Salivary acinic cell carcinoma: reappraisal and update.

Epidemiologic and clinicopathologic features, therapeutic strategies, and prognosis for acinic cell carcinoma of the major and minor salivary glands are critically reviewed. We explore histopathologic, histochemical, electron microscopic and immunohistochemical aspects and discuss histologic grading, histogenesis, animal models, and genetic events. In the context of possible diagnostic difficulties, the relationship to mammary analog secretory carcinoma is probed and a classification is suggested. Areas of controversy or uncertainty, which may benefit from further investigations, are also highlighted.

Hyalinizing clear cell carcinoma of salivary gland: an aggressive variant.

Although hyalinizing clear cell carcinoma (HCCC) had been previously illustrated by several authors, it was not until 1994 that this tumour was characterized by Milchgrub et al. [Am J Surg Pathol (1994),18,74] and separated from the heterogeneous group of clear cell carcinomas described in the literature. HCCC is a distinctive infiltrative low-grade, monomorphic, glycogen-rich clear cell carcinoma with prominent stromal hyalinization occurring most often in the minor salivary glands of adult women. A case of hyalinizing clear cell carcinoma arising in the tongue of an adult female is described with special reference to the presence of minor foci of mitotic activity, necrosis and anaplasia in this otherwise typical low-grade carcinoma. Widespread metastases and death within a year of initial presentation in this case suggests that there may be a subset of this indolent tumour in which these features are associated with a poor prognosis.

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 one's "own" criteria, and then according to the AFIP criteria proposed by Goode et al.10 Weighted kappa (kappa) 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 kappa value, ranged from good agreement (kappa = 0.79) to poor (kappa = 0.27) (average kappa = 0.49). A somewhat better interobserver reproducibility was achieved when the pathologists utilized the standardized AFIP criteria (average kappa = 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 one's own grading systems (p = 0.0001) but not in applying the AFIP "standardized" grading (p = 0.33). When one's 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.

Malignant solitary fibrous tumor of the pleura with liposarcomatous differentiation.

Pleural solitary fibrous tumors (SFTs) are uncommon tumors. Although these tumors have been well characterized, malignant pleural SFTs with liposarcomatous differentiation have not been reported. We report an unusual malignant pleural SFT intermixed with foci of well-differentiated liposarcoma. The patient was a 66-year-old, white man with a large, solid right pleural mass that measured 13.5 x 10.3 x 8.5 cm. The tumor was composed of spindle-shaped and plump cells embedded in dense collagenous stroma. The tumor cells were arranged in interlacing fascicles or in a patternless pattern. Marked nuclear atypia, a high mitotic rate (21 mitoses per 10 high-power fields), and areas of prominent necrosis were evident. In addition, numerous adipocytes mixed with typical lipoblasts were seen scattered throughout portions of the tumor. Immunohistochemistry revealed the tumor cells were strongly positive for CD34 and vimentin and negative for cytokeratin, desmin, smooth muscle actin (IA4), and S100. To the best of our knowledge, this case represents the first example of a malignant SFT with liposarcomatous differentiation.

Skeletal muscle in routine tonsillectomy specimens: a common finding.

Over the past 10 years, 1 of the authors (D.G.) has been consulted about several medical legal cases involving complications allegedly related to excessive surgery as documented by finding skeletal muscle in tonsillectomy specimens. A review of the literature showed little information about the incidence of skeletal muscle in routine tonsillectomy specimens; therefore, this study was undertaken. Thirty sequential tonsillectomy specimens from patients with histories of hyperplastic tonsils (10 males, 20 females; ages 5, 17 to 39; mean age, 24.3 years) were processed routinely (1 section/tonsil), and evaluated on a retrospective basis using routine light microscopy (group 1). In addition, 20 sequential tonsillectomy specimens were processed in a prospective fashion, excluding sleep apnea specimens (5 males, 15 females; ages 12 to 59 years; mean age, 28.9 years) (group 2). All specimens in the first group had lymphoid hyperplasia; 25 of the 30 (83%) had skeletal muscle in soft tissue adjacent to the lymphoid elements, 20 (67%) had seromucinous glands, and in 1 there was a focus of cartilage. In group 2, 18 had lymphoid hyperplasia and 2 contained carcinomas; 19 of 20 contained skeletal muscle ranging from a single fiber to abundant, multifocal areas with muscle, 16 (80%) had seromucinous glands, and 4 contained areas with cartilage. Additional tissue from the specimen without muscle and the tonsil with a single fiber was processed, and abundant skeletal muscle was identified in each. One may conclude that skeletal muscle is very frequently found in routine tonsillectomy specimens and, by itself, is not an indication of inappropriate surgical technique.

Intraosseous salivary tissue: jawbone examples of choristomas, hamartomas, embryonic rests, and inflammatory entrapment: another histogenetic source for intraosseous adenocarcinoma.

PROBLEM: Hundreds of primary salivary neoplasms have been found to be completely enclosed within the marrow spaces of the maxilla and mandible, yet nonneoplastic salivary tissue has never been convincingly identified within marrow, either separately or adjacent to such neoplasms. This situation has forced the acceptance of an inherently awkward odontogenic origin for all intramedullary salivary carcinomas and adenomas. OBJECTIVE: The purpose of this study was to microscopically evaluate a large number of maxillofacial marrow samples for the presence of intramedullary salivary tissue. STUDY DESIGN: We microscopically reviewed 5034 maxillofacial bone samples from the Latvala Inflammatory Bone Registry for evidence of heterotopic salivary inclusions within the marrow tissues. Contributing surgeons were contacted for each identified case of intraosseous salivary tissue to assure that all submitted tissue was removed from within the marrow spaces rather than from overlying soft tissue. RESULTS: Thirteen of 5034 marrow samples (0.3%) contained heterotopic acinic hamartomas, salivary choristomas, embryonic salivary rests, or entrapped surface glands. Four additional hamartomas of the condyle are described. We report also the chance finding of incipient odontogenic epithelial neoplasms (n = 6) and odontogenic epithelial rests (n = 84) within the fatty marrow and outside the periodontal ligament spaces, confirming that not all odontogenic neoplasms are necessarily of periodontal ligament origin. CONCLUSION: The frequency rate for salivary choristomas, hamartomas, embryonic rests, and displaced surface glands within alveolar bone is no less than 2.6 of 1000 biopsied marrow samples. This provides an additional and quite logical histogenetic explanation for the presence of intraosseous salivary neoplasms.

Occupational exposure to chlorophenol and the risk of nasal and nasopharyngeal cancers among U.S. men aged 30 to 60.

BACKGROUND: Elevated rates of nasal and nasopharyngeal cancers have been associated with wood-related occupational exposures, including chlorophenols, formaldehyde, and wood dust. METHODS: Occupational information was obtained from 43 nasal carcinoma cases, 92 nasopharyngeal carcinoma cases, and 1909 controls, by interview. Exact conditional logistic regression was used to evaluate the association of these cancers with chlorophenol exposure, estimated from a review of verbatim responses. RESULTS: Both nasal and nasopharyngeal cancers were significantly associated with estimated duration of chlorophenol exposure. For nasopharyngeal cancer, elevated risk was observed among those who held jobs assigned medium or high intensity chlorophenol exposure (n(exposed)=18, OR=1.94, 95% CI=1.03-3.50) and among those with 10+ years in jobs assigned high intensity with high certainty (n(exposed)=3, OR=9.07, 95% CI=1.41-42. 9). Controlling for estimated formaldehyde and wood dust exposure did not alter these findings, as much of the estimated chlorophenol exposure was among machinists. CONCLUSIONS: These findings support the hypothesis that occupational exposure to chlorophenol is a risk factor for nasal and nasopharyngeal cancer, although the role of machining-related exposures warrants further assessment.

Sarcomatoid salivary duct carcinoma of the parotid gland.

Salivary duct carcinoma (SDC) is a high-grade neoplasm known to histologically resemble high-grade ductal carcinoma in situ of the breast. We describe 3 cases of sarcomatoid salivary duct carcinoma, a heretofore unreported variant of SDC. Each case was a composite of SDC and sarcomatoid carcinoma and histologically similar to reported cases arising in the breast. The clinicopathologic features, including immunohistochemistry, of 3 cases were investigated. In the 3 men, ages 56, 68, and 70 years, the resected parotid tumors measured 1.5, 3.5, and 1.5 cm, respectively. Only the 3.5-cm tumor extended beyond the parotid gland into soft tissue. This patient died at 3 years with pulmonary metastases. The other patients were free of disease at 6 and 12 months. Histologically, each case was a composite of usual-type SDC and sarcomatoid carcinoma. SDC showed typical cribriform architecture, whereas anaplastic, spindled cells constituted the sarcomatoid areas. Immunohistochemically, epithelial elements stained as follows: cytokeratin (AE1/AE3 & CAM 5.2) positive in 3 of 3 cases, EMA positive in 3 of 3 cases, vimentin negative in 3 of 3 cases, desmin negative in 3 of 3 cases, c-erbB-2 positive in 1 of 2 cases. Sarcomatoid elements stained as follows: AE1/AE3 negative in 3 of 3 cases, CAM 5.2 rare positive cell in 1 of 3 cases, EMA focally positive in 3 of 3 cases, vimentin positive in 3 of 3 cases, desmin negative in 3 of 3 cases, c-erbB-2 negative in 2 of 2 cases. Electron microscopy, performed in one case, showed scattered junctional complexes congruent with epithelial differentiation. Immunohistochemical results, EMA and CAM 5.2 positivity, and ultrastructural findings supported our belief that these unique biphasic tumors represented SDC with sarcomatoid carcinoma. We conclude an element of sarcomatoid carcinoma rarely may arise in association with SDC, and it is erroneous to diagnose such tumors as "carcinosarcoma."

Frequent loss of heterozygosity at chromosome 3p14.2-3p21 in human pancreatic islet cell tumours.

OBJECTIVE: Pancreatic islet betacell tumours occur either sporadically or as part of inherited neoplastic syndromes, most commonly multiple endocrine neoplasia (MEN) type 1. Recently, a transgenic mouse model has been established in which the expression of the SV40 large T antigen was targeted to betacells by the rat insulin promoter, leading to the development of multiple pancreatic betacell tumours. In the advanced stages of tumour evolution, these tumours exhibited a high prevalence of loss of heterozygosity (LOH) on mouse chromosomes 9 and 16, at regions syntenic with regions 3q, 3p21, 6q12, 15q24 and 22q of the human genome. DESIGN: Loss of heterozygosity in human islet cell tumours was analysed in a PCR based approach at regions of the human genome syntenic with the mouse loci linked to pancreatic betacell tumours as well as the MEN1 gene on chromosome 11q13. These included 35 microsatellite markers in the human chromosomal regions 3q, 3p21, 6q12, 11q13, 15q24 and 22q. PATIENTS: 21 patients diagnosed with insulinoma were analysed. Histologically, 16 tumours were benign, while 5 were malignant insulinomas. RESULTS: Thirteen of 21 (62%) tumours were found to have loss of genetic material on chromosome 3. The shortest region of overlap implicated a deletion at 3p14.2-3p21 region, corresponding to the marker D3S1295. We did not detect a substantial frequency of LOH in the other syntenic regions, except for the region of MEN 1 gene on 11q13 found to be deleted in 6 (29%) cases, including 3 of 4 tumours from MEN 1 families. Deletions of 3p14. 2-3p21 were observed in 8 of 15 (53%) benign tumours, and in 5 of 6 (83%) malignant neoplasms. CONCLUSIONS: These results indicate the high frequency of 3p14.2-3p21 deletions in human pancreatic betacell neoplasms. These finding suggest the presence of a tumour suppressor gene in this region, that may be important in the microevolution of these tumours towards malignancy.

Pathomorphology of thyroid gland lesions associated with radiation exposure: the Chernobyl experience and review of the literature.

The common sources of ionizing radiation exposure to the thyroid gland in humans are accidental environmental exposure and medical, therapeutic, or diagnostic irradiation. Radiation often induces notable histologic changes in the thyroid tissue and is a well-established risk factor for benign and malignant thyroid tumors. In this paper, we review the acute and chronic histologic changes in the thyroid gland subjected to irradiation, and characterize benign thyroid nodules and malignant tumors arising after exposure, with particular emphasis on thyroid lesions in the population exposed to ionizing radiation as a result of the Chernobyl nuclear accident.

Basal cell adenocarcinoma of the salivary gland: an ultrastructural and immunohistochemical study.

OBJECTIVE: The purpose of this study was to examine the ultrastructural and immunohistochemical characteristics of basal cell adenocarcinoma. STUDY DESIGN: Three cases of basal cell adenocarcinoma of the salivary glands were studied by means of light microscopy, electron microscopy, and immunohistochemistry. RESULTS: Some of the architectural tumor patterns encountered were solid, some were trabecular, and some were mixed. Ultrastructurally, solid areas were composed of nonluminal cells, some of which contained tonofilaments and well-formed desmosomes; tubulo-trabecular areas differentiated into both luminal and nonluminal cells. Both growth patterns were associated with the formation of excess basal lamina, marginally and between nonluminal cells. Myofilaments were infrequent in nonluminal cells of solid or trabecular areas. Cytokeratin (AE1/AE3) stained all 3 tumors, more peripherally in the solid pattern and usually centrally in the trabecular areas; vimentin stained all 3 tumors diffusely; smooth muscle actin (IA4) stained all 3 tumors but was mainly confined to peripheral tumor cells in both the solid and the trabecular growth patterns; epithelial membrane antigen and carcinoembryonic antigen stained 1 of the 3 tumors, predominantly in the luminal cells; p53 oncoprotein was focally positive in 2 of the 3 tumors; Ki-67 stained less than 5% of the tumor cells in all cases; and c-erb-B2 was uniformly negative in all cases. Staining patterns of cytokeratin and actin varied with the architecture of the tumor. CONCLUSIONS: Neither ultrastructural characteristics nor immunohistochemistry findings appear to distinguish basal cell adenocarcinoma from basal cell adenoma.

Exophytic and papillary squamous cell carcinomas of the larynx: A clinicopathologic series of 104 cases.

Exophytic and papillary squamous cell carcinomas (SCCs) are uncommon variants of SCC of the upper aerodigestive tract mucosa. The histomorphologic distinction between these variants has not been previously attempted or correlated with prognostic outcome. One hundred four cases of exophytic and papillary SCCs of the larynx were identified in the files of the Armed Forces Institute of Pathology from 1971 to 1991. The patients included 25 women and 79 men, aged 27 to 89 years (average 60.7 years). Patients had hoarseness at presentation, and many patients were using tobacco (n = 87) and/or alcohol (n = 49). Tumors measured up to 6 cm in greatest dimension. The larger tumors were associated with vocal cord impairment (n = 39). Histologically, the SCCs were divided into 2 growth patterns: papillary-frond (n = 12) or broad-based, exophytic (n = 92). Patients were treated with excisional biopsy, vocal cord stripping, and/or laryngectomy, in conjunction with radiation therapy (n = 70). Eighty-seven patients had no evidence of disease at last follow-up (average follow-up 8.6 years). Seventeen patients with an exophytic pattern died with disease (10 disseminated disease; 7 local disease). No patients with papillary patterns died of disease, although there had been 4 recurrences. In conclusion, patients with papillary and exophytic SCCs have a better prognosis than those with conventional SCCs, and the prognosis for those with papillary SCCs is even better.

Does open biopsy before mastectomy affect the prevalence of so-called axillary lymph node micrometastases detected immunohistochemically.

OBJECTIVE: To determine the effect of a previous open biopsy on the presence of immunohistochemically detected micrometastases, particularly single cells, in axillary lymph nodes in patients with "node-negative" invasive breast carcinoma. METHODS: Node-negative breast cancer patients were divided into group 1 (diagnostic frozen-section biopsy with immediate mastectomy and axillary dissection) and group 2 (open surgical biopsy with temporally delayed mastectomy and axillary dissection). Archival slides of lymph nodes were examined and new sections stained with hematoxylin-eosin and immunohistochemically with a cytokeratin cocktail to detect micrometastases. RESULTS: Four (12%) of 33 patients had unequivocal lymph node metastases on additional hematoxylin-eosin sections (3 cases) or review of original material (1 case). Immunohistochemical analysis contributed additional data in only 1 group 2 patient. In this case a single strongly keratin-positive sinus-based cell was detected in 1 lymph node. CONCLUSION: The study suggests that previous surgical biopsy of the breast does not increase the incidence of immunohistochemically detected keratin positive cells in axillary lymph nodes.

Molecular characterization of Warthin tumor.

OBJECTIVE: Warthin tumor of the salivary gland is composed of oncocytic epithelium with a prominent follicular lymphoid infiltrate. The purpose of this study was to characterize the clonality of this lymphoid component by means of polymerase chain reaction technology. STUDY DESIGN: DNA was isolated from paraffin-embedded tissue from 20 cases of typical Warthin tumor of the salivary gland and amplified by polymerase chain reaction to assess B- and T-cell clonality. RESULTS: No dominant clonal populations were identified in any tumor. However, minor clonal expansions of both B and T cells were detected in up to 50% of tumors (immunoglobulin H, 50%; T-cell antigen receptor beta, 10%; T-cell antigen receptor gamma, 5%). No tumors showed evidence of bcl-2 proto-oncogene translocation, whereas 95% contained detectable Epstein-Barr virus DNA. CONCLUSION: The B- and T-cell components of Warthin tumor are polyclonal with oligoclonal expansion of both T and B cells in some lesions.

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.

Helicobacter pylori infection and adenocarcinoma arising in Barrett's esophagus.

Helicobacter pylori infection has been implicated in the development of chronic active gastritis and gastric neoplasms (ie, mucosa-associated lymphoid tumors and adenocarcinoma). The potential association between esophageal H pylori infection with Barrett's esophagus-associated adenocarcinoma has not been previously studied. Nineteen cases of adenocarcinoma arising in Barrett's esophagus were examined for the presence of H pylori. Barrett's esophagus was defined by the presence of metaplastic specialized-type epithelium (gastric-type epithelium with goblet cell metaplasia) in the distal esophagus. To detect the presence of H pylori, 5-microm sections, from several tissue blocks in each case, were stained with routine hematoxylin-eosin, modified Giemsa, and an antibody directed against H pylori (Dako a/s, Denmark, Lot # 111061). Stained sections were examined independently by two pathologists. All three staining methods failed to show H pylori in any of the cases examined. Sections of Barrett's esophagus (with and without dysplasia), adenocarcinoma, and stomach (when available) were uniformly negative for the presence of H pylori. We conclude that neither gastric nor esophageal infection with H pylori is a requisite for the development of adenocarcinoma in Barrett's esophagus. Moreover, it is unlikely that a significant association between H pylori infection and Barrett's-associated adenocarcinoma exists.

Dedifferentiated acinic cell carcinoma of the parotid gland: a distinct rarely described entity.

A case of dedifferentiated acinic cell carcinoma of the parotid gland is presented. A 46-year-old man presented with a parotid gland mass. At surgery the tumor was found adherent to the temporal bone and cervical adenopathy was present. Treatment included radical parotidectomy and intraoperative radiotherapy. Histologically, the tumor was a composite of a usual low-grade acinic cell carcinoma and high-grade, poorly differentiated carcinoma. Cervical lymph node metastases were composed entirely of high-grade carcinoma. Immunohistochemically, both low- and high-grade malignant components were negative for p53 oncoprotein expression. Moreover, polymerase chain reaction and nonisotopic single-stranded conformational polymorphism analyses were consistent with a germ line configuration of the p53 gene, exons five through eight, in both low- and high-grade elements of the tumor. The literature on this unusual variant of acinic cell carcinoma is reviewed.