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It’s time to modernize our approach to oral HPV lesions
LETTERS TO THE EDITOR
It’s time to modernize our approach to oral HPV lesions To the editor: In the recent article “Oral bowenoid lesions: Differential diagnosis and pathogenetic insights,” written by Daley et al, the authors reported 7 examples of “oral bowenoid lesions” and attempted to determine light microscopic and immunohistochemical features that would allow differentiation of oral Bowen’s disease (BD) from oral bowenoid papulosis (BP). The authors elected to use the “more specific” terms BD and BP to “avoid confusion” with the more “general concept” of koilocytic dysplasia (KD). We would like to suggest that the terms BD and BP are less specific than the term KD. Continued use of the terms BD and BP only adds to the confusion regarding the microscopic and clinical features of these lesions that have only begun to be identified and studied in the oral region. On the basis of the information presented in this article and the photomicrographs of the pathologic specimens presented, we consider the cases reported by Daley et al to represent examples of KD. There is considerable confusion regarding the definitions of BD and BP, and the use of these terms among clinicians and dermatopathologists reflects this fact. Bowen first identified BD in 1912.1 The term is currently most often used as an eponym for carcinoma in situ (CIS) presenting as a solitary plaque-like lesion. BP was described by Lloyd in 1970 as multicentric BD.2 In 1978, Wade, Kopf, and Ackerman reported 11 cases of CIS occurring in a multifocal pattern on the genitalia of young men and they coined the term BP.3 In keeping with the original criteria, the distinction between BD and BP is still most often made on the basis of clinical presentation. BD is CIS presenting as a single plaque. BP is CIS presenting as multiple papules, usually in a younger population. The authors of the current article failed to incorporate this concept into their approach to these lesions. As noted by Daley et al, investigators such as Gimeno et al, Albright et al, and Patterson et al also searched for subtle histologic differences between BD and BP. But Daley et al need only to note that the most recent study cited was from 1987 to see that the approach is obsolete. Continued use of the terms BD and BP, which were coined when molecular biology and the understanding
of the role of HPV in oncogenesis were in their infancy, should be abandoned in the study of oral epithelial dysplasias infected with HPV. These eponyms are misleading and potentially dangerous. For example, by current convention, case number 7 in the article by Daley et al should be considered BP—not BD—on the basis of the clinical presentation of multiple lesions. This particular case, however, had the most aggressive course of the 7 reported, because there were multiple recurrences despite complete clinical excision. Yet the authors state that BP should be regarded as benign, responding well to local treatment and even occasionally spontaneously regressing. It seems logical to us that the terms BD and BP should not be used because these diseases do not have well-defined histologic criteria and are most commonly differentiated on the basis of clinical presentation. We need to update our approach to oral HPV–infected lesions that display features of dysplasia by eliminating archaic terms and replacing them with more scientific terms. Terminology should be utilized that is reflective of the limitations of light microscopic evaluation of disease processes for which the prognosis is determined not on routine microscopy alone, but on multiple factors (eg, clinical data and molecular analysis). Only then can we begin to accurately subclassify these lesions and understand their biologic potential. If any attempt is made to quantify the malignant potential of a dysplastic HPV lesion, it must be made in keeping with the contemporary state of knowledge regarding HPV and oncogenesis. At a minimum, the type of HPV(s) infecting the lesion, the presence or absence of other cocarcinogens, and the nature of the host response must be evaluated to have a meaningful and modern approach to these lesions. In the gynecologic literature these facts are recognized and terms such as cervical intraepithelial neoplasia are used to describe premalignant conditions of the genital mucosa in which HPV is fully accepted as a major etiologic factor in cervical cancer. Just as our colleagues in obstetrics/gynecology are challenged to make sound recommendations to their patients regarding treatment and prognosis, we need to acknowledge that oral KD is a complex disease process associated with a known premalignant potential. It is for these reasons that we chose to use the term KD to describe oral lesions that display features of HPV infection and epithelial dysplasia.
494 May 2001 ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 91, Number 5
Letters to the editor 495
At the time of publication of our article, the biologic potential of KD was unknown, but we suggested that treatment should be complete surgical excision, if possible. Since our original publication, we have documented 3 cases of oral KD that, despite local excision, recurred as invasive squamous cell carcinoma. This neoplastic behavior serves to elucidate the biologic potential of oral KD. We are currently in the process of studying these cases, as well as more than 100 additional cases of oral KD.
such as generic epithelial dysplasia with occasional cells exhibiting nuclear hyperchromasia with perinuclear vacuolization in the superficial layers and even some cases of verrucous carcinoma would be diagnosed as koilocytic dysplasia (KD). That is a broader spectrum than the bowenoid lesions that exhibit atypical—and even bizarre—mitosis, apoptotic fragments or cells, karyomegally without hyperchromasia or cytoplasmic clearing, multinucleation, and dyskeratosis, all of which are randomly distributed throughout the epithelial layers. Consequently, we believe that their term koilocytic dysplasia is not discrete enough for the microscopically unique bowenoid lesions, and therefore we chose to maintain the bowenoid terminology to emphasize the potential for significantly different biological behavior of these lesions when they involve the oral mucosa. We do not share Fornatora et al’s concerns with the terms Bowen’s disease (BD) and bowenoid papulosis (BP). For those who may be uncertain about these terms, we carefully describe what is meant in the first 2 paragraphs of the introduction in our paper. Trying to sort out oral lesions that exhibit bowenoid features microscopically is the intent of our paper, because clinical features alone are obviously inadequate. Furthermore, the value of a term should not be based on how long it has existed, but on whether it is still relevant. We believe that the terms BD and BP are still applicable to oral lesions, and we recommend their continued use unless, or until, evidence shows otherwise. 2. Biological behavior: The bottom line is biological behavior and the ability of diagnosticians to predict it so that patients can receive appropriate treatment. It is clear from our data and from the asyet unpublished findings of Fornatora et al that 3 of their 100-plus cases had become malignant and that the present level of knowledge is insufficient. In our opinion, placing all lesions that exhibit bowenoid microscopic features into one group, along with other HPV-containing dysplasias not exhibiting bowenoid features, under the term KD does not help. We must try to find a means of differentiating these lesions, as we have attempted to do in our article. In their letter, Fornatora et al suggest that we “modernize” by assessing HPV status and host response. They seem somehow oblivious to the fact that we did assess HPV status—by in situ hybridization with probe cocktails and confirmation of expression of the HPV16 E6 gene by in situ rtPCR—and host response at the morphologic level by assessing lymphocyte infiltration, and at the molecular level with our attempts to determine the apoptotic and cell-cycling molecules involved.
Maria L. Fornatora, DMD Director, Division of Oral and Maxillofacial Pathology Department of Oral and Maxillofacial Pathology, Medicine and Surgery Temple University School of Dentistry Philadelphia, Pa Anne Cale Jones, DDS Associate Professor Department of Pathology The University of Texas Health Science Center at San Antonio San Antonio, Tex Stanley M. Kerpel, DDS Associate Director Section of Oral Pathology and Oral Medicine The New York Hospital Medical Center of Queens Flushing, NY Paul D. Freedman, DDS Director, Section of Oral Pathology and Oral Medicine The New York–Presbyterian Hospital/Weill College of Medicine of Cornell University and the New York Hospital Medical Center of Queens Flushing and New York, NY REFERENCES 1. Bowen JT. Precancerous dermatoses: A study of two cases of chronic atypical epithelial proliferation. J Cutan Dis 1912;30: 241-55. 2. Lloyd KM. Multicentric pigmented Bowen’s disease of the groin. Arch Dermatol 1970;101:48-51. 3. Wade TR, Kopf AW, Ackerman AB. Bowenoid papulosis of the penis. Cancer 1978;42:1890-903. doi:10.1067/moe.2001.115128
In reply: We would like to thank Drs Fornatora, Cale Jones, Kerpel, and Freedman for their interest in our paper; we appreciate the opportunity to reply to their letter. 1. Semantics: On the basis of the definition given by Fornatora et al (“oral lesions that displayed features of HPV infection and epithelial dysplasia”), lesions
It’s time to modernize our approach to oral HPV lesions To the editor: In the recent article “Oral bowenoid lesions: Differential diagnosis and pathogenetic insights,” written by Daley et al, the authors reported 7 examples of “oral bowenoid lesions” and attempted to determine light microscopic and immunohistochemical features that would allow differentiation of oral Bowen’s disease (BD) from oral bowenoid papulosis (BP). The authors elected to use the “more specific” terms BD and BP to “avoid confusion” with the more “general concept” of koilocytic dysplasia (KD). We would like to suggest that the terms BD and BP are less specific than the term KD. Continued use of the terms BD and BP only adds to the confusion regarding the microscopic and clinical features of these lesions that have only begun to be identified and studied in the oral region. On the basis of the information presented in this article and the photomicrographs of the pathologic specimens presented, we consider the cases reported by Daley et al to represent examples of KD. There is considerable confusion regarding the definitions of BD and BP, and the use of these terms among clinicians and dermatopathologists reflects this fact. Bowen first identified BD in 1912.1 The term is currently most often used as an eponym for carcinoma in situ (CIS) presenting as a solitary plaque-like lesion. BP was described by Lloyd in 1970 as multicentric BD.2 In 1978, Wade, Kopf, and Ackerman reported 11 cases of CIS occurring in a multifocal pattern on the genitalia of young men and they coined the term BP.3 In keeping with the original criteria, the distinction between BD and BP is still most often made on the basis of clinical presentation. BD is CIS presenting as a single plaque. BP is CIS presenting as multiple papules, usually in a younger population. The authors of the current article failed to incorporate this concept into their approach to these lesions. As noted by Daley et al, investigators such as Gimeno et al, Albright et al, and Patterson et al also searched for subtle histologic differences between BD and BP. But Daley et al need only to note that the most recent study cited was from 1987 to see that the approach is obsolete. Continued use of the terms BD and BP, which were coined when molecular biology and the understanding
of the role of HPV in oncogenesis were in their infancy, should be abandoned in the study of oral epithelial dysplasias infected with HPV. These eponyms are misleading and potentially dangerous. For example, by current convention, case number 7 in the article by Daley et al should be considered BP—not BD—on the basis of the clinical presentation of multiple lesions. This particular case, however, had the most aggressive course of the 7 reported, because there were multiple recurrences despite complete clinical excision. Yet the authors state that BP should be regarded as benign, responding well to local treatment and even occasionally spontaneously regressing. It seems logical to us that the terms BD and BP should not be used because these diseases do not have well-defined histologic criteria and are most commonly differentiated on the basis of clinical presentation. We need to update our approach to oral HPV–infected lesions that display features of dysplasia by eliminating archaic terms and replacing them with more scientific terms. Terminology should be utilized that is reflective of the limitations of light microscopic evaluation of disease processes for which the prognosis is determined not on routine microscopy alone, but on multiple factors (eg, clinical data and molecular analysis). Only then can we begin to accurately subclassify these lesions and understand their biologic potential. If any attempt is made to quantify the malignant potential of a dysplastic HPV lesion, it must be made in keeping with the contemporary state of knowledge regarding HPV and oncogenesis. At a minimum, the type of HPV(s) infecting the lesion, the presence or absence of other cocarcinogens, and the nature of the host response must be evaluated to have a meaningful and modern approach to these lesions. In the gynecologic literature these facts are recognized and terms such as cervical intraepithelial neoplasia are used to describe premalignant conditions of the genital mucosa in which HPV is fully accepted as a major etiologic factor in cervical cancer. Just as our colleagues in obstetrics/gynecology are challenged to make sound recommendations to their patients regarding treatment and prognosis, we need to acknowledge that oral KD is a complex disease process associated with a known premalignant potential. It is for these reasons that we chose to use the term KD to describe oral lesions that display features of HPV infection and epithelial dysplasia.
494 May 2001 ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 91, Number 5
Letters to the editor 495
At the time of publication of our article, the biologic potential of KD was unknown, but we suggested that treatment should be complete surgical excision, if possible. Since our original publication, we have documented 3 cases of oral KD that, despite local excision, recurred as invasive squamous cell carcinoma. This neoplastic behavior serves to elucidate the biologic potential of oral KD. We are currently in the process of studying these cases, as well as more than 100 additional cases of oral KD.
such as generic epithelial dysplasia with occasional cells exhibiting nuclear hyperchromasia with perinuclear vacuolization in the superficial layers and even some cases of verrucous carcinoma would be diagnosed as koilocytic dysplasia (KD). That is a broader spectrum than the bowenoid lesions that exhibit atypical—and even bizarre—mitosis, apoptotic fragments or cells, karyomegally without hyperchromasia or cytoplasmic clearing, multinucleation, and dyskeratosis, all of which are randomly distributed throughout the epithelial layers. Consequently, we believe that their term koilocytic dysplasia is not discrete enough for the microscopically unique bowenoid lesions, and therefore we chose to maintain the bowenoid terminology to emphasize the potential for significantly different biological behavior of these lesions when they involve the oral mucosa. We do not share Fornatora et al’s concerns with the terms Bowen’s disease (BD) and bowenoid papulosis (BP). For those who may be uncertain about these terms, we carefully describe what is meant in the first 2 paragraphs of the introduction in our paper. Trying to sort out oral lesions that exhibit bowenoid features microscopically is the intent of our paper, because clinical features alone are obviously inadequate. Furthermore, the value of a term should not be based on how long it has existed, but on whether it is still relevant. We believe that the terms BD and BP are still applicable to oral lesions, and we recommend their continued use unless, or until, evidence shows otherwise. 2. Biological behavior: The bottom line is biological behavior and the ability of diagnosticians to predict it so that patients can receive appropriate treatment. It is clear from our data and from the asyet unpublished findings of Fornatora et al that 3 of their 100-plus cases had become malignant and that the present level of knowledge is insufficient. In our opinion, placing all lesions that exhibit bowenoid microscopic features into one group, along with other HPV-containing dysplasias not exhibiting bowenoid features, under the term KD does not help. We must try to find a means of differentiating these lesions, as we have attempted to do in our article. In their letter, Fornatora et al suggest that we “modernize” by assessing HPV status and host response. They seem somehow oblivious to the fact that we did assess HPV status—by in situ hybridization with probe cocktails and confirmation of expression of the HPV16 E6 gene by in situ rtPCR—and host response at the morphologic level by assessing lymphocyte infiltration, and at the molecular level with our attempts to determine the apoptotic and cell-cycling molecules involved.
Maria L. Fornatora, DMD Director, Division of Oral and Maxillofacial Pathology Department of Oral and Maxillofacial Pathology, Medicine and Surgery Temple University School of Dentistry Philadelphia, Pa Anne Cale Jones, DDS Associate Professor Department of Pathology The University of Texas Health Science Center at San Antonio San Antonio, Tex Stanley M. Kerpel, DDS Associate Director Section of Oral Pathology and Oral Medicine The New York Hospital Medical Center of Queens Flushing, NY Paul D. Freedman, DDS Director, Section of Oral Pathology and Oral Medicine The New York–Presbyterian Hospital/Weill College of Medicine of Cornell University and the New York Hospital Medical Center of Queens Flushing and New York, NY REFERENCES 1. Bowen JT. Precancerous dermatoses: A study of two cases of chronic atypical epithelial proliferation. J Cutan Dis 1912;30: 241-55. 2. Lloyd KM. Multicentric pigmented Bowen’s disease of the groin. Arch Dermatol 1970;101:48-51. 3. Wade TR, Kopf AW, Ackerman AB. Bowenoid papulosis of the penis. Cancer 1978;42:1890-903. doi:10.1067/moe.2001.115128
In reply: We would like to thank Drs Fornatora, Cale Jones, Kerpel, and Freedman for their interest in our paper; we appreciate the opportunity to reply to their letter. 1. Semantics: On the basis of the definition given by Fornatora et al (“oral lesions that displayed features of HPV infection and epithelial dysplasia”), lesions