Reticular Myxoid Odontogenic Neoplasm with Novel STRN::ALK Fusion: Report of 2 Cases in 3-Year-Old Males.

Odontogenic tumors represent a collection of entities ranging from hamartomas to destructive benign and malignant neoplasms. Occasionally, pathologists encounter gnathic lesions which clearly exhibit an odontogenic origin but do not fit within the confines of established diagnoses. Here, we describe two such odontogenic tumors, both affecting 3-year-old males. Each case presented as a destructive, radiolucent mandibular lesion composed of mesenchymal cells, some with unique multi-lobed nuclei, frequently arranged in a reticular pattern and supported by a myxoid stroma with focal laminations. Production of odontogenic hard tissues was also seen. Because of their unique microscopic features, both cases were investigated by next-generation sequencing and found to harbor the same STRN::ALK oncogene fusion. To our knowledge, these cases represent the first report of an odontogenic tumor with a STRN::ALK gene rearrangement. We propose the possibility that this neoplasm could be separate from other known odontogenic tumors. Both patients were treated with surgical resection and reconstruction. The prognosis of patients with this entity is currently uncertain but shall become more apparent over time as more cases are identified and followed.

Black and Brown: Non-neoplastic Pigmentation of the Oral Mucosa.

Black and brown pigmentation of the oral mucosa can occur due to a multitude of non-neoplastic causes. Endogenous or exogenous pigments may be responsible for oral discoloration which can range from innocuous to life-threatening in nature. Physiologic, reactive, and idiopathic melanin production seen in smoker's melanosis, drug-related discolorations, melanotic macule, melanoacanthoma and systemic diseases are presented. Exogenous sources of pigmentation such as amalgam tattoo and black hairy tongue are also discussed. Determining the significance of mucosal pigmented lesions may represent a diagnostic challenge for clinicians. Biopsy is indicated whenever the source of pigmentation cannot be definitively identified based on the clinical presentation.

Oral Mycosis Fungoides: A Report of Three Cases and Review of the Literature.

Mycosis fungoides (MF) and Sézary syndrome are clonal T-cell proliferations that exhibit skin homing and represent the majority of cutaneous T-cell lymphomas. Early MF is a diagnostic challenge as both the clinical and microscopic features often mimic benign inflammatory conditions. Oral MF is very rare and has been associated in the past with advanced disease and a poor prognosis. Skin lesions are present for an average of > 6 years before oral involvement occurs. The clinical appearance is highly variable with tongue, palate and gingiva most often affected. We report 3 additional cases of oral MF, including one in which oral lesions are the initial disease presentation. Survival in patients presenting with oral MF is improving and can be attributed to advances in therapy.

Detection of human papillomavirus DNA in formalin-fixed, paraffin-embedded squamous papillomas of the oral cavity.

BACKGROUND: Squamous papillomas are exophytic proliferations of surface oral epithelium. Human papillomavirus (HPV) infection is widely accepted as the etiology of squamous papillomas however the virus cannot be detected in a significant percentage of lesions. MATERIAL AND METHODS: Using polymerase chain reaction (PCR), we tested 35 formalin-fixed paraffin-embedded (FFPE) squamous papillomas for the presence of HPV DNA. RESULTS: Six papillomas (17%) tested positive for HPV DNA; four contained HPV-6 and two contained HPV-11. Given that ß-globin DNA was only identified in half of the samples, DNA degradation appears to have significantly impacted the results. CONCLUSIONS: The results likely represent an underestimation of the true number of HPV-positive specimens in our study. Potential explanations for HPV-negative squamous papillomas include transient HPV infection, failure of the experiment to detect HPV if present, or the possibility that some lesions may not result from HPV infection. Key words:HPV, PCR, FFPE, papilloma, oral.

Histologic Evaluation of Acellular Dermal Matrix Allografts in Humans.

INTRODUCTION: Acellular dermal matrix (ADM) is a cell-free dermal matrix comprised of a structurally integrated basement membrane complex and extracellular matrix in which collagen bundles and elastic fibers are the main components. There are several commercially available ADM allografts that have different processing methods. This case series reports the histologic presentation of two of the most widely used ADM allografts, referred to as ADM-A and ADM-B, in patients that had specific situations involving reentry. CASE SERIES: Two patients referred to the Louisiana State University Department of Periodontics, New Orleans, Louisiana, with 1- to 3-mm recession of at least two non-contiguous sites needing soft tissue augmentation, were treated with appropriate mucogingival procedures using ADM-A or ADM-B. After ≈6 to 8 months of healing, and due to clinical findings that necessitated further periodontal procedures, small tissue biopsies were obtained and examined microscopically. CONCLUSIONS: All samples of ADM (A and B) analyzed after staining with hematoxylin and eosin had a generally similar appearance under light microscopic examination, which suggests they are both well incorporated into native tissues after 6 to 8 months of healing. When stained with Verhoeff-Van Gieson, all samples showed elastin fibers, a finding consistent with previously published light microscopic observations of ADM. There appeared to be a more densely packed elastin pattern in the deep base of ADM-A compared with ADM-B. This might be an indication these two materials have a different healing pathway when used to augment the oral mucosa.

Peripheral giant cell granulomas: a series of 279 cases.

OBJECTIVE: This study investigated the demographic, clinicopathologic, and histopathologic findings of lesions diagnosed as peripheral giant cell granuloma (PGCG) by the Louisiana State University Oral Pathology Biopsy Service from 1974 to 2011. STUDY DESIGN: Clinical, demographic, and histopathologic evaluation was completed for 279 cases. A follow-up questionnaire was mailed to all surgeons who performed these biopsies from 1990 to 2011. RESULTS: Of the 279 lesions, 58% occurred in the mandible, 44% occurred in the anterior portion of the arches, 83% were adjacent to teeth, 14% occurred in edentulous areas, and 2% were adjacent to implants. Average duration was 10.5 months, and the average size was 12.7 mm. The recurrence rate was 17.5%. Histopathologically, 78% of lesions extended to the base of the specimen, 50% exhibited ulceration, 41% contained calcifications, and 6% exhibited features overlapping with another pathologic entity. CONCLUSIONS: PGCG is a well-defined pathologic entity among reactive gingival lesions. Recurrent lesions were more likely to contain calcifications.

Weekly chemotherapy with radiation versus high-dose cisplatin with radiation as organ preservation for patients with HPV-positive and HPV-negative locally advanced squamous cell carcinoma of the oropharynx.

BACKGROUND: Optimal treatment for locally advanced squamous cell carcinoma of the oropharynx (SCCOP) is not well defined. Here we retrospectively compare survival and toxicities from 2 different organ preservation protocols. METHODS: The matched dataset consisted of 35 patients from each trial matched for age, stage, smoking, and tumor human papillomavirus (HPV) status. Patients in the University of Michigan Cancer Center (UMCC) trial 9921 were treated with induction chemotherapy (IC) followed by high-dose cisplatin and radiation in responders or surgery in nonresponders. Patients in the UMCC trial 0221 were treated with weekly carboplatin and paclitaxel and radiation. RESULTS: Survival was comparable for both studies and did not differ significantly across each trial after stratifying by HPV status. Grade 3 and 4 toxicities were more frequent in UMCC 9921. At 6 months posttreatment, gastrostomy tube (G-tube) dependence was not statistically different. CONCLUSION: These data suggest that survival outcomes in patients with locally advanced SCCOP are not compromised with weekly chemotherapy and radiation therapy, and such treatment is generally more tolerable.

Minor salivary gland mucoepidermoid carcinoma in children and adolescents: a case series and review of the literature.

INTRODUCTION: Because well-documented cases of mucoepidermoid carcinomas that are of minor salivary gland origin and occur in children and adolescents have rarely been reported, little information regarding their clinical features and biologic behavior is available. This case report represents a retrospective clinical analysis of five minor salivary gland mucoepidermoid carcinomas accessioned from a 35-year period at the Louisiana State University School of Dentistry and combines the data with 15 well-documented cases from the English language literature. CASE PRESENTATION: The five mucoepidermoid carcinomas in patients from birth to 19 years of age accounted for 1.3% of the accessioned minor salivary gland neoplasms. There were an additional 15 well-documented cases in the literature. Combining the data for the 20 mucoepidermoid carcinomas resulted in a mean age of 13.5 years and a 2.3:1 female-to-male ratio. Collectively, the hard palate, soft palate, and hard palate/soft palate junction accounted for 85% of the cases. Thirty-five percent of the cases presented as a fluctuant submucosal swelling with surface color alterations. The average duration was five months, and bone involvement occurred in seven cases. A histologic grade of low to intermediate predominated (95%). Surgical removal was the treatment in all cases. Thirteen cases had adequate follow-up of three years or more, and recurrence was documented in only one case. There were no cases of death or metastasis in this series. CONCLUSIONS: In children and adolescents, mucoepidermoid carcinomas have a female predilection and occur most commonly on the hard or soft palate or both. A fluctuant submucosal lump with a bluish color is a helpful diagnostic clue. The histologic grades of most mucoepidermoid carcinomas in the first and second decades of life are low and, to a lesser degree, intermediate. Complete surgical excision is the treatment of choice and results in a recurrence rate of less than 10%.

High SEPT9_v1 Expression Is Associated with Poor Clinical Outcomes in Head and Neck Squamous Cell Carcinoma.

The purpose of this work was to determine SEPT9_v1 expression levels in head and neck squamous cell carcinoma (HNSCC) and to analyze whether SEPT9_v1 expression is relevant to clinical outcomes. Recently, the SEPT9 isoform SEPT9_v1 has been implicated in oncogenesis, and methylation of the SEPT9 promoter region was reported in HNSCC. These findings led us to hypothesize that SEPT9_v1 could be differently expressed in HNSCC. To determine whether SEPT9_v1 is expressed in HNSCC, tissue microarray immunohistochemical analysis was performed using a SEPT9_v1-specific antibody. Tissue microarrays stained with a polyclonal SEPT9_v1-specific antibody was used to determine protein expression levels in HNSCC tissue samples, some with known clinical outcomes. This analysis showed that SEPT9_v1 is in fact highly expressed in HNSCC compared with normal epithelium, and high expression levels directly correlated with poor clinical outcomes. Specifically, a high SEPT9_v1 expression was associated with decreased disease-specific survival (P = .012), time to indication of surgery at primary site (P = .008), response to induction chemotherapy (P = .0002), and response to chemotherapy (P = .02), as well as advanced tumor stage (P = .012) and N stage (P = .0014). The expression of SEPT9_v1 was also strongly correlated with smoking status (P = .00094). SEPT9_v1 is highly expressed in HNSCC, and a high expression of SEPT9_v1 is associated with poor clinical outcomes. These data indicate that SEPT9_v1 warrants additional investigation as a potential biomarker for HNSCC.

Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence.

PURPOSE: The goal of this study was to examine the effect of tobacco use on disease recurrence (local/regional recurrence, distant metastasis, or second primary) among patients with human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx (SCCOP) following a complete response to chemoradiation therapy. EXPERIMENTAL DESIGN: Between 1999 and 2007, 124 patients with advanced SCCOP (86% with stage IV) and adequate tumor tissue for HPV analysis who were enrolled in one of two consecutive University of Michigan treatment protocols were prospectively included in this study. Patients were categorized as never-, former, or current tobacco users. The primary end points were risk of disease recurrence and time to recurrence; secondary end points were disease-specific survival and overall survival. RESULTS: One hundred and two patients (82.3%) had HPV-positive tumors. Over two thirds (68%) of patients with HPV-positive tumors were tobacco users. Among HPV-positive patients, current tobacco users were at significantly higher risk of disease recurrence than never-tobacco users (hazard ratio, 5.2; confidence interval, 1.1-24.4; P = 0.038). Thirty-five percent of HPV-positive ever tobacco users recurred compared with only 6% of HPV-positive never users and 50% of HPV-negative patients. All HPV-negative patients were tobacco users and had significantly shorter times to recurrence (P = 0.002), and had reduced disease-specific survival (P = 0.004) and overall survival (P < 0.001) compared with HPV-positive patients. Compared with HPV-positive never-tobacco users, those with a tobacco history showed a trend for reduced disease-specific survival (P = 0.064) but not overall survival (P = 0.221). CONCLUSIONS: Current tobacco users with advanced, HPV-positive SCCOP are at higher risk of disease recurrence compared with never-tobacco users.

HPV-positive/p16-positive/EBV-negative nasopharyngeal carcinoma in white North Americans.

BACKGROUND: Human papillomavirus (HPV) has been detected in keratinizing nasopharyngeal carcinomas (NPCs); however, the relationship between HPV and Epstein-Barr virus (EBV) among whites with nonkeratinizing NPCs remains unclear. The HPV, p16, and EBV status was examined in current University of Michigan patients with NPC. METHODS: From 2003 to 2007, 89 patients, 84 with oropharyngeal cancer (OPC) and 5 with NPC, were enrolled in an organ-sparing trial. Biopsy tissues from all 89 patients were evaluated for HPV and p16 expression. A separate HPV analysis of the 84 OPC patients is in progress. Among the patients with NPC, tumor tissue was also analyzed for EBV-encoded RNA (EBER). RESULTS: Five of 89 patients (5.6%) had NPC, all with nonkeratinizing histology. The 4 white patients with NPC were HPV(+) (subtype-16, subtype-18 [2 patients], and subtype-59)/p16(+)/EBER(-). One Asian patient with NPC had an HPV(-)/p16(-)/EBER(+) NPC tumor that developed distant metastases. CONCLUSION: We postulate that HPV may be the etiologic factor in some EBV-negative, nonkeratinizing NPCs among whites.

Adenomatoid odontogenic tumor developing in association with an odontoma: report of a case.

The adenomatoid odontogenic tumor is an unusual lesion that usually presents in the anterior maxilla. In contrast, the odontoma is the most common odontogenic tumor. The concurrent occurrence of these tumors in a single lesion is extremely rare. Such a lesion occurred in the mandibular canine region of a 13-year-old boy. While the hard tissue component of the lesion consisted of irregularly organized enamel and dentin matrix, the soft tissue component was composed of loosely arranged spindle cells and whorled masses of cells. Ductlike structures were observed around eosinophilic matrix. The histopathologic findings were consistent with concurrent occurrence of an odontoma and adenomatoid odontogenic tumor.

Rap1GAP promotes invasion via induction of matrix metalloproteinase 9 secretion, which is associated with poor survival in low N-stage squamous cell carcinoma.

The objective of the current study was to investigate the effects of Rap1GAP on invasion and progression of head and neck squamous cell carcinoma (SCC) and the role of matrix metalloproteinase (MMP) 9 and MMP2 in this process. Rap1GAP functions by switching off Rap1, the Ras-like protein that has been associated with carcinogenesis. Previous findings suggest that Rap1GAP acts as a tumor suppressor protein in SCC by delaying the G(1)-S transition of the cell cycle. However, cells transfected with Rap1GAP exhibit a more invasive phenotype than corresponding vector-transfected control cells. MMP2 and MMP9 are enzymes that mediate SCC invasion via degradation of the extracellular matrix. Using SCC cells transfected with empty vector or Rap1GAP, cell invasion and MMP secretion were determined by Matrigel assays and gelatin zymography, respectively. Rap1GAP up-regulated transcription and secretion of MMP2 and MMP9, as assayed by quantitative reverse transcription-PCR and zymography. Furthermore, chemical and RNA interference blockade of MMP2/MMP9 inhibited invasion by Rap1GAP-transfected cells. Immunohistochemical staining of a human oropharyngeal SCC tissue microarray showed that Rap1GAP and MMP9 expression and staining intensity are correlated (P < 0.0001) and that, in early N-stage lesions of SCC, high MMP9 is prognostic of poor disease-specific survival (P < 0.05). Furthermore, Rap1GAP staining is correlated with MMP2 (P < 0.03). MMP2 in combination with N stage has a prognostic effect on time to indication of surgery at primary site. MMP2 intensity is also positively correlated with T stage (P < 0.015). In conclusion, Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated SCC invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive SCCs.

EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer.

PURPOSE: To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer. PATIENTS AND METHODS: Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status. RESULTS: EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (rho(EGFR) = 0.008; rho(HPV) = 0.03) and DSS (rho(EGFR) = 0.01; rho(HPV) = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002). CONCLUSION: Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.

Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number.

PURPOSE: To test induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) or surgery/radiotherapy (RT) for advanced oropharyngeal cancer and to assess the effect of human papilloma virus (HPV) on response and outcome. PATIENTS AND METHODS: Sixty-six patients (51 male; 15 female) with stage III to IV squamous cell carcinoma of the oropharynx (SCCOP) were treated with one cycle of cisplatin (100 mg/m(2)) or carboplatin (AUC 6) and with fluorouracil (1,000 mg/m(2)/d for 5 days) to select candidates for CRT. Those achieving a greater than 50% response at the primary tumor received CRT (70 Gy; 35 fractions with concurrent cisplatin 100 mg/m(2) or carboplatin (AUC 6) every 21 days for three cycles). Adjuvant paclitaxel was given to patients who were complete histologic responders. Patients with a response of 50% or less underwent definitive surgery and postoperative radiation. Pretreatment biopsies from 42 patients were tested for high-risk HPV. RESULTS: Fifty-four of 66 patients (81%) had a greater than 50% response after IC. Of these, 53 (98%) received CRT, and 49 (92%) obtained complete histologic response with a 73.4% (47 of 64) rate of organ preservation. The 4-year overall survival (OS) was 70.4%, and the disease-specific survival (DSS) was 75.8% (median follow-up, 64.1 months). HPV16, found in 27 of 42 (64.3%) biopsies, was associated with younger age (median, 55 v 63 years; P = .016), sex (22 of 30 males [73.3%] and five of 12 females [41.7%]; P = .08), and nonsmoking status (P = .037). HPV titer was significantly associated with IC response (P = .001), CRT response (P = .005), OS (P = .007), and DSS (P = .008). CONCLUSION: Although the numbers in this study are small, IC followed by CRT is an effective treatment for SCCOP, especially in patients with HPV-positive tumors; however, for patients who do not respond to treatment, alternative treatments must be developed.

Expression of p53 and Bcl-xL as predictive markers for larynx preservation in advanced laryngeal cancer.

OBJECTIVE: To assess tumor markers in advanced laryngeal cancer. DESIGN: Marker expression and clinical outcome. PATIENTS: Pretreatment tumor biopsy specimens were analyzed from patients enrolled in the Department of Veterans Affairs Laryngeal Cancer Study. MAIN OUTCOME MEASURES: Expression of p53 (OMIM TP53) and Bcl-xL (OMIM 600039) in pretreatment biopsy specimens was assessed for correlation with chemotherapy response, laryngeal preservation, and survival. RESULTS: Higher rates of larynx preservation were observed in patients whose tumors expressed p53 vs those that did not (80% [36 of 45 patients] vs 59% [24 of 41 patients], P =.03). Higher rates of larynx preservation were also observed in patients whose tumors expressed low levels of Bcl-xL vs high levels of Bcl-xL (90% [18 of 20 patients] vs 60% [30 of 50 patients], P =.02). Patients were categorized into 3 risk groups (low, intermediate, and high) based on their tumor p53 and Bcl-xL expression status. Patients whose tumors had the high-risk biomarker profile (low p53 expression and high Bcl-xL expression) were less likely to preserve their larynx than patients whose tumors had the intermediate-risk biomarker profile (high p53 expression and low or high Bcl-xL expression) or the low-risk biomarker profile (low p53 expression and low Bcl-xL expression). The larynx preservation rates were 100% (10 of 10 patients), 77% (26 of 34 patients), and 54% (7 of 13 patients) for the low-risk, intermediate-risk, and high-risk groups, respectively (P =.04, Fisher exact test). CONCLUSION: Tumor expression of p53 and Bcl-xL is a strong predictor of successful larynx preservation in patients treated with induction chemotherapy and followed by radiation therapy in responding tumors.

Targeting apoptosis to overcome cisplatin resistance: a translational study in head and neck cancer.

PURPOSE: Cisplatin resistance remains a barrier to organ-sparing and survival of patients with advanced head and neck squamous cell carcinoma (HNSCC). Targeted therapies to overcome cisplatin-resistant HNSCC are being developed. METHODS AND MATERIALS: Cisplatin-sensitive parental HNSCC cell lines and cisplatin-resistant progeny were studied. Pretreatment HNSCC biopsies were used to construct tissue microarrays which were stained for p53 and Bcl-xL. RESULTS: HNSCC cell lines selected for cisplatin resistance had wild-type p53 and high levels of Bcl-xL. Expression of wild-type p53 in cell lines with low Bcl-xL enhanced cisplatin sensitivity. Expression of both Bcl-xL and wild-type p53 caused tumor cells to become cisplatin resistant. Patients whose tumors expressed low levels of p53 and Bcl-xL enjoyed the best organ preservation and disease-free survival whereas patients whose tumors expressed low levels of p53 and high levels of Bcl-xL had the worst outcome. Novel agents that inhibit Bcl-xL or activate p53 function may target cisplatin-resistant HNSCC. CONCLUSION: Cisplatin resistance in HNSCC is mediated, at least in part, by high Bcl-xL and functional p53.

Response to therapy and outcomes in oropharyngeal cancer are associated with biomarkers including human papillomavirus, epidermal growth factor receptor, gender, and smoking.

Induction chemotherapy and concurrent chemoradiation for responders or immediate surgery for non-responders is an effective treatment strategy head and neck squamous cell carcinoma (HNSCC) of the larynx and oropharynx. Biomarkers that predict outcome would be valuable in selecting patients for therapy. In this study, the presence and titer of high risk human papilloma virus (HPV) and expression of epidermal growth factor receptor (EGFR) in pre-treatment biopsies, as well as smoking and gender were examined in oropharynx cancer patients enrolled in an organ sparing trial. HPV16 copy number was positively associated with response to therapy and with overall and disease specific survival, whereas EGFR expression, current or former smoking behavior, and female gender (in this cohort) were associated with poor response and poor survival in multivariate analysis. Smoking cessation and strategies to target EGFR may be useful adjuncts for therapy to improve outcome in the cases with the poorest biomarker profile.

Metastatic tumors in the jaws: a retrospective study of 114 cases.

BACKGROUND: Malignancies involving the bones are metastatic tumors more commonly than primary tumors. In this retrospective study, the authors review metastatic disease in the jaws. METHODS: The authors retrieved cases of metastatic disease in the jaws over a 45-year period from the pathology archives at the University of Michigan School of Dentistry, Ann Arbor, and Indiana University School of Dentistry, Indianapolis. RESULTS: The authors conducted a retrospective analysis of 114 cases of metastatic disease in the jaws and found that approximately 60 percent of subjects had no history of malignancy. The sex distribution was equivalent. Mandibular predilection was more prominent in females than in males. Metastases from the breast were significantly greater than those from the lung and prostate (P < or = .05), the second and third most frequent sites, respectively. Women exhibited twice as many jaw metastases as did men 31 to 40 years of age and significantly fewer metastases than did men 71 to 80 years of age (P < or = .05). CONCLUSION: In the majority of cases, subjects had an undiagnosed primary cancer at the time the metastatic jaw disease presented. The most common site of origin of the primary cancer was the breast, when primary sites were considered independent of sex. CLINICAL IMPLICATIONS: Patients with metastatic disease in the jaws may have innocuous dental symptoms, such as pulpal or periodontal pain; therefore, clinicians will play a significant role in diagnosing the life-threatening disease.