Robert O. Greer

Primary malignant melanoma of the oral cavity. A review of 177 cases.

Malignant melanoma of the oral cavity is rare, accounting for about 1% to 8% of all melanomas. There have been no prospective studies of melanoma in this location, and all previous papers have reported small numbers of cases or have retrospectively reviewed case reports from the literature. The authors report six new cases and review 171 cases published since the last major review in 1975. The classification of oral melanomas with radial growth phases is discussed.

Randomized, Double-Blind, Placebo-Controlled Phase IIB Trial of the Cyclooxygenase Inhibitor Ketorolac as an Oral Rinse in Oropharyngeal Leukoplakia

Purpose: Nonselective cyclooxygenase (COX) inhibitors have been reported to decrease the frequency of upper aerodigestive cancers. Ketorolac tromethamine oral rinse has been shown to resolve another COX-dependent process, periodontal disease, without incurring gastrointestinal side effects. This trial evaluated if a topically delivered oral rinse containing ketorolac was as safe as and more effective than oral rinse alone in reducing the area of oral leukoplakia. Experimental Design: 57 patients were randomized (2:1 ratio) in a double-blind, placebo-controlled study of ketorolac (10 ml of a 0.1% ketorolac rinse solution; n = 38) or placebo (10 ml of rinse solution; n = 19) given twice daily for 30 s over 90 days. Primary end point was evaluated visually obtaining bidimensional measurement of the size of leukoplakia lesion(s) at entry and at 90 days. Secondary end point was histological assessment of the leukoplakia as sampled by serial punch biopsy and independently reviewed by three pathologists. Results: The patients included 67% males, 11% non-Caucasian, and 86% used tobacco with no significant differences between the two arms. Both rinses were well tolerated with good compliance, and there was no significant difference in adverse events (P = 0.27). Major response rate (complete response and partial response) was 30% for ketorolac and 32% for the placebo arm. There was no significant difference in change in histology between the two arms. Conclusion: Local delivery of a COX-containing oral rinse was well tolerated but produced no significant reduction in the extent of leukoplakia compared with the placebo. However, the favorable response rate to placebo arm remains unexplained and additional investigation of the tissue penetration with ketorolac is warranted.

Detection of human papillomavirus DNA by in situ DNA hybridization and polymerase chain reaction in premalignant and malignant oral lesions

The sensitivity of detection of human papillomavirus (HPV) DNA in premalignant and malignant oral lesions by in situ hybridization (ISH) and polymerase chain reaction (PCR) were compared. With both methods HPV DNA was found in 4 of 24 cases of epithelial dysplasia, 4 of 14 cases of verrucous hyperplasia, and 1 of 10 cases of squamous cell carcinoma. The 10 cases of smokeless tobacco keratoses and 3 cases of verrucous carcinoma that we examined were all negative for HPV DNA. The PCR for the E6 open reading frame of HPV-16 correctly identified all cases that were positive by ISH. Only a single case that was positive by PCR was negative by ISH for HPV DNA. However, the PCR demonstrated the presence of HPV-16 infection in one case, which had hybridized most intensely with the probe for types 31/33/35 in the ISH. This discrepancy probably is due to the high degree of cross-hybridization in the ISH assay. PCR appears to be an effective technique for identifying HPV-16 DNA sequences in biopsy material from premalignant and malignant oral lesions.

Botryoid odontogenic cyst: Clinicopathologic analysis of ten cases with three recurrences

The botryoid odontogenic cyst (BOC) is a rare cyst of odontogenic origin originally described in 1973 by Weathers and Waldron as a variant of the lateral periodontal cyst. Ten examples of this rare lesion were studied by light and electron microscopy and the clinical and radiographic findings were analyzed. Eight of ten lesions were located in the mandible; the anterior mandible being the dominant site. Five of the ten lesions were unilocular, the largest measuring 4.5 X 1.2 cm. Only two of the ten botryoid odontogenic cysts were radiographically multilocular. Three lesions represented recurrences 8, 10, and 10 years after previous surgical intervention. All patients were white with an average age of 46 years. Perhaps the most significant information gained from this investigation of botryoid odontogenic cysts is the fact three of ten lesions recurred after initial surgical removal. It is important that practitioners take note of the fact that: 1) a recurrence potential may exist for the botryoid odontogenic cyst that has gone unrecognized, 2) recurrence may not occur until a decade after initial surgery, and 3) lesions may occasionally become destructive.

Necrotizing sialometaplasia obscuring an underlying malignancy: report of a case.

Necrotizing sialometaplasia poses many diagnostic problems, both clinically and microscopically. Caution had most frequently been urged for distinguishing between malignancy and NS, so as to avoid mutilating surgical treatment resulting from the misdiagnosis of a lesion that is benign and self-limiting. This case has been presented to alert the practitioner to the possibility that NS may obscure an underlying malignant disease process, possibly resulting in delays in referral or treatment. The exceedingly rapid growth of this mesenchymal neoplasm may have caused obstruction of the blood supply to the overlying mucosa and submucosa, thereby producing the ischemic alterations observed in the first biopsy specimens. Some of the difficulties encountered in the detection and diagnosis of neoplasms arising in the parapharyngeal space were discussed, and some previously published suggestions to aid in these efforts were reiterated.

Oral Manifestations of Smokeless Tobacco Use

Smokeless tobacco (SLT) has been smoked, chewed, and inhaled in various forms for hundreds of years. The primary oral, mucosal, and hard tissue changes associated with SLT use include SLT keratosis (STK); gingival inflammation, periodontal inflammation, and alveolar bone damage; and dental caries, tooth abrasion, and dysplasia and oral squamous cell carcinoma (SCC). Some high-risk STKs are human papillomavirus associated, and the highest level of transition of STK to dysplasia or oral SCC appears to be in those lesions that have a diffuse velvety or papillary texture clinically. There is minimal risk for oral cancer associated with SLT use.

Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14

ABSTRACT High-risk human papillomaviruses (HPVs) are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immune responses in the tumor microenvironment, we analyzed gene expression changes of all known chemokines and their receptors using our global gene expression data sets from human HPV-positive and -negative head/neck cancer and cervical tissue specimens in different disease stages. We report that, while many proinflammatory chemokines increase expression throughout cancer progression, CXCL14 is dramatically downregulated in HPV-positive cancers. HPV suppression of CXCL14 is dependent on E7 and associated with DNA hypermethylation in the CXCL14 promoter. Using in vivo mouse models, we revealed that restoration of Cxcl14 expression in HPV-positive mouse oropharyngeal carcinoma cells clears tumors in immunocompetent syngeneic mice, but not in Rag1-deficient mice. Further, Cxcl14 reexpression significantly increases natural killer (NK), CD4+ T, and CD8+ T cell infiltration into the tumor-draining lymph nodes in vivo. In vitro transwell migration assays show that Cxcl14 reexpression induces chemotaxis of NK, CD4+ T, and CD8+ T cells. These results suggest that CXCL14 downregulation by HPV plays an important role in suppression of antitumor immune responses. Our findings provide a new mechanistic understanding of virus-induced immune evasion that contributes to cancer progression. IMPORTANCE Human papillomaviruses (HPVs) are causally associated with more than 5% of all human cancers. During decades of cancer progression, HPV persists, evading host surveillance. However, little is known about the immune evasion mechanisms driven by HPV. Here we report that the chemokine CXCL14 is significantly downregulated in HPV-positive head/neck and cervical cancers. Using patient tissue specimens and cultured keratinocytes, we found that CXCL14 downregulation is linked to CXCL14 promoter hypermethylation induced by the HPV oncoprotein E7. Restoration of Cxcl14 expression in HPV-positive cancer cells clears tumors in immunocompetent syngeneic mice, but not in immunodeficient mice. Mice with Cxcl14 reexpression show dramatically increased natural killer and T cells in the tumor-draining lymph nodes. These results suggest that epigenetic downregulation of CXCL14 by HPV plays an important role in suppressing antitumor immune responses. Our findings may offer novel insights to develop preventive and therapeutic tools for restoring antitumor immune responses in HPV-infected individuals. Human papillomaviruses (HPVs) are causally associated with more than 5% of all human cancers. During decades of cancer progression, HPV persists, evading host surveillance. However, little is known about the immune evasion mechanisms driven by HPV. Here we report that the chemokine CXCL14 is significantly downregulated in HPV-positive head/neck and cervical cancers. Using patient tissue specimens and cultured keratinocytes, we found that CXCL14 downregulation is linked to CXCL14 promoter hypermethylation induced by the HPV oncoprotein E7. Restoration of Cxcl14 expression in HPV-positive cancer cells clears tumors in immunocompetent syngeneic mice, but not in immunodeficient mice. Mice with Cxcl14 reexpression show dramatically increased natural killer and T cells in the tumor-draining lymph nodes. These results suggest that epigenetic downregulation of CXCL14 by HPV plays an important role in suppressing antitumor immune responses. Our findings may offer novel insights to develop preventive and therapeutic tools for restoring antitumor immune responses in HPV-infected individuals.

Is p16INK4a protein expression in oral ST lesions a reliable precancerous marker

This study correlates the expression of p16(INK4a) and p53 with the detection of high risk human papillomavirus (HPV) in three clinical grades of smokeless tobacco keratosis (STK) as compared with patients without a history of smokeless tobacco use. Tissue samples, including squamous cell carcinoma (SCC) were evaluated for the expression of p16(INK4a) and p53 by indirect immunohistochemical methods using commercially obtained antibodies. HPV DNA analysis was performed using consensus sequence polymerase chain reaction (PCR). At least focal p16(INK4a) expression was detected in Grade I, II and III STK, SCC and control samples of alveolar ridge keratoses (ARK). p16(INK4a) expression in STK and in ARK was typically weak but was relatively strong in all SCC. Strong p53 nuclear staining was detected in STK, SCC and ARK. HPV DNA was detected in Grade I, II and III STK, SCC and ARK, but did not correlate with p16(INK4a) expression. p16(INK4a) distribution did not correlate with STK grade and does not appear to be related to the detection of HPV DNA by PCR in either STK or in SCC. There is an apparent relationship between the grade of STK and the presence of HPV. HPV was rarely detected in high-grade lesions.

Differential diagnosis of some simple osseous lesions associated with sickle-cell anemia

Sickle-cell disease is characterized by chronic hemolytic anemia, rapid destruction of defective erythrocytes, with consequent circulatory disturbances. Thromboses and infarctions with resultant osseous manifestations tend to be localized in the ends of the long bones or in the medullary area, the latter often becoming apparent in the jaws. Three case reports are presented to illustrate osseous changes observed in the jaws of these sickle-cell patients. The radiographic findings demonstrate the adaptive mechanisms of bone metabolism in response to vascular infarction, infection, or both in some sickle-cell anemia patients. A differential diagnosis is suggested for osseous lesions observed in the jaws of these patients.

Estrogen and Progesterone Receptor and p53 Gene Expression in Adenoid Cystic Cancer

Objectives The current study examined the role of estrogen receptors (ER), progesterone receptors (PR) and p53 expression in adenoid cystic carcinoma (ACC) to determine if simple expression or possible overexpression of these products might influence the development and natural course of this cancer. Study Design ER and PR status and p53 overexpression were retrospectively evaluated utilizing immunohistochemical evaluation of 47 ACC specimens. Methods Formalin-fixed paraffin-embedded tissues from 47 ACC specimens and 47 samples of normal salivary gland tissue were evaluated histochemically for the presence of ER, PR and p53. Immunoreactivity was scored using a 0 to +3 scale in which staining was either (0) negative, (+1) spotty, (+2) weakly positive, or (+3) strongly positive. Results ER was expressed in 8 of 47 tumors while PR was expressed in 4 of 47 tumors. p53 aberrations were demonstrated in 26 of 47 tumors. Tumors showed varying degrees of immunopositivity ranging from 0 to +3. Conclusions These studies suggest that p53 aberrations may be involved in ACC tumor progression and that ER and PR may play a role in ACC development.