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Papillomaviruses and oral cancer
LETTERS TO THE EDITOR
Leukoplakia and malignant transformation To the editor: We read with interest the guest editorial by Silverman et al. entitled "Leukoplakia, dysplasia, and malignant transformation" in the August 1996 issue Of this journal (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:117). We agree with several of the authors' conclusions and applaud their emphatic warning that red mucosal changes are particularly ominous. However, there are two central issues that warrant additional comment. First, we believe valid determinations of progression may not be possible. A dilemma exists because areas of suspect mucosal change may contain foci of varied degrees of dysplasia and because histologic evaluation requires the removal of some or all of the involved tissue. Complete excision permits a thorough evaluation of every part of a lesion, helping assure an accurate diagnosis. However, it precludes the ability to assess progression because the entire original lesion has been removed and cannot be revisited. Conversely, an incisional biopsy technique preserves much of the original tissue in situ, allowing one to follow the lesion and document subsequent changes. Unavoidably, however, the baseline diagnosis may not have accurately represented the greatest degree of dysplasia initially present because only a portion of the lesion was subjected to histologic evaluation. The picture is further clouded by the acknowledged inability of pathologists to agree with each other or themselves when grading dysplasias. 1 Given such limitations, conclusions about the progression (or regression) of dysplasias are of questionable validity. Second, the definition of "leukoplakia" has expanded to the point at which we believe the term is misleading and counterproductive. Leukoplakia now describes areas of mucosal change with various textures and colors, including red. 2 The authors' review supports the well-documented concept that redness is the mucosal change most likely to be associated with carcinoma-in-situ or invasive cancer. 3 Nonetheless, red lesions continue to be presented in most medical and dental texts as an afterthought, whereas undue attention is paid to leukoplakias. We suggest that mucosal changes be described and characterized according to their actual clinical presentation, (red or white or mixed, smooth or granular, ulcerated or elevated, etc.), avoiding catch phrases that serve only
to confuse and mislead. This would seem to be a more reasonable approach than bending existing terminology to conform to reality. The studies referenced by Silverman et al. and the large volume of material generated by Mashberg 3 prompt the following conclusions: 1. Flat white patches on the oral mucosa are very unlikely ever to be associated with carcinoma. 2. Persistent red lesions, with or without a white component, should be regarded as carcinoma until proven otherwise, particularly in patients at high risk. 3. Valid conclusions about progression and regression are very difficult to make, raising questions about the clinical significance of malignant transformation and chemoprevention studies. 4. The use of simple terms to describe lesions of the oral mucosa may help to eliminate the confusion and misdirection that result when a wide variety of clinical lesions are included under a single label.
Hillel Ephros, DMD, M D Seton Hall University School of Graduate Medical Education South Orange, NJ Alan Samit, DDS Department of Veteran's Affairs Medical Center East Orange, NJ
REFERENCES
1. Abbey L, Kangars GE, Gunsolley JC, Burns JC, Page DG, Svirsky JA, et al. Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol 1995;80:188-91. 2. Neville B, Damm D, Allen C, Bouquot J, editors. Oral and maxillofacial pathology. Philadelphia: WB Saunders 1995: 280-8. 3. Mashberg A, Samit A. Early diagnosis of asymptomaticoral and oropharyngeal squamous cancers. CA 1995;45:328-51.
Papillomaviruses and oral cancer To the editor: The article by Miller and White 1 in the July issue of this Journal (1996;82:57-68) represents a milestone in the analysis of viral carcinogenesis relative to oral cancer. The authors are to be commended for a superlative job, not only in their review effort, but more importantly in their critical analysis of extant data.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY February 1997
1,37
188 Letters to the editor
That human papillomavirus (HPV) is an important causative factor in what is probably a multifactorial disease is supported by their indePth analysis of published reports. They relate a higher prevalence of mucosatropic oncogenic HPV types in dysplasias, carcinomas, and metastatic foci even though oral epithelial HPV carriage in normal subjects is significant, perhaps approaching 15%. What is an essential element in the analysis of Miller and White, and was in fact alluded to briefly in their discussion, is the method of detection by polymerase chain reaction (PCR). Most cervical carcinoma cell lines are associated with only subgenomic early region HPV DNA sequences (i.e. E6, E7) that are integrated into host DNA; some of these lines harbor only one copy per cell. 2 The use of DNA extraction techniques with southern blot hybridization may not be sensitive enough to detect low copy number. Many of the investigators using PCR for detection of HPV in normal, preneoplastic, and neoplastic oral tissues, have used late region consensus primers. Because only early region genes have been associated with malignant transformation, the detection of late region sequences may be of no significance. 3 Certainly, in tumors with integrated early region sequences, analysis with late region primers will result in false negative findings. The persistence of early gene regulatory and transforming regions and loss of late region genes that encode proteins essential for viral capsid assembly may be footprints of the oncogenic process. Before dismissing the role of HPV in oral cancer, arguing that the prevalence is not as robust as seen in cervical carcinomas or that normal mucosa is often infected, prevalence data should be based on identification of early region D N A with documentation of integration into host cell DNA. The authors make this point, yet it is buried in the discussion and requires more emphasis.
Lewis R. Eversole Professor of Oral and Maxillofacial Pathology UCLA School of Dentistry CHS 53-058 Los Angeles, CA 90095 REFERENCES
l. Miller CS, White DK. Human papillomavirus expression in oral mucosa, premalignant conditions and sqnamous cell carcinoma: a retrospective review of the literature. Oral Snrg Oral Med Oral Pathol Oral Radiol Endod 1996;82:57-68. 2. SchwarzE, Freese UK, Gissmann L, Mayer W, Roggenbuck B, Stremlau A, zur Hausen H. Structure and transcription of human papillomavirus sequences in cervical carcinomacells. Nature 1985;314:111-4. 3. Watts SL, Brewer EE, Fry TL. Human papillomavirus DNA types in squamous cell carcinomasof the head and neck. Oral Surg Oral Med Oral Pathol 1991;71:701-7.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY February 1997
Sialolithiasis of the submandibular gland in an 8-year-old child To the editor: Submandibular gland sialolithiasis in children is uncommon. A review of the world literature reveals fewer than 100 cases of sialolithiasis of the submandibular gland in children ages 3 weeks to 15 years. We evaluated an 8-year-old girl who had three episodes of painful right submandibular swelling of the floor of the mouth over a 6-month period. An occlusal radiograph showed a 2 x 2 m m radiopaque mass interpreted as a sialolith. Probing of the duct was ineffective in locating the sialolith and a subsequent CT scan revealed two separate radiopacities, one anterior and the other more posterior. The submandibular gland was removed by an extraoral approach, and sectioning of the gland revealed multiple calcifications within the gland with a calculus at the hilum. A subsequent review of the literature revealed alternative methods of management. Current literature suggests the use of scintigraphy to determine the residual functional status of the gland, thereby determining whether the gland should be surgically removed to alleviate chronic symptoms. A number of authors have suggested use of extracorporeal shock wave lithotripsy (ESWL) and more recently the use of endoscopic intracorporeal lithotripsy (ESIL) for removal of salivary calculus. Continued advances in ESWL, ESIL, scintigraphy, ultrasound, and lasers offer an expanded array of effective therapeutic options in the management of submandibular calculi in children.
Martin Steiner, DDS Professor of Oral and Maxillofacial Surgery Alan R. Gould, DDS, MS Professor of Oral and Maxillofacial Pathology George M. Kushner, DMD, MD Assistant Professor of Oral and Maxillofacia1 Surgery Department of Surgical/Hospital Dentistry School of Dentistry University of Louisville Louisville, KY 40292 Richard Weber, MD, DDS 5864 Centerfield Ct. St. Charles, MO 63304 Alfred Pesto, DDS 2533 Larkin Road Lexington, KY 40503
Leukoplakia and malignant transformation To the editor: We read with interest the guest editorial by Silverman et al. entitled "Leukoplakia, dysplasia, and malignant transformation" in the August 1996 issue Of this journal (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:117). We agree with several of the authors' conclusions and applaud their emphatic warning that red mucosal changes are particularly ominous. However, there are two central issues that warrant additional comment. First, we believe valid determinations of progression may not be possible. A dilemma exists because areas of suspect mucosal change may contain foci of varied degrees of dysplasia and because histologic evaluation requires the removal of some or all of the involved tissue. Complete excision permits a thorough evaluation of every part of a lesion, helping assure an accurate diagnosis. However, it precludes the ability to assess progression because the entire original lesion has been removed and cannot be revisited. Conversely, an incisional biopsy technique preserves much of the original tissue in situ, allowing one to follow the lesion and document subsequent changes. Unavoidably, however, the baseline diagnosis may not have accurately represented the greatest degree of dysplasia initially present because only a portion of the lesion was subjected to histologic evaluation. The picture is further clouded by the acknowledged inability of pathologists to agree with each other or themselves when grading dysplasias. 1 Given such limitations, conclusions about the progression (or regression) of dysplasias are of questionable validity. Second, the definition of "leukoplakia" has expanded to the point at which we believe the term is misleading and counterproductive. Leukoplakia now describes areas of mucosal change with various textures and colors, including red. 2 The authors' review supports the well-documented concept that redness is the mucosal change most likely to be associated with carcinoma-in-situ or invasive cancer. 3 Nonetheless, red lesions continue to be presented in most medical and dental texts as an afterthought, whereas undue attention is paid to leukoplakias. We suggest that mucosal changes be described and characterized according to their actual clinical presentation, (red or white or mixed, smooth or granular, ulcerated or elevated, etc.), avoiding catch phrases that serve only
to confuse and mislead. This would seem to be a more reasonable approach than bending existing terminology to conform to reality. The studies referenced by Silverman et al. and the large volume of material generated by Mashberg 3 prompt the following conclusions: 1. Flat white patches on the oral mucosa are very unlikely ever to be associated with carcinoma. 2. Persistent red lesions, with or without a white component, should be regarded as carcinoma until proven otherwise, particularly in patients at high risk. 3. Valid conclusions about progression and regression are very difficult to make, raising questions about the clinical significance of malignant transformation and chemoprevention studies. 4. The use of simple terms to describe lesions of the oral mucosa may help to eliminate the confusion and misdirection that result when a wide variety of clinical lesions are included under a single label.
Hillel Ephros, DMD, M D Seton Hall University School of Graduate Medical Education South Orange, NJ Alan Samit, DDS Department of Veteran's Affairs Medical Center East Orange, NJ
REFERENCES
1. Abbey L, Kangars GE, Gunsolley JC, Burns JC, Page DG, Svirsky JA, et al. Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol 1995;80:188-91. 2. Neville B, Damm D, Allen C, Bouquot J, editors. Oral and maxillofacial pathology. Philadelphia: WB Saunders 1995: 280-8. 3. Mashberg A, Samit A. Early diagnosis of asymptomaticoral and oropharyngeal squamous cancers. CA 1995;45:328-51.
Papillomaviruses and oral cancer To the editor: The article by Miller and White 1 in the July issue of this Journal (1996;82:57-68) represents a milestone in the analysis of viral carcinogenesis relative to oral cancer. The authors are to be commended for a superlative job, not only in their review effort, but more importantly in their critical analysis of extant data.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY February 1997
1,37
188 Letters to the editor
That human papillomavirus (HPV) is an important causative factor in what is probably a multifactorial disease is supported by their indePth analysis of published reports. They relate a higher prevalence of mucosatropic oncogenic HPV types in dysplasias, carcinomas, and metastatic foci even though oral epithelial HPV carriage in normal subjects is significant, perhaps approaching 15%. What is an essential element in the analysis of Miller and White, and was in fact alluded to briefly in their discussion, is the method of detection by polymerase chain reaction (PCR). Most cervical carcinoma cell lines are associated with only subgenomic early region HPV DNA sequences (i.e. E6, E7) that are integrated into host DNA; some of these lines harbor only one copy per cell. 2 The use of DNA extraction techniques with southern blot hybridization may not be sensitive enough to detect low copy number. Many of the investigators using PCR for detection of HPV in normal, preneoplastic, and neoplastic oral tissues, have used late region consensus primers. Because only early region genes have been associated with malignant transformation, the detection of late region sequences may be of no significance. 3 Certainly, in tumors with integrated early region sequences, analysis with late region primers will result in false negative findings. The persistence of early gene regulatory and transforming regions and loss of late region genes that encode proteins essential for viral capsid assembly may be footprints of the oncogenic process. Before dismissing the role of HPV in oral cancer, arguing that the prevalence is not as robust as seen in cervical carcinomas or that normal mucosa is often infected, prevalence data should be based on identification of early region D N A with documentation of integration into host cell DNA. The authors make this point, yet it is buried in the discussion and requires more emphasis.
Lewis R. Eversole Professor of Oral and Maxillofacial Pathology UCLA School of Dentistry CHS 53-058 Los Angeles, CA 90095 REFERENCES
l. Miller CS, White DK. Human papillomavirus expression in oral mucosa, premalignant conditions and sqnamous cell carcinoma: a retrospective review of the literature. Oral Snrg Oral Med Oral Pathol Oral Radiol Endod 1996;82:57-68. 2. SchwarzE, Freese UK, Gissmann L, Mayer W, Roggenbuck B, Stremlau A, zur Hausen H. Structure and transcription of human papillomavirus sequences in cervical carcinomacells. Nature 1985;314:111-4. 3. Watts SL, Brewer EE, Fry TL. Human papillomavirus DNA types in squamous cell carcinomasof the head and neck. Oral Surg Oral Med Oral Pathol 1991;71:701-7.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY February 1997
Sialolithiasis of the submandibular gland in an 8-year-old child To the editor: Submandibular gland sialolithiasis in children is uncommon. A review of the world literature reveals fewer than 100 cases of sialolithiasis of the submandibular gland in children ages 3 weeks to 15 years. We evaluated an 8-year-old girl who had three episodes of painful right submandibular swelling of the floor of the mouth over a 6-month period. An occlusal radiograph showed a 2 x 2 m m radiopaque mass interpreted as a sialolith. Probing of the duct was ineffective in locating the sialolith and a subsequent CT scan revealed two separate radiopacities, one anterior and the other more posterior. The submandibular gland was removed by an extraoral approach, and sectioning of the gland revealed multiple calcifications within the gland with a calculus at the hilum. A subsequent review of the literature revealed alternative methods of management. Current literature suggests the use of scintigraphy to determine the residual functional status of the gland, thereby determining whether the gland should be surgically removed to alleviate chronic symptoms. A number of authors have suggested use of extracorporeal shock wave lithotripsy (ESWL) and more recently the use of endoscopic intracorporeal lithotripsy (ESIL) for removal of salivary calculus. Continued advances in ESWL, ESIL, scintigraphy, ultrasound, and lasers offer an expanded array of effective therapeutic options in the management of submandibular calculi in children.
Martin Steiner, DDS Professor of Oral and Maxillofacial Surgery Alan R. Gould, DDS, MS Professor of Oral and Maxillofacial Pathology George M. Kushner, DMD, MD Assistant Professor of Oral and Maxillofacia1 Surgery Department of Surgical/Hospital Dentistry School of Dentistry University of Louisville Louisville, KY 40292 Richard Weber, MD, DDS 5864 Centerfield Ct. St. Charles, MO 63304 Alfred Pesto, DDS 2533 Larkin Road Lexington, KY 40503