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.

Prevalence of mutations of ras and p53 in benign and malignant thyroid tumors from children exposed to radiation after the Chernobyl nuclear accident.

Starting 4 years after the Chernobyl accident, a dramatic increase in incidence of thyroid carcinoma was noticed in children from contaminated areas. The incidence of benign thyroid lesions in the exposed population was also increased. To study the possible role of ras and p53 genes in radiation-induced thyroid tumorigenesis, 33 papillary carcinomas, one follicular carcinoma and 22 benign lesions removed from children aged 5-19 were screened for point mutations of H-, K-, and N-ras, as well as of p53 (exons 5-8) using single strand conformation polymorphism (SSCP) analysis. Ras point mutations were detected in 1/1 case of follicular carcinoma (N-ras codon 61 CAAgln-->AAAlys), and in 3/7 follicular adenomas (N-ras codon 61 CAAgln-->CGAarg x 2, CAAgln-->AAAlys). None of the cases of papillary thyroid carcinoma was positive for ras oncogene abnormalities. The lack of K-ras mutations was confirmed by allele-specific oligonucleotide hybridization (ASOH), and by sequencing in five cases. Somatic point mutations in p53 were found by SSCP in 2/33 papillary thyroid carcinomas, with one missense mutation (exon 5, codon 160 ATGmet-->GTGval) and another silent mutation (codon 182, TGCcys-->TGTcys). Immunohisto-chemically, focally positive p53 staining was found in four papillary carcinomas being primarily confined to solid and poorly-differentiated areas in tumors. These data demonstrate that as opposed to the few reports on tumors arising after therapeutic external irradiation, ras mutations are not primary events in the development of post-Chernobyl thyroid papillary carcinomas. p53 mutations do not appear to be important in the development of these tumors, but may in some cases have a role in progression to a more aggressive phenotype that has not yet fully manifested in these pediatric neoplasms.

Thyroid lesions in children and adolescents after the Chernobyl disaster: implications for the study of radiation tumorigenesis.

Eight years after the Chernobyl nuclear accident, the most obvious effect is manifested by an increase in the prevalence of thyroid gland diseases in the exposed children and adolescents. In this study, we describe a comparative analysis of epidemiological, clinical, and morphological features of 92 malignant and 59 benign thyroid lesions from patients 5-18 yr of age exposed to radiation in Belarus as a result of the Chernobyl disaster. All of them were operated at the same institution during the period from September 1991 through December 1992. The highest number of patients that subsequently developed thyroid carcinomas was in the group that was less that 1 yr of age at the time of Chernobyl, and this number decreased progressively through age 12 yr. Conversely, none of the patients with benign lesions only was less than 2 yr old at the time of the accident, and an exposure age of 5-6 yr was a threshold separating significant prevalence of malignant tumors in younger children from the more frequent benign lesions in older patients (P < 0.001). Fifty-two percent of children with carcinomas and only 24% with benign lesions (P < 0.005) were residents of the Gomel region, which is the most contaminated in Belarus. The morphology of thyroid tissue adjacent to carcinomas showed a high prevalence of multinodular and diffuse changes, but not of adenomas or solitary adenomatoid nodules. There was a high prevalence of focal micropapillary hyperplasia with graded degrees of severity, which we hypothesize may correspond to precursors for papillary thyroid carcinoma in post-Chernobyl radiation-associated tumors.

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.

Composite follicular variant of papillary carcinoma and mucoepidermoid carcinoma of the thyroid. Report of a case and review of the literature.

The follicular variant of papillary carcinoma of the thyroid gland is a commonly recognized, well-defined entity. However, primary mucoepidermoid carcinoma of the thyroid is rare, with only 21 cases reported. We describe a 29-year-old woman who presented with a mass in the right lobe of the thyroid. The tumor was classified as the follicular variant of papillary carcinoma of the thyroid with several foci of mucoepidermoid carcinoma. Both components were invading the capsule and had spread to regional lymph nodes. This is the first reported case in which both the papillary and mucoepidermoid carcinomas were present in the primary tumor and in the metastases.

Fat-containing lesions of the thyroid gland.

Thyroid lesions containing adipose tissue are rare; only scattered case reports are recorded. This study of 17 lipomatous thyroid lesions on file at the Armed Forces Institute of Pathology was undertaken to better document the full range of these abnormalities. Patient ages ranged from 11 to 75 years; nine patients were female and eight were male. Fat-containing thyroid neoplasms included seven papillary carcinomas, four adenomatoid nodules, one follicular adenoma, and one minimally invasive follicular carcinoma. Nonneoplastic conditions associated with adipose tissue included four cases of amyloid goiter, two cases of lymphocytic thyroiditis, one case of dyshormonogenetic goiter, and one case of thyroid atrophy. This study documents the presence of adipose tissue in a wider range of benign and malignant thyroid lesions than has previously been reported.

Laryngeal and hypopharyngeal liposarcoma. A clinicopathologic study of 10 cases with a comparison to soft-tissue counterparts.

We report the clinicopathologic findings of 10 cases of primary laryngeal and hypopharyngeal liposarcoma. The tumors occurred in patients ranging in age from 37 to 77 years. They showed a marked male to female predominance of 9 to 1. The tumors, which occurred exclusively in the supraglottic larynx or hypopharynx (pyriform sinus), caused airway obstruction; this was the most common presenting symptom. All of the cases were well-differentiated liposarcomas (grade I). Atypical cells, scattered lipoblasts, and infiltration differentiated malignant laryngeal fatty tumors from benign ones. To date, none of these tumors has metastasized; however, multiple recurrences are common. Surgery is the treatment of choice; radiotherapy should be decided on an individual basis.

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.

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 recurrences 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.

Hyalinizing clear cell carcinoma of salivary gland.

We describe 11 patients with a distinctive salivary gland neoplasm. Most of the patients were adult women who presented with a painless mass. Nine tumors arose in minor salivary glands of the oral cavity (82%). Microscopically, they were characterized by the formation of trabeculae, cords, islands, and/or nests of monomorphic clear cells that were glycogen rich and mucin negative and were surrounded by hyalinized bands with foci of myxohyaline stroma. Cells with eosinophilic and granular cytoplasm were also noted. Both cell types showed minimal nuclear pleomorphism and a very low mitotic index. The neoplasms all had infiltrative borders. Immunohistochemically, the tumor cells expressed cytokeratins and epithelial membrane antigen, but not S-100 protein and smooth muscle actin. Ultrastructurally, the tumor cells contained abundant glycogen, desmosomes, peripheral tonofilaments, and prominent interdigitating microvilli without actin myofilaments or dense bodies. These immunohistochemical and ultrastructural findings provide evidence of epithelial differentiation without myoepithelial differentiation. For these tumors, we propose the name, hyalinizing clear cell carcinoma (HCCC). These are low-grade malignant neoplasms. Two patients had ipsilateral cervical lymph node metastases at presentation, but with surgical excision and either preoperative or post-operative radiotherapy in three cases, eight of 10 patients with clinical follow-up are alive and well without evidence of recurrence. The mean clinical follow-up is 3.6 years, with a range of 6 months to 11 years. One patient died as a result of surgery, another died of unrelated causes, and one patient was lost to follow-up.

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.

Massive coronary arterial aneurysm.

The pathologic and echocardiographic findings of a massive right coronary arterial aneurysm in a 62 year old man are presented. The thrombosed aneurysm simulated a cardiac tumor, destroying one pulmonary valve cusp. It also caused marked pulmonary stenosis with elongation and narrowing of the outflow tract of the right ventricle and fixation of half of one cusp of the tricuspid valve.

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.

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."

Focal mucinosis of the upper aerodigestive tract in children.

Cutaneous mucinosis is an uncommon lesion characterized by mucin accumulation in the dermis. Rarely, mucinosis may arise in the oral cavity; reported cases have been observed in patients older than 16 years. We identified two children younger than 5 years of age with focal mucinosis of the upper aerodigestive tract. A 3-year-old boy had been intubated at age 2 months, suffered from recurrent respiratory infections, and developed mucinosis of the larynx, a previously unreported site for this unusual lesion. The second patient, a 4-year-old girl with a cleft palate, developed palatine mucinosis.

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.

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.

Benign lymphoepithelial parotid cyst with sebaceous differentiation--cystic sebaceous lymphadenoma.

A case of benign lymphoepithelial parotid cyst with sebaceous differentiation, or cystic sebaceous lymphadenoma, in a 57-year-old white man is presented. The literature on lymphoepithelial cysts and sebaceous lymphadenomas of the parotid gland is reviewed, and the alternative hypotheses of "branchial cleft origin" and "intranodal salivary gland inclusion origin" are compared. This case lends support to the intranodal glandular inclusion theory for lymphoepithelial cysts of the parotid.

Hepatic granuloma resulting from Enterobius vermicularis.

A nodule of the liver was incidentally noted during left colectomy for a large villous adenoma in a 74-year-old man. Microscopic examination disclosed a granuloma of the liver containing numerous Enterobius vermicularis ova and a cross-section of the nematode. This is the fourth reported case of hepatic oxyuriasis and the second case reported in North America.

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.