 in oral head and neck squamous cell carcinogenesis. EXPERIMENTAL DESIGN: We examined 102 microdissected premalignant head and neck lesions (85 from the oral cavity), 34 invasive oral cavity squamous cell carcinomas, as well as 18 invasive tumors known to be HPV positive by traditional molecular technology for the presence of HPV-16 DNA using real-time quantitative PCR. RESULTS: HPV DNA was detected in 1 of 102 premalignant lesions (0.98%), 1 of 34 (2.9%) invasive oral cavity carcinomas, and 14 of 18 (78%) known HPV-positive tumors. CONCLUSIONS: HPV-16 infection and integration is seldom found in oral premalignant lesions and invasive carcinoma, and therefore rarely contributes to malignant progression in the oral cavity. Furthermore, quantitative PCR is a useful technique that reliably excludes contaminated samples and those with minimal HPV DNA content that is unlikely to be significant in carcinogenesis.     

National survey of head and neck verrucous carcinoma: patterns of presentation, care, and outcome.

BACKGROUND: Verrucous carcinoma is distinguished by controversy regarding appropriate diagnosis and treatment. This study provides a contemporary survey of demographics, patterns of care, and outcome for this disease in the United States. METHODS: The National Cancer Data Base had 2350 cases of verrucous carcinoma of the head and neck diagnosed between 1985 and 1996. Statistical procedures included chi-square analyses, Student t tests, and relative survival. RESULTS: Tumors originated most frequently in the oral cavity (55.9%) and larynx (35.2%). Although most patients were male (60.0%), oral cavity tumors were more common among older females. The most prevalent treatment was surgery alone (69.7%), followed by surgery combined with irradiation (11.0%) and irradiation alone (10.3%). For oral cavity tumors, surgery alone was more common among early (85.8%) than advanced cases (56.9%); a larger proportion of advanced disease received radiation alone or surgery and irradiation combined. Most laryngeal tumors were treated with surgery (60.3% for early and 55.6% for advanced disease), but a higher proportion received radiation alone or surgery combined with radiation compared with oral cavity cases. Five-year relative survival was 77.9%. For localized disease, survival after surgery was 88.9% compared with 57.6% after irradiation. CONCLUSIONS: Demographic differences implicate different mechanisms of carcinogenesis for verrucous carcinoma arising in the oral cavity and the larynx. Although selection bias may account for the differences observed, patients receiving initial treatment with surgery had better survival than those treated with irradiation, especially for cases originating in the oral cavity.     

S100A2 expression as a predictive marker for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral cavity

The purpose of this study was to discover whether S100A2 expression is associated with late cervical metastasis in patients with stage I and II invasive squamous cell carcinoma of the oral cavity. We retrospectively investigated the clinicopathological parameters and S100A2 expression in surgical specimens taken from 52 patients with T1-2N0M0 invasive squamous cell carcinoma of the oral cavity (OSCC) who had not undergone elective neck dissection or irradiation to the neck. All of the clinicopathological factors and S100A2 expression were compared in terms of late cervical metastasis. In univariate analysis, late cervical metastasis correlated with poor overall survival. A higher rate of late cervical metastasis was observed in patients with S100A2-negative tumors than those with S100A2-positive tumors. Multivariate analysis on late cervical metastasis revealed that S100A2 expression was demonstrated to be the only independent factor for late cervical metastasis. Our results indicate that patients with stage I or II invasive OSCC without S100A2 expression should be considered a high-risk group for late cervical metastasis when a wait-and-see policy for the neck is being considered.     

基质金属蛋白酶MMP-9在口腔疣状癌中的表达及意义

目的　研究MMP-9在口腔疣状癌和鳞癌中的表达,探讨口腔疣状癌和鳞癌的不同生物行为的分子基础。方法　取 15例口腔疣状癌, 10例正常口腔粘膜, 20例口腔鳞癌(高、低分化鳞癌各 10例),应用免疫组织化学S-P法检测上述标本MMP-9表达和分布。结果　口腔疣状癌组织中MMP-9阳性表达率为 40% (6 /15),明显低于高分化鳞癌 70% (7 /10)和低分化鳞癌 80% ( 8 /10 ) (P<0. 05 );平均染色强度低于高分化鳞癌和低分化鳞癌(P<0. 05);口腔疣状癌、口腔高分化鳞癌、口腔低分化鳞癌组织中MMP-9表达均高于正常口腔粘膜组织(P<0. 05)。结论　MMP-9在口腔疣状癌的发生中起重要作用。MMP-9在口腔疣状癌、口腔高分化鳞癌、口腔低分化鳞癌的表达存在明显差异,说明口腔疣状癌是一种独立类型的恶性肿瘤。     

An orthotopic nude mouse model of oral tongue squamous cell carcinoma.

PURPOSE: Despite advances in our understanding, prevention, and treatment of head and neck squamous cell carcinoma (SCC), the 5-year survival rates for patients remain low. This poor prognosis for head and neck SCC and SCC of the oral tongue (SCCOT) in particular reflects a limited understanding of the mechanisms of local and regional metastasis, which accounts for a majority of deaths. To analyze the molecular and cellular mechanisms of metastasis, we have developed an orthotopic nude mouse model of SCCOT. EXPERIMENTAL DESIGN: Nude mice were injected submucosally in the tongue or subcutis with human squamous cell carcinoma of the oral cavity cell lines Tu159, Tu167, and MDA1986. The mice were necropsied and examined for the presence of primary tumors, and regional and systemic metastases. RESULTS: For all three of the squamous cell carcinoma of the oral cavity cell lines, tumors developed more readily in the orthotopic site, the tongue, than in the ectopic subcutis. MDA1986 cells were highly tumorigenic, particularly at the orthotopic site, with as few as 5 x 10(3) cells producing tumors in all of the mice. In contrast, s.c. tumor formation required at least 1 x 10(5) cells. The tumorigenicity observed between those mice given submucosal inoculation and those mice given s.c. inoculation (P < 0.0001). Regional metastases initially occurred in <10% of mice. To generate tumor lines of increased metastatic potential, regional metastases were isolated from cervical lymph nodes after the development of orthotopic tongue tumors. Serial passage of these lymph nodes resulted in a cell line more metastatic than its parental line. When injected into the tongues of mice, these cells metastasized to regional lymph nodes in 30% of mice and to the lungs in 20%. CONCLUSIONS: In this orthotopic murine model, oral tongue cancer recapitulates the behavior of human SCCOT, allowing for detailed studies of its biology and therapy.     

Cytogenetic progression and prognosis in oral-carcinoma - a DNA flow cytometric study on 317 cases

A total number of 317 consecutive patients with squamous cell carcinoma of the oral cavity were analysed by DNA flow cytometry. The proportion of tumors consisting exclusively of diploid cells decreased from 75% in T1G1 carcinomas to less than 10% in advanced tumors in favor of cases characterized by the presence of cell lines with aberrant DNA content. This observation indicates a genetic evolution of tumor clones with severe karyotype aberrations from diploid progenitors which obviously represents an ultimate event in the pathogenesis of oral carcinomas. Aneuploidy formation clearly contributes to the acquisition of progressive malignant behaviour as is underlined by a dramatic difference of the survival outcome of patients with diploid tumors (5-year overall survival: 88%) as compared to those who had aneuploid tumors (36%; P<0.001), a relationship which held true even if identical tumor stages were considered. There were no indications of successive genetic changes of the cellular DNA contents during tumor progression which would explain the wide range of variation of the individual DNA values. This observation supports the hypothesis of an aneuploidy formation by a single cytogenetic event, such as an abnormal mitosis. Although there were indications of an even worse survival outcome in the group of patients with peri-diploid tumor cell lines (P<0.1), a significant influence of different DNA contents on the prognosis could not be detected.     

Cytogenetic characteristics of oral squamous cell carcinomas in Fanconi anemia

Fanconi anemia (FA) is an autosomal recessive syndrome with a marked predisposition to malignancies, in particular acute myeloid leukemia and squamous cell carcinoma of the oral cavity. We examined oral squamous cell carcinoma tissue from two FA patients (FA-A and FA-C) by comparative genomic hybridization. Both tumors, which were negative for human papilloma as well as Epstein-Barr viral sequences, showed multiple alterations with a high proportion of whole-arm chromosomal gains and losses. This combination of features as well as the sites involved in chromosomal breakage are very similar to what is typically observed in non-FA oral tumors. These results suggest that the process leading to early occurrence of oral cancer in FA patients follows a similar pathway as in non-FA cancer patients, which would support a caretaker function for FA genes in the protection against oral carcinogenesis. Since FA patients are uniquely hypersensitive to DNA cross-linking agents, while oral cancer in the general population is thought to be environmentally induced, these results also suggest that environmental DNA cross-linkers may be causally involved in oral carcinogenesis.