Douglas R. Gnepp

Tumors of the intraoral minor salivary glands: A demographic and histologic study of 426 cases

In a demographic and histologic study of 426 oral minor salivary gland tumors, 57.5% were classified as benign and 42.5% were classified as malignant or potentially malignant. There was an overall female preponderance (1.59/1). The mean age for females was 53.1 years and for males was 50.6 years. The mean age for patients with malignant tumors was 5.4 years greater than for patients with benign tumors and was statistically significant. The palate was the most common site for oral minor salivary gland tumors followed by the upper lip and the buccal mucosa. These three sites accounted for 76.1% of all cases. Pleomorphic adenoma was the most common benign tumor (41% of all cases and 71% of benign tumors) followed by monomorphic adenoma of the canalicular and basal cell subtypes (10% of all tumors and 18.9% of benign lesions). Mucoepidermoid carcinoma was the most commonly encountered malignant tumor, accounting for 15.2% of all tumors and 35.9% of malignant lesions. Low-grade (terminal duct, lobular, polymorphous) adenocarcinoma was the most second most common type, making up 11% of all tumors and 26.4% of all malignant tumors. The results of this study are compared with other recent studies.

Mucoepidermoid carcinoma: A clinicopathologic study of 80 patients with special reference to histological grading

We sought to review our experience with salivary mucoepidermoid carcinoma (MEC) over two decades to confirm the validity and reproducibility of histologic grading and to investigate MIB-1 index as a prognosticator. Diagnosis was confirmed on 80 cases, and chart review or patient contact was achieved for 48 patients, with follow-up from 5 to 240 months (median 36 months). Immunohistochemistry with citrate antigen retrieval for MIB-1 was performed on a subset of cases. Kaplan-Meier survival curves were generated for each stage, site, and grade according to our proposed grading system. To address the issue of grading reproducibility, 20 slides were circulated among five observers, without prior discussion; slides were categorized as low-, intermediate-, or high-grade according to ones “own” criteria, and then according to the AFIP criteria proposed by Goode et al. 10 Weighted kappa (&kgr;) estimates were obtained to describe the extent of agreement between pairs of rating. The Wilcoxon signed rank test or the Friedman test as appropriate tested variation across ratings. There was no gender predominance and a wide age range (15–86 years, median 49 years). The two most common sites were parotid and palate. All grade 1 MECs presented as Stage I tumors, and no failures were seen for this category. The local disease failure rates at 75 months for grades 2 and 3 MEC were 30% and 70%, respectively. Tumor grade, stage, and negative margin status all correlated with disease-free survival (DFS) (p = 0.0091, 0.0002, and 0.048, respectively). The MIB index was not found to be predictive of grade. Regarding the reproducibility of grading, the interobserver variation for pathologists using their “own” grading, as expressed by the &kgr; value, ranged from good agreement (&kgr; = 0.79) to poor (&kgr; = 0.27) (average &kgr; = 0.49). A somewhat better interobserver reproducibility was achieved when the pathologists utilized the standardized AFIP criteria (average &kgr; = 0.61, range 0.38–0.77). This greater agreement was also reflected in the Friedman test (statistical testing of intraobserver equality), which indicated significant differences in using ones own grading systems (p = 0.0001) but not in applying the AFIP “standardized” grading (p = 0.33). When ones own grading was compared with the AFIP grading, there were 100 pairs of grading “events,” with 46 disagreements/100 pairs. For 98% of disagreements, the AFIP grading “downgraded” tumors. This led us to reanalyze a subset of 31 patients for DFS versus grade, for our grading schema compared with the AFIP grading. Although statistical significance was not achieved for this subset, the log rank value revealed a trend for our grading (p = 0.0993) compared with the Goode schema (p = 0.2493). This clinicopathologic analysis confirms the predictive value of tumor staging and three-tiered histologic grading. Our grading exercise confirms that there is significant grading disparity for MEC, even among experienced ENT/oral pathologists. The improved reproducibility obtained when the weighted AFIP criteria were used speaks to the need for an accepted and easily reproducible system. However, these proposed criteria have a tendency to downgrade MEC. Therefore, the addition of other criteria (such as vascular invasion, pattern of tumor infiltration [i.e., small islands and individual cells vs cohesive islands]) is necessary. We propose a modified grading schema, which enhances predictability and provides much needed reproducibility.

Palisaded myofibroblastoma. A benign mesenchymal tumor of lymph node.

We report 22 examples of an unusual and distinctive benign mesenchymal tumor arising exclusively from lymph nodes of the groin. The tumor, which presents clinically as a swelling, is composed of spindled cells arranged in solid sheets or short, vaguely palisaded fascicles similar to a neurilemoma. The spindled cells blend gradually with large mats of eosinophilic material that appear as thick bands, ellipses, or circular profiles, depending on the plane of section. These eosinophilic structures, which represent a highly characteristic feature of the tumor, contain deeply eosinophilic, collagen-rich cores surrounded by a weakly eosinophilic, actin-rich cuff. The actin within these eosinophilic structures is derived by coalescence of intracellular actin globules extruded from neighboring cells. In all cases, a thin, compressed rim of normal lymph node was identified. Immunohistochemical analysis indicates that the cells express actin but lack S-100 protein, synaptophysin, desmin, keratin, and epithelial membrane antigen. Delicate, linear striations were identified in only two cases by conventional histochemical techniques. The foregoing features suggest that the tumor is related to a myofibroblast or a specialized smooth-muscle cell. These tumors, therefore, probably arise from smooth-muscle-like cells, which are normally present in some lymph node capsules or stroma. Follow-up information on 17 patients indicated that all are alive and well without any evidence of recurrence or metastasis.

A review of neuroendocrine neoplasms of the larynx: update on diagnosis and treatment.

Neuroendocrine neoplasms of the larynx have been divided into those of epithelial or neural origin. The latter consist of paragangliomas while the epithelial origin group can be divided into the typical and atypical carcinoids and small cell neuroendocrine carcinomata, the latter consisting of the oat cell type, the intermediate cell type and the combined cell type. There are now over 500 cases of neuroendocrine neoplasms of the larynx in the literature. The diagnosis is primarily based on light microscopy, and, in some instances, it may be supported by special histochemical studies. It should be confirmed by immunocytochemical and/or ultrastructural investigation. The different biological behaviour of neuroendocrine neoplasms of the larynx makes a specific diagnosis of paramount importance, since treatment depends on diagnostic accuracy. Typical carcinoid is an extremely rare lesion. It is treated preferably by conservative surgery; elective neck dissection is not necessary because of the lack of lymph node metastases at diagnosis. Chemotherapy and/or radiotherapy have not been effective in the limited number of patients treated thus far. Prognosis is excellent with cure following surgery. Atypical carcinoid is the most frequent non-squamous carcinoma of the larynx. The mainstay of treatment is surgery. Elective neck dissection should be performed because of the high likelihood of cervical lymph node metastases. Primary radiation therapy with adjuvant chemotherapy is not indicated. The survival rate is 48 per cent at five years and 30 per cent at 10 years. Although the larynx is one of its most common extrapulmonary sites, small cell neuroendocrine carcinoma is still a rare tumour. Surgical results for this tumour have been disappointing and is reserved for cases of local relapse with no evidence of metastasis. Chemotherapy and radiotherapy currently appear to offer the least disabling and most effective forms of therapy. The two- and five-year survival rates are 16 per cent and five per cent, respectively. Paraneoplastic syndromes have occasionally been reported in association with carcinoid tumours (typical and atypical) and small cell neuroendocrine carcinoma. There have been also rare reports of an elevated neuropeptide serum level. Paraganglioma is the only laryngeal neuroendocrine neoplasm with a female preponderance (3:1). Confusion with atypical carcinoid has led to incorrect diagnosis and inappropriate classification schemes, erroneously suggesting that laryngeal paraganglioma has the potential for aggressive behaviour. Conservative surgery represents the treatment of choice; elective neck dissection is not necessary, and the prognosis is excellent.

Surgical margins in head and neck cancer: a contemporary review.

Adequate resection margins are critical to the treatment decisions and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). However, there are numerous controversies regarding reporting and interpretation of the status of resection margins. Fundamental issues relating to the basic definition of margin adequacy, uniform reporting standards for margins, optimal method of specimen dissection, and the role of intraoperative frozen section evaluation, all require further clarification and standardization. Future horizons for margin surveillance offer the possible use of novel methods such as “molecular margins” and contact microscopic endoscopy, However, the limitations of these approaches need to be understood. The goal of this review was to evaluate these issues to define a more rational, standardized approach for achieving resection margin adequacy for patients with HNSCC undergoing curative resection.

Metastasizing mixed tumor of salivary glands. A clinicopathologic and flow cytometric analysis

Among salivary gland neoplasms are a group of rare tumors that are histologically identical to benign mixed tumors that inexplicably metastasize; they have been called metastasizing mixed tumor (MZMT) of salivary glands. We report the clinicopathologic features and flow cytometric findings for 11 cases of MZMT. At the time of discovery of metastatic disease, the patients, six women and five men, ranged in age from 20 to 83 years. Primary sites of involvement included the parotid gland (eight cases), submandibular gland (two cases), and the nasal septum (one case). With one exception, all the patients had at least a single recurrence of their primary mixed tumor, but two or more recurrences were the norm before development of metastatic foci. The metastases were discovered from six to 52 years following the occurrence of the primary tumor. Metastatic deposits were identified in bone, lung, regional lymph nodes, skin, kidney, retroperitoneum, oral cavity, pharynx, calvarium, and central nervous system. The metastases either occurred simultaneously with an episode of recurrent mixed tumor (n=5) or from 5 to 29 years after a recurrence (n=6). The treatment of the primary, recurrent, and metastatic neoplasms was surgical excision. Follow-up, ranging from 8 months to 16 years following the diagnosis of MZMT, revealed seven patients to be alive without disease (64%) and two dead of causes unrelated to metastatic disease (18%). Two patients (18%) died as a direct result of metastatic tumor at 3 and 2 years after metastasis of their mixed tumors. Flow cytometric analysis revealed a diploid DNA cell population in the primary and/or metastatic tumors in nine cases. Aneuploid DNA cell content was identified in two of the cases. DNA ploidy levels and cell proliferation rates were compared with those of conventional benign mixed tumors and also with malignant mixed tumors. Retrospective analysis of histologic parameters (mitotic rate, cellular pleomorphism, infiltrative growth, vascular or lymphatic invasion) and flow cytometric analysis failed to identify criteria to predict the development of metastasis in these neoplasms.

Small cell carcinoma of the major salivary glands

Small cell carcinoma is primarily a pulmonary neoplasm that rarely arises in extrapulmonic sites including salivary glands of the head and neck. Twelve cases of small cell carcinoma of salivary gland origin were retrieved from the Armed Forces Institute of Pathology files. Six tumors occurred in the parotid gland and six in the submandibular gland. Tumors were classified into two categories: those with areas of histologically typical small cell carcinoma (7 cases) and those with areas of typical small cell carcinoma with foci of ductal differentiation (5 cases). Follow‐up information was available in all 12 cases. Electron microscopy was done on eight tumors; only one demonstrated round electron dense intracytoplasmic neurosecretory granules. These observations further support evidence in the literature suggesting most of the small cell carcinomas of salivary gland origin are not true neuroendocrine (“oat cell”) carcinomas, but actually are small cell ductal carcinomas. These tumors appear to have a better prognosis than small cell carcinoma of the lung or nonsalivary gland sites in the head and neck region, with an estimated 2‐and 5‐year survival of 70 and 46%, respectively. Cancer 58:705‐714, 1986.

Low-grade salivary duct carcinoma: description of 16 cases.

Low-grade salivary duct carcinoma is a rare neoplasm. We report on 16 patients, with a median age of 64 years. All but one tumor arose from the parotid gland, including one tumor that arose in an intraparotid lymph node; one arose in the submandibular gland. Tumors consist of single to multiple dominant cysts, accompanied by adjacent intraductal proliferation. Cysts are lined by small, multilayered, proliferating, bland ductal cells with finely dispersed chromatin and small nucleoli. Separate, smaller ductal structures are variably filled by proliferating ductal epithelium with cribriform, micropapillary, and solid areas. The overall appearance is very similar to breast atypical ductal hyperplasia and low-grade ductal carcinoma in situ. Foci of definitive stromal invasion were seen in four tumors. Two tumors demonstrated transition from low- to intermediate- or high-grade cytology, with scattered mitotic figures and focal necrosis. S-100 revealed diffuse strong expression in all 9 cases studied. Myoepithelial markers (calponin) highlighted supportive myoepithelial cells rimming the cystic spaces, confirming the intraductal nature of most, or all, of six tumors studied. Nine tumors studied for Her2-neu antigen were uniformly negative. Follow-up was obtained on 13 of our 16 patients. All patients were disease-free after surgery 6 to 132 months (median 30 months). Low-grade salivary duct carcinoma is a low-grade neoplasm with an excellent prognosis; it may be treated by conservative but complete resection. Its resemblance to atypical breast ductal hyperplasia, or micropapillary/cribriform intraductal carcinoma, distinguishes it from high-grade salivary duct carcinoma, papillocystic acinic cell carcinoma, and cystadenocarcinoma.

Sebaceous neoplasms of salivary gland origin. Report of 21 cases

Primary sebaceous tumors of salivary glands are extremely rare, although sebaceous glands are commonly present in parotid and submandibular glands. A review of the files of the Armed Forces Institute of Pathology yielded 21 cases of primary salivary gland sebaceous tumors. Five were sebaceous adenomas, 9 sebaceous lymphadenomas, 5 sebaceous carcinomas and 2 sebaceous lymphadenocarcinomas. Seventeen tumors were located in the parotid gland and one each in the submandibular gland, the minor salivary glands of buccal mucosa and in ectopic salivary gland tissue in a periparotid lymph node. Thirteen tumors occurred in males and six in females. The peak incidence for all the sebaceous tumors, occurred in the sixth and seventh decades. The influence of age, sex, race, clinical symptoms, and pathology on survival is reviewed for each tumor group. Our histopathologic observations strongly suggest that sebaceous lymphadenoma and sebaceous lymphadenocarcinoma arise from sebaceous glandular rests in a lymph node in a fashion similar to that of a Warthin tumor.

Polymorphous low-grade adenocarcinoma of minor salivary gland: an immunohistochemical and clinicopathologic study

Polymorphous low-grade adenocarcinoma (PLGA) is a minor salivary gland carcinoma usually arising intraorally, primarily in the palate. It is characterized by cytologic uniformity, histologic blandness, and a variable, infiltrating growth pattern. To date, 117 tumors have been reported but the immunohistochemical features of this neoplasm have not been adequately described. This report describes the immunohistochemical distribution of epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), high-molecular-weight keratin, muscle-specific actin (MSA), and S-100 protein in four palatal polymorphous low-grade adenocarcinomas arising in two men and two women. Three patients were treated with a combination of radiation and surgery, and one was treated with just surgery; none of the tumors recurred or metastasized. More than 90% of tumor cells in all four tumors stained with S-100 and EMA, while 75 to 95% stained with keratin. MSA staining intensity was variable; it ranged from less than 10% to 67% of tumor cells staining positively. CEA staining also was markedly variable; it ranged from very focal luminal positivity to 75% of tumor cells staining positive. The diffuse staining pattern of EMA and S-100 and the difference in staining patterns of EMA and CEA in PLGA is distinct from that found in adenoid cystic carcinoma. In the latter neoplasm, EMA and CEA staining patterns are similar and they are localized to ductal lumina; S-100 stains much less diffusely. These differences are useful in the differential diagnosis between these two tumors.