Oral Verrucous Carcinoma Research Articles

The Men Behind the Eponym - Abraham Buschke and Ludwig Lowenstein: Giant Condyloma (Buschke-Loewenstein)

In 1925 Abraham Buschke and Ludwig Loewenstein described a neoplasm of the penis (carcinomähnliche condylomata acuminata des penis), which, to them, bore resemblances to common condyloma acuminatum and squamous cell carcinoma, but it had histopathologic and clinical characteristics that differed from these 2 proliferations. Later Lauren V. Ackerman described a similar neoplasm of the oral mucosa that he termed "verrucous carcinoma." I have previously reviewed that neoplasm, now referred to as "oral verrucous carcinoma of Ackerman." Still later Aird and his colleagues described a unique neoplasm of the foot, "carcinoma cuniculatum." These 3 have been grouped generically as "verrucous carcinoma." Verrucous carcinomas occur at many sites including the female genitalia and the aerodigestive system. This report will synopsize the lives of Abraham Buschke and Ludwig Loewenstein, review their original articles, and mention the changing concepts over time concerning condylomata, particularly large condylomata. Some other reports of giant condyloma (verrucous carcinoma of the penis) will be discussed, emphasizing the histopathology of this neoplasm and its differentiation from "warty-like" carcinomas of the penis. Verrucous carcinoma of other sites and epithelioma (carcinoma) cuniculatum will not be discussed.

Dermatopathology in Historical Perspective: Epithelioma Cuniculatum (Aird)

Professor Ian Aird, a renowned British surgeon of the mid-twentieth century, described a peculiar neoplasm of the foot in 3 patients under the term epithelioma cuniculatum, now more commonly called carcinoma cuniculatum. I will recount the life of Professor Aird and then summarize his original report emphasizing the clinical and more particularly the histopathologic criteria of epithelioma cuniculatum as described by Aird et al. Then I will summarize some of the subsequent reports of epithelioma (carcinoma) cuniculatum. Authors have grouped carcinoma cuniculatum with giant condyloma of the penis of Buschke-Loewenstein and oral verrucous carcinoma of Ackerman and similar neoplasms at other sites under the generic title "verrucous carcinoma." Although this classification has been accepted, I will stress that the clinical picture and histopathology described by Aird et al differ from those in later reports of carcinoma cuniculatum. These correspond to descriptions of the verrucous carcinomas of Buschke-Loewenstein and Ackerman. Finally, I will conclude that carcinoma cuniculatum as delineated by Aird and his colleagues is an extremely rare, indolent, nonmetastasizing squamous cell carcinoma composed of banal keratinocytes with unique clinical and histopathologic features that almost always arises on the foot. If a neoplasm on the foot has the characteristics of verrucous carcinoma that occurs at others sites, but not those of Aird et al, it should be called verrucous carcinoma of the foot, and not "epithelioma (carcinoma) cuniculatum."

Oral verrucous carcinoma: a retrospective study in São Paulo Region, Brazil

Oral verrucous carcinoma (OVC) is a rare variant of squamous cell carcinoma with a characteristic morphology and specific behavior. To date, few studies are available focusing the prevalence and clinicopathologic features of the oral verrucous carcinoma in Brazilian population. A total of 3,500 primary oral well-differentiated squamous cell carcinoma surgically excised in the A.C. Camargo Cancer Hospital and Amaral Carvalho Cancer Hospital, Brazil, from 1980 to 2000 were retrospectively reviewed. Twenty cases of verrucous carcinomas were identified, most of them occurring in older male with age above the sixth decade, the sites frequently affected being the lower lip and the hard palate. Microscopically, the tumor showed a heavily keratinized lesion with compressive invasion pattern, little atypia, and free surgical margins. The local recurrence was verified in 38.5% of the patients with oral verrucous carcinoma; however, regional recurrence and distant metastasis were not verified. The results suggest that, although it is less frequent and with excellent prognosis, the verrucous carcinoma presents a potential for local recurrence that should be considered during the surgical planning of this neoplasm in the oral cavity.

Immunohistochemical evaluation of intermediate filament proteins in squamous papilloma and oral verrucous carcinoma

Cytokeratins (CKs) are the intermediate filament proteins of the epithelium cells, which have become important markers of normal and abnormal cell differentiation. The goal of the present study was to investigate the expression pattern of CK 10, 13, 14 and 16 in oral verrucous carcinoma (OVC) and oral squamous papilloma (OSP). Formalin-fixed paraffin-embedded sections from eight cases of each lesion were assessed. Immunohistochemistry was carried out using streptoavidin-biotin complex method. In OVC, CK 10 was expressed in suprabasal to superficial layers whereas in OSP mainly in superficial layer. CK 13 was detected in prickle and superficial cells in most cases of OVC and in suprabasal to superficial cells of OSP. All the cell layers of OVC reacted positively for CK 14 while basal and suprabasal layers of OSP were more pronounced for CK 14. Finally, CK 16 was observed in suprabasal to superficial layer in OVC and the majority cases in OSP showed only superficial reactive cells. CK 10, 13, 14 and 16 immunohistochemical profile emphasis the biological behavior of the studied lesions and confirm the use of these proteins as markers of differentiation.

PD.72 oral verrucous carcinoma: Its biological behaviour and an immunohistochemical analysis of the expression of its basement membrane proteins

PD.72 oral verrucous carcinoma: Its biological behaviour and an immunohistochemical analysis of the expression of its basement membrane proteins

P.87 Surgical outcome and second malignant tumor in patients with oral verrucous carcinoma

P.87 Surgical outcome and second malignant tumor in patients with oral verrucous carcinoma

P.162 Oral verrucous carcinoma: Clinical data, natural history and results of treatment

P.162 Oral verrucous carcinoma: Clinical data, natural history and results of treatment

The man behind the eponym: Lauren V. Ackerman and verrucous carcinoma of Ackerman.

In 1948, Lauren V. Ackerman described a neoplasm of the oral mucous membrane, which he thought represented a unique type of squamous cell carcinoma and that is now termed verrucous carcinoma of Ackerman. "Verrucous carcinoma" has also been used as a generic term under which are placed giant condyloma of Buschke-Loewenstein and carcinoma cuniculatum. This report will synopsize the life of Lauren Vedder Ackerman, review the original and subsequent report by Ackerman, and discuss some other reports of oral verrucous carcinoma. Because this review is directed to histopathologists, the histopathology will be emphasized. Other aspects of the neoplasm (eg, clinical picture, incidence, etiopathogenesis, and treatment) will not be discussed, or if so, only briefly. Giant condyloma acuminatum of Buschke-Loewenstein and carcinoma cuniculatum and studies that mention the occurrence of Ackerman's verrucous carcinoma in the pharynx, larynx, and esophagus will be mentioned only in the section on classification.

Treatment results of oral verrucous carcinoma and its biological behavior

The biologic behavior of and optimal treatment for oral verrucous carcinoma (VC) remain controversial. We analyzed the clinicopathological characteristics of 12 patients with oral VC. Immunohistochemical techniques were used to evaluate p53 protein, CD44 variant 9, and proliferating cell nucleus antigen. The TNM classification (UICC, 1997) was T1 in 1 patient, T2 in 3, T3 in 4, and T4 in 4. All patients were classified as N0M0. Four patients were treated by surgery alone and 8 by surgery after chemotherapy, radiotherapy, or both. After surgery, two patients had primary recurrence of disease. Immunohistochemically, the proliferative activity of tumor cells as evaluated by proliferating cell nuclear antigen labeling index and p53 protein expression was similar in VC and well-differentiated squamous cell carcinoma. However, CD44 varient 9 expression was positive in 8 of 10 VC, suggesting that oral VC is associated with a low risk of lymph node metastasis. Positive CD44 variant 9 expression by most oral VCs, indicating a low risk of cervical lymph node metastasis, suggests that most cases can be controlled by surgical intervention.

Differential expression of matrilysin-1 (MMP-7), 92 kD gelatinase (MMP-9), and metalloelastase (MMP-12) in oral verrucous and squamous cell cancer.

Squamous cell carcinoma (SCC) of the oral cavity is a highly invasive tumour of stratified squamous epithelium that spreads through degradation of the basement membrane (BM) and extracellular matrix (ECM). There are currently no reliable tissue or serum markers to predict whether the tumour has metastasized at the time of diagnosis. Verrucous carcinoma (VC) of the oral cavity is a rare low-grade variant of oral SCC that penetrates into the subepithelial connective tissue. Many matrix metalloproteinases (MMPs), such as MMP-1, -2, -7, -9, -13, and -14, as well as integrin receptors have been implicated in cancer invasion. Integrin alphavbeta6 is induced in SCC and appears to be involved in up-regulation of MMP-9 expression by oral keratinocytes and promotion of their migration. The aim of this study was to investigate whether the pattern of MMP expression or that of alphavbeta6 integrin contributes to the differences in the biological behaviour of oral SCC and VC. The results show that the less aggressive nature of oral VC may be connected to its MMP expression profile. Typically, VCs were devoid of epithelial MMP-3, -7, -9, -12 and -13 expression, compared with SCCs. MMP-19 was expressed by epithelial keratinocytes in hyperproliferative areas of verrucous hyperplasia, VC, and SCC, but was absent in the invasive cancer cell nests of SCC. MMP-26 was expressed by hyperproliferative keratinocytes in VC as well as by invasive cancer cells in SCCs. MMP-10 was expressed widely in the epithelium of all SCC specimens. alphavbeta6 integrin expression was also detected in some cases of epithelial hyperplasia but was significantly more abundant in cancers at the invasive front. The absence of MMP-7, -9 and -12 from epithelial cells may serve as a good prognostic marker of non-invasive oral carcinoma. Blocking the activity of invasion-specific MMPs or alphavbeta6 integrin might offer novel therapeutic modalities in early-stage oral carcinoma.

Carcinoma Verrucoso e Leucoplasia em um mesmo paciente: relato de caso clínico

Os autores descrevem o caso clínico de duas lesões presentes há mais de 4 anos, em uma paciente do sexo feminino, 65 anos de idade, que negou hábitos de tabagismo e etilismo. Uma das lesões encontrava-se em mucosa jugal, lado direito, exofítica, com superfície verrucóide e esbranquiçada; outra localizava-se na borda da língua, lado direito, em forma de placa branca. Os diagnósticos clínicos estabelecidos foram de Carcinoma Verrucoso para a lesão de mucosa jugal e de Leucoplasia para a lesão de língua, os quais foram confirmados no exame histopatológico. A paciente foi encaminhada para remoção cirúrgica de ambas as lesões. Decorridos 6 meses da cirurgia, a mesma encontra-se em bom estado de saúde geral, recuperando os movimentos faciais e linguais, através de fisioterapia.

Increased expression of inducible nitric oxide synthase for human oral submucous fibrosis, verrucous hyperplasia, and verrucous carcinoma

Abstract.Three isoforms of nitric oxide synthase (NOS), endothelial, neuronal and inducible NOS (iNOS), have been identified in humans. Enhanced expression of iNOS protein has been previously reported for human oral epithelial dysplasias, a human oral premalignant epithelial lesion; however, this expression has not been demonstrated for other premalignant epithelial lesions, namely, oral submucous fibrosis (SF) and verrucous hyperplasia (VH). On the other hand, iNOS protein expression has not been reported in human oral verrucous carcinoma (VCa). The aim of this current study was to determine whether iNOS protein also occurs for oral SF, VH and VCa lesions. We found that membranous stainings were observed chiefly in oral SF lesions (17/20, 85%), whereas cytoplasmic stainings were mainly found in the VH variants (16/20, 80%). By contrast, cytoplasmic and/or nuclear stainings were observed in the specimens of verrucous carcinoma (17/20, 85%). Since no iNOS activity could be detected for any of our specimens of normal buccal mucosa in the present immunohistochemical study, this suggests that an NOS-dependent mechanism may be involved in the malignant transformation of these two premalignant oral epithelial lesions.

Immunohistochemical Study of CD1a-labeled Langerhans Cells and Anti-tumor Immune Cells in Oral Verrucous Carcinomas.

To clarify the possible role of Langerhans cells (LCs) in oral verrucous carcinoma (OVC), LCs and anti-tumor immune cells in OVCs were immunohistochemically investigated with the use of anti-CD1a, 3, 4, 8, 68, and 79α antibodies. In OVCs, mucosa adjacent to OVCs, and normal oral mucosa, most intraepithelial CD1a-positive LCs were located in parabasal regions. Subepithelial LCs were scatteredly throughout the lamina propria. The densities of intraepithelial and subepithelial CD1a-positive LCs in OVCs were significantly higher than those in adjacent mucosa or normal oral mucosa. The density of CD1a-positive LCs in T3 stage OVCs was slightly lower than those in T1 and T2 stage OVCs. The majority of infiltrating CD3-, CD4-, and CD8-positive T lymphocytes, CD79α-positive B lymphocytes, and CD68-positive macrophages were observed in subepithelial portions of OVCs, but scattered CD3-, CD4-, and CD8-positive T lymphocytes were observed in intraepithelial portions of OVCs. CD8-positive T lymphocytes were more numerous than CD4-positive T lymphocytes in subepithelial portions of OVCs. In mucosa adjacent to OVCs and in normal oral mucosa, infiltration by CD3-, CD4-, and CD8-positive T lymphocytes, CD79α-positive B lymphocytes, and CD68-positive macrophages was minimal in both intraepithelial and subepithelial regions. LCs were slightly more numerous in CD8-positive T-cell dominant OVCs than in CD4-positive T-cell dominant OVCs. These results suggest that CD1a-positive LCs are related to CD8-positive T lymphocytes and that CD1a-positive LCs play a role in the anti-tumor immune response in OVCs.

Treatment modalities for oral verrucous carcinomas and their outcomes: contribution of radiotherapy and chemotherapy.

This clinical study focused, firstly, on the results of treatment and, secondly, on the anaplastic transformation, of oral verrucous carcinomas (OVCs) diagnosed and treated from 1981 to 1997 at the Department of Oral and Maxillofacial Surgery at Shimane Medical University Hospital. We analyzed the treatment modalities and outcomes for 15 patients with OVC. Excluding the results for 4 palliatively treated patients, the disease-free survival rates of the patients after the initial treatments, were 82% at 5 years and 66% at 10 years; for all 15 patients, these rates were 57% and 46%, respectively. Surgery alone and surgery combined with other treatments (such as radiotherapy and chemotherapy) appeared to yield disease-free survival rates to those achieved superior with other treatments whether single or combined; (78% vs 33% for 5-year disease-free survival; 52% vs 33% for 10-year disease-free survival); however, the difference was not significant (P = 0.47). Well differentiated squamous cell carcinomas (W-SCCs) (n = 5) as well as spindle cell carcinoma (n = 1) were found in subsequent operative or biopsy specimens. Surgery was the most reliable treatment method for OVC; however, radiotherapy combined with chemotherapy was the next most preferable treatment when surgery was not undertaken. We also found that highly malignant transformation (anaplastic transformation) occasionally occurred during treatments for OVC.

Increased expression of c-erbB-3 protein and proliferating cell nuclear antigen during development of verrucous carcinoma of the oral mucosa.

The roles of c-erbB-3 gene and protein in the pathogenesis, progression, and outcome of oral carcinoma remain unknown. To determine whether c-erbB-3 expression could serve as an indicator of progression from premalignant to malignant transformation and of prognoses in patients with oral carcinoma, the authors examined the relation between the expression of c-erbB-3 protein and cell proliferation activity during the development of oral verrucous carcinoma (VC). Immunohistochemical techniques were used to evaluate c-erbB-3 protein and proliferative cell nuclear antigen (PCNA). Sixty-one samples (36 patients) of verrucous hyperplasia (VH), VC, and well differentiated squamous cell carcinoma arising from verrucous carcinoma (V-WSCC) in the oral mucosa were examined. Normal human oral mucosa showed weak c-erbB-3 immunostaining, predominantly on the epithelial surface. In contrast, 7 (39%) of 18 VHs, 25 (84%) of 31 VCs, and all (100%) of 12 V-WSCCs demonstrated overexpression of c-erbB-3 protein with increased expression of PCNA in some premalignant epithelial cells and many tumor cells. This finding suggested the involvement of c-erbB-3 gene in the progression from VH to VC and V-WSCC. Overexpression of c-erbB-3 protein correlated with increased PCNA labeling index, indicating that c-erbB-3 may contribute to malignant transformation and tumor growth. Further, patients with high expression of both c-erbB-3 and PCNA had a poor outcome. Study results suggested that c-erbB-3 expression was an index of malignancy during progression from VH to VC and V-WSCC and might have been involved in the outcome of oral carcinoma patients.

Verrucous carcinoma, then and now

The salient clinical and pathological features of verrucous carcinoma, as first described by Ackerman in 1948, are reviewed. Two case reports are presented. The first concerns a personal experience with a patient who had five surgical procedures for multifocal oral verrucous carcinoma and remains alive and well 28 years after her initial treatment. The second report highlights the remarkable story of President Grover Cleveland’s secret surgery for verrucous carcinoma of the palate in 1893. Current concepts about the management of this uncommon tumor are reviewed, as well as some recent investigations that deal with its etiology.

Oral verrucous carcinoma: Incidence in two US populations

Much is known about the clinical appearance, biological behavior, and treatment of verrucous carcinoma of the oral cavity. However, the epidemiologic characteristics are completely unknown. This cancer is considered to be rare in Western cultures because it is not common in oral pathology biopsy services, but there is no epidemiologic evidence for this belief. To provide this evidence, 2 population-based incidence investigations were carried out, one in Rochester, Minn., and the other in the state of West Virginia. The results were as follows: the age-adjusted average annual incidence rate for oral verrucous carcinoma among Rochester residents was 0.1 100,000 person-years (0.2 for males, 0.0 for females), whereas the incidence rate for all intraoral carcinomas was 3.6 100,000 person-years (5.4 for males, 2.1 for females). Among men over 64 years of age, the incidence rate for verrucous carcinoma was increased to 3.2 100,000 person-years. Verrucous carcinoma was among the least common of the oral carcinomas in this population, representing only 3% of the total. The age-adjusted incidence rate for oral and pharyngeal verrucous carcinoma among West Virginia residents was somewhat greater, 0.3 100,000 person-years, and showed an even gender predilection (0.28 for males, 0.29 for females). The incidence rate for all oral/pharyngeal cancers in West Virginia was 8.8 100,000 person-years (13.4 for males, 5.7 for females), which was below the US average. The conclusion is that oral verrucous carcinoma is a rare tumor of older people, diagnosed in only 1 to 3 of every 1,000,000 persons each year.

Radiotherapy in the treatment of verrucous carcinoma of the oral cavity

Verrucous carcinomas are considered to have poor radioresponsiveness and radiotherapy has been reported to induce anaplastic transformation. Surgery has been considered to be the primary mode of treatment for these tumours. The clinical features, response to radiotherapy, survival and prognostic factors of a group of 53 patients with oral verrucous cancers, were studied and compared to patients with oral well-differentiated, squamous cancers, treated during the same time period. The buccal mucosa was the commonest primary site in both groups. 42 patients with verrucous cancer underwent primary radiotherapy and 11 underwent primary surgery. Complete response to radiotherapy was achieved in 76% of patients with verrucous cancer and partial response in 24%. Patients with verrucous cancer had a five year actuarial disease-free survival of 66% and overall survival of 86%. The corresponding survival figures were 43% and 56% in well-differentiated squamous cancers (P = 0.004). Composite stage of disease was a significant predictor of disease-free survival in both groups. None of the 16 patients with verrucous cancers that recurred after radiotherapy, had features of anaplastic transformation. Oral verrucous carcinoma appears to have similar radioresponsiveness and improved disease-free survival, compared to well-differentiated squamous cancers. The treatment policies for other oral squamous cancers are applicable to these tumours.

P53, Rb, and cyclin D1 expression in human oral verrucous carcinomas

The verrucous carcinoma (VC), a tumor with low grade malignancy, appears to be associated with tobacco and human papillomavirus. The pathobiology of these tumors has not been extensively studied, and molecular genetic alterations have not been reported. In this study we investigated by immunohistochemistry the expression of p53, Rb, and cyclin D1 in a series of well-defined oral VC. Changes in the expression of these genes have been commonly reported in a variety of human tumors. We studied 29 cases of VC, fixed in formalin and embedded in paraffin. Immunohistochemistry was carried out using the avidin-biotin immunoperoxidase technique. Polyclonal antibody CM-1 was used for p53, a rabbit polyclonal human RB antibody, Rb-WL-1 antibody for Rb and a rabbit polyclonal human cyclin D antibody for cyclin D1. Positive p53 expression (protein accumulation) was detected in 15 of the 29 VC analyzed. In some cases, p53-positive areas were small foci but in most of the cases extensive positive areas were observed. None of the cases studied showed alterations of Rb protein. The expression of cyclin D1 was determined in 18 cases of VC. Positive nuclear immunostaining was seen in 11 cases. p53 protein accumulation is frequently observed in these tumors suggesting possible mutations of this gene in VC. Overexpression of cyclin D1 but no alterations of Rb staining were also observed in this low grade tumor suggesting that Rb may be functionally inactivated by overexpression of cyclin D1 or HPV infection.

H-ras oncogene mutation and human papillomavirus infection in oral carcinomas.

Previous in vitro studies have demonstrated that transfection of an activated ras gene induces malignant transformation in epithelial cell lines infected with the human papillomavirus (HPV). The results of these studies support the hypothesis that HPV may cooperate with an activated ras gene in epithelial tumor carcinogenesis. To test this hypothesis in head and neck cancers, we screened 35 oral carcinomas for the presence of HPV DNA and for a mutated H-ras gene. The design of the study was screening survey type. Twenty-seven oral squamous cell carcinomas and eight verrucous carcinomas were analyzed for the presence of HPV DNA using the polymerase chain reaction, followed by Southern blot and probe hybridization. The tumors were also screened for point mutations of the H-ras gene using the polymerase chain reaction and restriction fragment length polymorphism analysis. Six (22%) of the 27 oral squamous cell carcinomas demonstrated point mutation in the H-ras gene. In addition, six tumors (22%) were positive for HPV DNA, with three tumors (11%) demonstrating both HPV DNA and H-ras gene point mutation. While the rate of simultaneous HPV infection and ras gene activation by point mutation was 11% in oral squamous cell carcinomas, 25% of oral verrucous carcinomas contained both HPV DNA and mutation in the H-ras gene. These results suggest a stronger association between HPV infection and activation of the H-ras gene in oral verrucous carcinomas. These results continue to confirm the multihit hypothesis of tumorigenesis and suggest that in some cases of oral cancer at least two of these events are H-ras gene mutation and HPV infection.