Lymphadenoma of the salivary gland: clinicopathological and immunohistochemical analysis of 33 tumors.

Lymphadenomas (LADs) are rare salivary gland tumors. Their clinicopathologic characteristics and etiopathogenesis are poorly understood. We examined 33 LADs in 31 patients (17 women and 14 men) aged 11-79 years (median 65 years). There were 22 sebaceous LADs in 21 patients (9 women and 12 men) and 11 non-sebaceous LADs in 10 patients (8 women and 2 men). Two patients had synchronous double tumors. Twenty-six tumors (79%) arose in parotid, three in the neck, and two each in submandibular gland and oral cavity. Extraparotid tumors were seen in 2 of 21 (10%) patients with sebaceous and 4 of 10 (40%) patients with non-sebaceous LADs. Seven of twenty-three (30%) patients had immunosuppressive therapy for unrelated diseases. The tumors were well circumscribed, encapsulated (n=28, 84%) painless masses, varying in size from 0.6 to 6 cm (median 2.2). The cut surfaces were gray-tan to yellow, homogeneous and multicystic (n=24, 72%). The epithelial cells were basaloid, squamous and glandular, forming solid nests, cords, tubules, and cysts. Sebaceous differentiation was restricted to sebaceous lymphadenoma. The epithelial cells expressed basal cell markers (p63, 34BE12, and/or CK5/6, 18/18, 100%) and the luminal glandular cells expressed CK7 (12/12, 100%). Myoepithelial cells were absent (n=10/16, 63%) or focal. The lymphoid stroma was reactive, with germinal centers in 28 (84%). There was no evidence of HPV (0/11), EBV (0/7), and HHV-8 (0/8). Malignant transformation to sebaceous and basal cell adenocarcinoma was seen in one patient each. None of the 11 patients with follow-up (1-8 years) recurred. In summary, sebaceous and non-sebaceous LADs are benign, encapsulated, solid and cystic tumors affecting older adults. Non-sebaceous LADs affect women and extraparotid sites more frequently than sebaceous LADs. Altered immune status may have a role in their etiopathogenesis. Multiple synchronous tumors, origin in buccal mucosa, and malignant transformation may rarely occur.

Seromucinous hamartomas: a clinicopathological study of a sinonasal glandular lesion lacking myoepithelial cells.

AIMS: To describe seven cases of sinonasal seromucinous hamartoma. MATERIALS AND RESULTS: The clinicopathological and immunohistochemical features of seven seromucinous hamartomas were analysed. There were four men and three women. Six lesions involved the posterior nasal septum and one the lateral wall. Size ranged from 6 to 40 mm. Four patients had no recurrences. One patient had local recurrences 24 and 60 months after diagnosis. The masses were covered by respiratory epithelium. Their stroma was oedematous to fibrous and contained invaginated respiratory epithelium forming glands and cysts, cysts with cuboidal to flat epithelium, and small serous glands, ducts and tubules with lobular and irregular haphazard patterns. One case had numerous glands surrounded by hyalinized basement membrane with features of respiratory epithelial adenomatoid hamartoma (REAH). One case had focal REAH-like changes. Both respiratory and serous components were positive for cytokeratin (CK) 7 and CK19. The serous component lacked myoepithelial cells when stained for CK14, p63, calponin and muscle-specific antigen in five cases. CONCLUSIONS: Seromucinous hamartomas show a broader histopathological appearance than previously reported. The serous proliferation in these lesions lacks myoepithelial cells. The presence of occasional REAH-like features and common location in the posterior nasal septum suggest a spectrum from pure seromucinous hamartoma to REAH.

Epithelial-myoepithelial carcinoma: a review of the clinicopathologic spectrum and immunophenotypic characteristics in 61 tumors of the salivary glands and upper aerodigestive tract.

To further define the clinicopathologic spectrum of epithelial-myoepithelial carcinoma (EMCa), we report the gross, histologic, and immunophenotypic characteristics of 61 tumors seen within a 30-year-period. The mean age at presentation was 60.9 years, with a female predominance (1.5:1). The most common sites were parotid (62.1%), sinonasal mucoserous glands (10.3%), palate (8.6%), and submandibular (8.6%). Most EMCas showed a characteristic nodular/multinodular growth pattern and classic biphasic tubular histology. However, new morphologies in EMCa such as ancient change (8.2%), "Verocay"-like change (3.3%), and sebaceous differentiation (13.1%) were noted. Specific histologic variants were dedifferentiated EMCa (3.3%), oncocytic EMCa (8.2%), EMCa ex pleomorphic adenoma (1.6%), double-clear EMCa (3.3%), and EMCa with myoepithelial anaplasia (3.3%). All cytokeratin cocktails selectively highlighted the epithelial component well. Of the myoepithelial markers, p63, smooth muscle actin and vimentin performed best. Bcl-2 and c-kit were frequently positive (66.7% and 69.2%, respectively). p53 was highly expressed only in 1 dedifferentiated EMCa. The recurrence rate was 36.3% (median disease-free survival 11.34 y), but death was rare with 5-year and 10-year disease-specific survivals of 93.5% and 81.8%, respectively. The most important univariate predictors of recurrence were margin status (log rank P=0.006), angiolymphatic invasion (P=0.002), tumor necrosis (P=0.004), and myoepithelial anaplasia (P=0.038). Thus, EMCa is generally a low-grade tumor with a broader morphologic spectrum than previously thought, with several key features predictive of recurrence. Immunohistochemistry can aid diagnosis by highlighting the biphasic nature of the tumor.

Potential diagnostic use of p16INK4A, a new marker that correlates with dysplasia in oral squamoproliferative lesions.

Protein products of tumor suppressor genes are often involved in regulating the cell cycle, and aberrant expression can correlate with underlying genetic mutations. Mutations in the p16 gene have been detected at relatively high rates in squamous cell carcinomas of the oral cavity. However, immunohistochemical staining for the protein product has not been examined as a diagnostic tool for identifying dysplastic lesions in the oral cavity. Sixty cases of biopsies of reactive, inflammatory, and dysplastic lesions of all grades were stained with an antibody to p16INK4A and analyzed for which layer of the epithelium had positive cells. Staining was seen only in the basal or lower third in keratoses and mild dysplasias and was seen in the mid and upper thirds in moderate to severe dysplasia. The staining across larger fragments of biopsied epithelium highlighted skip lesions, with strong staining restricted to dysplastic regions. Inflammatory lesions, including chronic ulcers, showed absent or minimal basal layer staining with p16INK4A. In this preliminary study, p16INK4A shows promise as to a potential marker to aid in recognizing the presence of dysplasia in squamous mucosa of the head and neck, particularly in subtle lesions, and in an inflammatory or ulcerated background.

A comparative analysis of LEF-1 in odontogenic and salivary tumors.

LEF-1 is a nuclear transcription factor of the Wnt pathway that regulates multipotent skin stem cell differentiation. ß-Catenin is considered a transcriptional coactivator that interacts with LEF-1.This study evaluates LEF-1 in a variety of odontogenic and salivary tumors and determines the prevalence of ß-catenin coexpression. Ninety-eight salivary gland tumors and 51 odontogenic tumors were evaluated for LEF-1 and ß-catenin immunohistochemical staining. Positivity was defined as at least 2+ intensity in more than 50% of tumor cells, which required a composite score of 6 or more. LEF-1 was positive in 64% (7/11) of calcifying cystic odontogenic tumors (CCOT). Nuclear ß-catenin was present in 82% (9/11) of CCOT. Coexpression of LEF-1 and nuclear ß-catenin was noted in all LEF-1-positive CCOT. Strong and diffuse LEF-1 expression was seen in 69% (11/16) of basal cell adenocarcinomas (BCAC) and 63% (5/8) of basal cell adenomas (BA). Nuclear ß-catenin was present in 50% (4/8) of BA and 43% (6/14) of BCAC. For BA, 4 of 5 LEF-1-positive tumors showed coexpression of ß-catenin, and for BCAC, 5 of 9 LEF-1-positive tumors showed coexpression. In conclusion, this study documents for the first time the presence of LEF-1 expression and nuclear ß-catenin coexpression in select basaloid salivary gland tumors and various odontogenic tumors. We demonstrate LEF-1 expression in both BA and BCAC preferentially over other salivary gland tumors suggesting some utility as a diagnostic marker.

Ceruminous adenomas: a clinicopathologic study of 41 cases with a review of the literature.

BACKGROUND: Ceruminous gland neoplasms are rare neoplasms. To date, a large clinicopathologic study of benign ceruminous gland neoplasms has not been reported. DESIGN: Forty-one cases of ceruminous gland adenomas diagnosed between 1970 and 2000 were retrieved from the files of the Armed Forces Institute of Pathology. Histologic features were reviewed, immunohistochemical analysis was performed (n = 21), and patient follow-up was obtained (n = 40). RESULTS: The patients included 22 men and 19 women, 24 to 85 years of age (mean, 54.2 years). Patients presented clinically with a painless mass of the outer half of the external auditory canal (n = 33) or with hearing changes (n = 11). Symptoms were present for an average of 16.3 months. The polypoid masses affected the external auditory canal only and ranged in size from 0.4 to 2 cm in greatest dimension (mean, 1.1 cm). Histologically, the tumors demonstrated glands and small cysts lined by a tubuloglandular proliferation of inner ceruminous cells (cerumen-secreting epithelium with decapitation secretion) subtended by a spindled to cuboidal myoepithelial layer. A hyalinized stroma created an infiltrative pattern of growth; surface involvement (n = 8) was seen. Tumors were divided into ceruminous adenoma (n = 36), ceruminous pleomorphic adenoma (n = 4), and syringocystadenoma papilliferum (n = 1) types. The luminal cells were strongly and diffusely immunoreactive with CK7, while the basal cells were highlighted with CK5/6, S-100 protein, and p63. CD117 highlighted the luminal cells preferentially. The proliferation markers revealed a low index. Adenocarcinoma and middle ear adenoma are the principal differential consideration. Surgical excision was used in all patients. Four patients developed a recurrence due to incomplete excision. All patients were without evidence of disease at the last follow-up: alive (n = 28, mean 16.3 years) or dead (n = 12, mean 11.8 years). CONCLUSION: Ceruminous gland adenomas are the most common external auditory canal tumors. They demonstrate a dual cell population of basal myoepithelial-type cells and luminal ceruminous (ceruminal) cells. Cerumen pigment, CK7, and p63 can help to distinguish this tumor from other neoplasms that occur in the region. Complete surgical excision results in an excellent long-term clinical outcome.

Molecular evidence of anaplastic transformation in coexisting well-differentiated and anaplastic carcinomas of the thyroid.

Anaplastic thyroid cancer is a rare but nearly universally fatal tumor. Epidemiologic data suggest that many anaplastic thyroid carcinomas arise from transformation of preexisting or coexisting well-differentiated thyroid carcinomas. At the molecular level, the mutations responsible for the anaplastic transformation are incompletely understood, although the mutational events are thought to involve tumor suppressor genes. To examine transformation from a well-differentiated thyroid carcinoma to anaplastic carcinoma, we studied coexisting well-differentiated (Hürthle cell and papillary carcinoma) and anaplastic tumors with a molecular genotyping panel of tumor suppressor genes associated with thyroid neoplasia. The patterns of allelic loss in our results showed that the majority of cases have a core of conserved mutations in the two morphologically distinct areas and substantial increases in mutation rates in the anaplastic components.

Molecular genotyping of medullary thyroid carcinoma can predict tumor recurrence.

Medullary thyroid carcinoma can have an aggressive behavior, and little is known about the molecular basis for clinical outcome. Defining risk of recurrent or metastatic disease is difficult, and it has been limited to clinical and pathologic features, such as advanced age, cervical lymph node metastases, and stage at presentation. Using microdissection and genotyping, we studied 11 cases of medullary carcinoma for allelic losses in a panel of known tumor suppressor genes. The tumor suppressor genes with the most frequent allelic losses were NF2, l-myc, and p53 (75%, 44%, and 44%, respectively). The average frequency of allelic loss across all tumors was 44% and was higher in tumors that recurred. A combination of previously described high-risk variables (increased patient age and cervical lymph node metastases) with the frequency of allelic loss yielded a high-risk group, in which 6 of 6 patients recurred, and a low-risk group, in which 0 of 5 patients recurred (P = 0.004). Frequency of allelic loss in tumor suppressor genes may provide a useful adjunctive prognostic test in medullary thyroid carcinoma.

Microscopic papillary thyroid carcinoma compared with clinical carcinomas by loss of heterozygosity mutational profile.

The clinical significance of microscopic papillary thyroid carcinoma (PTCa) is controversial. Many authors think that microscopic PTCa (<1 cm) have the same pathogenetic origin as clinically sized papillary carcinomas (>1 cm). Despite the fact that all clinical risk prognostication schemes have the size of the tumor as a primary category, small tumors do have malignant potential and can metastasize. There is growing evidence that small PTCa have the molecular translocations between the proto-oncogene RET and various activating partner genes that are characteristic of clinically sized PTCa. This study used a microdissection and genotyping assay to study the patterns of loss of heterozygosity of tumor suppressor genes in microscopic and clinically sized PTCa. Our results indicate that all PTCa harbor mutations with similar frequencies and distribution patterns, regardless of the size of the tumor. These data are further evidence that microscopic and clinically sized PTCa are pathogenetically related.

A novel microdissection and genotyping of follicular-derived thyroid tumors to predict aggressiveness.

Distinguishing thyroid follicular adenoma from minimally invasive or encapsulated angioinvasive carcinoma can be diagnostically challenging. In some cases, tumors are distorted, fragmented, or stripped of their capsule, and a definitive diagnosis becomes nearly impossible. In other cases, the foci of capsular and/or vascular invasion are subtle, thus making the diagnosis of carcinoma difficult. We developed a microdissection genotyping assay for assessing a panel of tumor-suppressor genes for loss of heterozygosity mutations. The frequency of allelic loss (FAL) in follicular-derived neoplasms correlates with the histologic aggressiveness of the tumor. Furthermore, we calculated the amount of genetic heterogeneity within each tumor, as a second important measure of a tumor's ability for clonal expansion and a surrogate marker for its malignant potential. The follicular adenomas had a low FAL (average 9%) and low intratumoral heterogeneity (5% variability). The minimally invasive and encapsulated angioinvasive carcinomas had an intermediate FAL (average 30%) and intermediate intratumoral heterogeneity (10% variability). The widely invasive carcinomas had a high FAL (average 53%) and high intratumoral heterogeneity (24% variability). Although a larger retrospective study is needed to correlate genotyping studies with patient outcome and prognosis, our results indicate that performing a mutational genotyping assay can stratify tumors into the histologically well-defined categories of adenomas, minimally invasive/angioinvasive carcinomas, and widely invasive follicular carcinomas.

Non-tumor-associated psammoma bodies in the thyroid.

Psammoma bodies in the thyroid are common in glands with papillary thyroid carcinoma. Psammoma bodies that are not associated with tumor cells, however, represent a diagnostic problem for pathologists. Should we treat isolated psammoma bodies as representing metastatic disease? This study included patients who had non-tumor-associated psammoma bodies in their thyroids or in the perithyroidal lymph nodes. Clinical, pathologic, and follow-up information was obtained for the patients. Our results indicate that 27 of 29 patients had a contralateral or an ipsilateral tumor, the majority of which were papillary. We noted a high frequency of microscopic carcinomas (12/27) and of tall cell variants of papillary thyroid carcinoma (8/27 cases). Based on these findings, we recommend that thyroid glands with non-tumor-associated psammoma bodies and no histologically identified carcinoma be entirely submitted to identify any microscopic carcinoma. If no carcinoma is identified in a lobectomy, discussion with the surgeon should indicate the need for close clinical follow-up.

Squamous cell carcinoma metastatic to neck from an unknown primary: the potential impact of modern pathologic evaluation on perceived incidence of human papillomavirus-positive oropharyngeal carcinoma prior to 1970.

OBJECTIVES/HYPOTHESIS: From the 1950s through the 1960s, an unknown number of oropharyngeal squamous cell carcinomas (SCCs) presented with metastases to cervical lymph nodes from an unknown primary (SCCUP) and were not recognized as oropharyngeal in origin. At present, pathologic evaluation of SCCUP for human papillomavirus (HPV) improves discovery of occult oropharyngeal SCC and may partially explain increased incidence of HPV-positive oropharyngeal SCC. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective study of 13 cases of SCCUP diagnosed from 1956 to 1969 was performed. The probability of these cases of metastatic SCC to originate from the oropharynx was assessed by characterizing their morphology (keratinizing vs. nonkeratinizing) and HPV status by in situ hybridization and p16 immunostaining. RESULTS: Two cases of nonkeratinizing SCC positive for HPV by in situ hybridization and p16 immunohistochemistry were identified. These cases were most likely of oropharyngeal origin. CONCLUSIONS: These two cases can be added to the other 15 cases of HPV-positive primary oropharyngeal SCC identified in our department from 1956 to 1969. When determining the incidence of HPV-positive oropharyngeal SCC before the 1970s, a correction factor of about +13% (2/15) accounting for modern pathologic workup of SCCUP during the last couple of decades may be appropriate.

Common Malignant Salivary Gland Epithelial Tumors.

Malignant salivary gland epithelial tumors are histologically diverse with at least 24 recognized distinct entities. In general, malignant tumors account for 15% to 30% of parotid tumors, 40% to 45% of submandibular tumors, 70% to 90% of sublingual tumors, and 50% of minor salivary tumors. Common malignancies include mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, salivary duct carcinoma, carcinoma ex pleomorphic adenoma, polymorphous lowgrade adenocarcinoma, and myoepithelial carcinoma. Each tumor type has its own unique histologic variants and prognostic pathologic features, and only mucoepidermoid carcinomas have a formalized grading system. The molecular pathogenesis of certain tumors, such as mucoepidermoid carcinoma and adenoid cystic carcinoma, has recently begun to be elucidated.

Rare Malignant and Benign Salivary Gland Epithelial Tumors.

Although at least 24 distinct histologic salivary gland carcinomas exist, many of them are rare, comprising only 1% to 2% of all salivary gland tumors. These include epithelial-myoepithelial carcinoma, (hyalinizing) clear cell carcinoma, basal cell adenocarcinoma, cystadenocarcinoma, low-grade salivary duct carcinoma (low-grade cribriform cystadenocarcinoma), oncocytic carcinoma, and adenocarcinoma not otherwise specified. Few tumors (clear cell carcinoma and basal cell adenocarcinoma) have unique molecular correlates. Benign tumors, although histologically less diverse, are far more common, with pleomorphic adenoma and Warthin tumor the most common salivary gland tumors. Many benign tumors have malignant counterparts for which histologic distinction can pose diagnostic challenge.

Pathology archive: evaluation of integrity, regulatory compliance, and construction of searchable database from print reports.

Tissue repositories maintained by pathology departments represent an abundant resource of clinically annotated human specimens. The storage expenses associated with pathology archives are known to administrators of most pathology departments. However, such basic repository characteristics as the quality of stored materials, ease of access, and search and retrieval rates are often unclear. The aims of our work were to design a framework to assess the quality of a historic pathology archive, to propose the definition of "archive integrity," and to provide benchmarks for tissue block retrieval rates and DNA integrity. We share our experience with scanning approximately 120,000 pathology reports from 1956 to 1979 into an electronically searchable archive, with a $9,000 budget, completed in 6 weeks. Several ethical and legal considerations that shaped the technical side of this project are discussed.

Progressive genetic alterations of adenoid cystic carcinoma with high-grade transformation.

CONTEXT: Although genome-wide imbalances have been characterized in conventional adenoid cystic carcinoma, other than p53 mutational status, the molecular profile of adenoid cystic carcinoma with high-grade transformation has not been explored. OBJECTIVE: To evaluate progressive genetic alterations in adenoid cystic carcinoma with high-grade transformation using array comparative genomic hybridization. DESIGN: Five adenoid cystic carcinomas with high-grade transformation (4 primary tumors and 1 paired metastasis) were selected and characterized at the DNA level by array comparative genomic hybridization on formalin-fixed paraffin-embedded tissue. Select alterations were validated by fluorescence in situ hybridization. RESULTS: Chromosomal gains were mostly confined to the areas of high-grade transformation while losses were seen only in the conventional areas. Chromosomal regions with significant gains included 8q24, 17q11.2-q12, 17q23, and 15q11-13. Regions that showed the significant losses included 9q34, 4p16, 1p36.1, and 11q22. Fluorescence in situ hybridization analysis demonstrated increases in C-MYC (8q24.12-q24.13) and a low level increases in ERBB2 ( formerly HER2/neu ) (17q11.2-q12) in cases showing gains by array comparative genomic hybridization in these regions. However, no tumor showed HER2/ neu immunopositivity. CONCLUSIONS: High-grade transformation in adenoid cystic carcinoma is a complex process that is reflected by several chromosomal alterations. Our findings implicate C-MYC amplification in this progression, although the role of HER2/neu is still unclear. Other candidate oncogenes, particularly on chromosome 17q23, warrant investigation in this rare tumor.

Clear cell carcinoma and clear cell odontogenic carcinoma: a comparative clinicopathologic and immunohistochemical study.

Clear cell carcinoma or hyalinizing clear cell carcinoma (CCC) and clear cell odontogenic carcinoma (CCOC) are rare, low-grade and typically indolent malignancies that can be diagnostically challenging. In this study the clinicopathologic, histologic, and immunohistochemical features of 17 CCCs and 12 CCOCs are examined. The differential diagnosis of clear cell malignancies in the head and neck is discussed. The relationship of CCCs and CCOCs to other clear cell tumors on the basis of their immunohistochemical staining patterns is postulated.

Fluorescence in situ hybridization for detection of MAML2 rearrangements in oncocytic mucoepidermoid carcinomas: utility as a diagnostic test.

Oncocytic mucoepidermoid carcinoma poses diagnostic challenge because of its histologic overlap with other oncocytic salivary gland lesions, including Warthin tumor. Although the prognostic value of the t(11;19) MECT1-MAML2 fusion gene has been established in mucoepidermoid carcinoma, its diagnostic use in discriminating oncocytic mucoepidermoid carcinoma from histologic mimics is unexplored. We evaluated the translocation status in 14 cases of oncocytic mucoepidermoid carcinoma using a MAML2-11q21 break-apart probe spanning the entire chromosome region of the MAML2 gene and correlated these findings with clinicopathologic parameters including age, sex, stage, predominant growth pattern, grade, and p63 immunostaining pattern. All oncocytic mucoepidermoid carcinomas were parotid tumors with a mean patient age of 54.6 years (range, 9-85) and a female to male ratio of 5:2. Grade distribution was as follows: low grade, 9; intermediate grade, 2; and high grade, 3. The histologic patterns observed were as follows: solid, 4; cystic, 8 (of these, 5 had Warthin-like lymphoid stroma); and mixed, 2. Solid oncocytic mucoepidermoid carcinomas showed a diffuse p63 staining pattern, whereas cystic oncocytic mucoepidermoid carcinomas showed staining of the outer layer of intermediate cells ranging from a bilayer to areas of complex multilayering and plaque-like proliferation. Ten (71%) of the 14 cases showed a MAML2 rearrangement by fluorescence in situ hybridization. No correlation was seen between rearrangement status and histologic grade, growth pattern, or p63 staining pattern. However, we demonstrate that the presence of MAML2 rearrangement can be used as supportive evidence to distinguish oncocytic mucoepidermoid carcinoma from other oncocytic lesions.

Polymorphous low-grade adenocarcinoma: the University of Pittsburgh experience.

OBJECTIVE: To reappraise the clinical and histologic variables associated with a more aggressive outcome in polymorphous low-grade adenocarcinoma (PLGA). DESIGN: Retrospective cohort. SETTING: University hospital. PATIENTS: Twenty-four patients with PLGA treated from January 1, 1973, through December 31, 2005. MAIN OUTCOME MEASURE: Analysis of clinical and pathologic variables in 30 biopsy or resection specimens from 24 patients. RESULTS: Only 4 PLGAs were not initially diagnosed as such. However, 8 non-PLGAs (thus excluded) were incorrectly diagnosed as PLGA. Most carcinomas (14 of 24 [58%]) were palatal. Recurrent carcinomas had a significantly higher mitotic rate (2.7 mitoses per 10 high-power fields) compared with primary tumors (1.2 mitoses per high-power fields, P = .046), and 3 of 7 (43%) recurrences showed progression to an intermediate-grade histologic type. No patient died of disease. Median disease-free survival was 12.8 years. Four of 24 patients (17%) had regional lymph node metastases, 3 with carcinomas of the base of the tongue. One PLGA metastasized to the subcutaneous tissue of the face, orbit, and lungs at 19.6 years. An extrapalatal site was the only significant determinant of disease-free survival (P = .03). CONCLUSIONS: Diagnosis of PLGA remains a challenge. Extrapalatal carcinomas appear to behave in a more aggressive fashion than those of the palate, and cancer arising from the base of the tongue frequently metastasizes to the cervical lymph nodes, suggesting a role for neck dissection in these patients. Recurrent cancers show evidence of histologic progression, justifying an aggressive approach to achieving initial complete excision.