Targeting X chromosome-linked inhibitor of apoptosis protein in mucoepidermoid carcinoma of the head and neck: A novel therapeutic strategy using nitidine chloride.

Nitidine chloride (NC) was recently reported to exhibit a wide range of pharmacological properties for several diseases, including cancer. Here we report for the first time that NC is a potential therapeutic agent for mucoepidermoid carcinoma (MEC) occurring in the head and neck because it suppresses X chromosome-linked inhibitor of apoptosis protein (XIAP) in human MEC in vitro and in vivo. The antitumor effects of NC were evaluated by trypan blue exclusion assay, western blotting, live/dead assay, 4',6-diamidino-2-phenylindole (DAPI) staining, human apoptosis antibody array, immunofluorescence staining, immunohistochemistry, small interfering RNA assay, transient transfection of XIAP overexpression vector, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and histopathological examination of organs. NC inhibited cell viability and induced caspase-dependent apoptosis in vitro. A human apoptosis antibody array assay showed that XIAP is suppressed by NC treatment. XIAP was overexpressed in oral squamous cell carcinoma (OSCC) tissues that arose from the head and neck, and high XIAP expression was correlated with poor prognosis in OSCC patients. XIAP depletion significantly increased apoptosis, and ectopic XIAP overexpression attenuated the apoptosis induced by NC treatment. NC suppressed tumor growth in vivo at a dosage of 5 mg/kg/day. The number of TUNEL-positive cells increased and the protein expression of XIAP was consistently downregulated in NC-treated tumor tissues. In addition, NC caused no histopathological changes in the liver or kidney. These findings provide new insights into the mechanism of action underlying the anticancer effects of NC and demonstrate that NC is a promising therapeutic agent for the treatment of human MEC of the head and neck. KEY MESSAGES: • Nitidine chloride induces caspase-dependent apoptosis in MEC of the head and neck. • High XIAP expression correlates with poor prognosis of OSCC patients. • Nitidine chloride suppresses tumor growth in vivo without any systemic toxicities. • Targeting XIAP is a novel chemotherapeutic strategy for MEC of the head and neck.

Ablation of Cancer Stem Cells by Therapeutic Inhibition of the MDM2-p53 Interaction in Mucoepidermoid Carcinoma.

PURPOSE: Unique cells characterized by multipotency, self-renewal, and high tumorigenic potential have been recently discovered in mucoepidermoid carcinomas. These cells are defined by high aldehyde dehydrogenase activity and high CD44 expression (ALDHhighCD44high) and function as cancer stem cells (CSC). It has been recently shown that p53 regulates cell differentiation, suggesting that induction of p53 by therapeutic blockade of the MDM2-p53 interaction may constitute a novel strategy to ablate CSCs. Here, we evaluated the effect of a small-molecule inhibitor of MDM2-p53 interaction (MI-773) on the fraction of CSCs in mucoepidermoid carcinoma. EXPERIMENTAL DESIGN: Human mucoepidermoid carcinoma cells (UM-HMC-1,-3A,-3B) were used to assess the effect of MI-773 on cell survival, cell cycle, fraction of CSCs, and expression of p53, p21, MDM2, and Bmi-1 (key regulator of self-renewal). Mice bearing xenograft tumors generated with these mucoepidermoid carcinoma cells were treated with MI-773 to determine the effect of MDM2-p53 inhibition on CSCs in vivo. RESULTS: MDM2 is highly expressed in human mucoepidermoid carcinoma tissues. MI-773 induced expression of p53 and its downstream targets p21 and MDM2, caused G1 cell-cycle arrest, and induced mucoepidermoid carcinoma tumor cell apoptosis in vitro. Importantly, a marked decrease in expression of Bmi-1 and in the fraction of ALDHhighCD44high (CSCs) was caused by MI-773 in vitro and in mice harboring mucoepidermoid carcinoma xenografts. CONCLUSIONS: Collectively, these data demonstrate that MI-773 reduces the fraction of CSCs, suggesting that patients with mucoepidermoid carcinoma might benefit from therapeutic inhibition of the MDM2-p53 interaction.

Mucoepidermoid carcinoma post-radioactive iodine treatment of papillary thyroid carcinoma: unique presentation and putative etiologic association.

We report the development of mucoepidermoid carcinomas of the parotid gland in 2 adult patients after a relatively short duration of radioactive iodine (RAI) treatment of papillary thyroid carcinoma. Both instances, together with those previously reported, underscore the selective nature of the mucoepidermoid carcinoma phenotype development in patients with papillary thyroid carcinoma as a consequence of RAI treatment. Efforts to alleviate salivary pathophysiologic damage by RAI in these patients are warranted.

Spectrum of Salivary Gland Lesions in a Tertiary Level Hospital.

Salivary gland tumors are relatively infrequent and account for less than 2% of all human tumors. This study was conducted to see the prevalence of patterns of non neoplastic and neoplastic lesions of salivary glands in greater Mymensingh. It was a retrospective study carried out in the department of Pathology, Community Based Medical College Bangladesh from January 2010 to December 2012. Heamatoxylin and eosin stained sections were studied in all cases. Total 98 cases of salivary gland lesions were retrieved and evaluated. Out of them 55 cases were female and 43 were male. Mean age of the cases were 42 years. Among the salivary gland lesions non-neoplastic lesions 24.48% and neoplastic lesions 75.51%. Among neoplastic lesions benign tumor comprises 91.89% and malignant tumor comprises 8.10%.

HER2 and EGFR gene copy number alterations are predominant in high-grade salivary mucoepidermoid carcinoma irrespective of MAML2 fusion status.

AIMS: In this study, we aimed to investigate the molecular mechanisms underlying the development of mucoepidermoid carcinoma (MEC). METHODS AND RESULTS: In 31 cases, we examined the MAML2 fusion status using reverse transcriptase-polymerase chain reaction, and HER2 and EGFR status using immunohistochemistry and chromogenic in-situ hybridization. MAML2 fusions were detected in 15 (57.7%) of 26 MECs analysed, including 11 of 16 (68.8%) low-grade, two of four (50%) intermediate-grade and two of six (33.3%) high-grade MECs. HER2 gene amplification and an increased EGFR gene copy number (with balanced chromosome 7 high-polysomy) were each detected in four of 28 (14.3%) MECs analysed. Irrespective of MAML2 fusion status, all seven high-grade MECs had an increased gene copy number of either HER2 or EGFR, in a mutually exclusive manner, whereas such abnormalities were extremely rare in low- and intermediate-grade MEC. CONCLUSIONS: These results suggest that HER2 or EGFR gene abnormality could play an important role in the development of high-grade MEC, and also in the progression from MAML2 fusion-positive low-/intermediate-grade to high-grade in a subset of MEC. Furthermore, we suggest that high-grade MEC comprises a heterogeneous group of tumours in terms of molecular pathogenesis, in particular MAML2 fusion status.

Atypical presentation of mucoepidermoid carcinoma after radiation therapy for the treatment of keloids.

Radiation therapy to the head and neck for the treatment of benign diseases carries the potential for the late development of carcinoma. Low-dose radiation has been used as an adjunctive treatment for recurrent keloids, especially massive keloids, but the carcinogenic potential of ionizing radiation in this setting remains controversial. We report the case of a 37-year-old black woman with a history of severe earlobe keloids who had been first treated with resection and postoperative radiation at the age of 9 years. When she had reached the age of 36 years, she required reoperation for massive keloid scarring, after which she underwent a second course of postoperative radiation to the right side of her face and neck. Some 20 months after the second administration of radiation therapy, she developed a mucoepidermoid carcinoma in the right parotid gland. The tumor was successfully treated with surgery.

Characteristics and outcome of radiation and chemotherapy-related mucoepidermoid carcinoma of the salivary glands.

BACKGROUND: Mucoepidermoid carcinoma (MEC) of the salivary glands has been reported to occur in patients previously treated with chemotherapy and/or radiation. The purpose of our study is to review the patient, tumor, and treatment characteristics of patients who develop a treatment-related MEC. PROCEDURE: A PubMed search of English language articles was performed using the keywords and MeSH terms: mucoepidermoid, salivary gland, radiation-induced, second malignancy, radiotherapy, and chemotherapy. RESULTS: The search yielded 23 articles describing 58 patients who received chemotherapy and/or radiotherapy (RT) and subsequently developed MEC. The most common initial diagnoses were acute lymphoblastic leukemia (n = 18), acne (n = 9), and Hodgkin lymphoma (n = 6). Patients were divided into three groups according to chemotherapy and RT treatment: chemotherapy alone (n = 14), RT alone (n = 14), or chemotherapy and RT (n = 30). The parotid gland was the most common site for secondary MEC. Latent time (LT) to development of MEC from initial tumor treatment was significantly shorter in the patients treated with chemotherapy ± RT versus RT alone (7.9 years vs. 27.2 years, P < 0.01). The most common treatment for MEC was surgery alone followed by surgery and postoperative RT. The 2- and 5-year overall survival rates were 98% and 93.4% while the 2- and 5-year locoregional control rates were 97.7% and 92.5%, respectively. There was no difference in survival or locoregional control between groups exposed to RT alone, chemotherapy alone, or chemotherapy with RT for the initial tumor. CONCLUSION: Radiation and chemotherapy-related MEC has an excellent prognosis.

Salivary gland tumours as second neoplasms: two cases and literature review.

OBJECTIVES: Patients who survive malignant tumours have an increased risk of second neoplasms, including those of the salivary glands. Mucoepidermoid carcinoma of the parotid gland is by far the most common type of second salivary gland tumour; other types have rarely been reported. We describe here two patients with a second tumour of the salivary glands. CASE REPORTS: The first patient was a 22-year-old woman with a low grade mucoepidermoid carcinoma of the parotid gland, which developed 21 years after completion of chemoradiotherapy for acute lymphoblastic leukaemia. The second patient was a 40-year-old woman with an epithelial-myoepithelial carcinoma of the buccal mucosa, which arose 11 years after treatment for two malignant neoplasms - retroperitoneal liposarcoma and squamous cell carcinoma of the uterine cervix. CONCLUSIONS: It is mandatory that survivors of cancer should be monitored carefully, so that the complications related to their previous disease and therapy are detected early and managed properly.

[Mucoepidermoid carcinoma of the parotid gland as a secondary malignancy developed ten years after chemotherapy for childhood acute lymphoblastic leukemia].

We report on a case of mucoepidermoid carcinoma of the parotid gland following treatment of acute lymphoblastic leukemia (ALL) in childhood. The female patient was diagnosed as having T-cell ALL at the age of 13 years. Treatment included multidrug chemotherapy and prophylactic 18 Gy cranial irradiation. She developed low-grade mucoepidermoid carcinoma of the right parotid gland at the age of 24 years, the most probable cause of the secondary malignancy being radiation. In a literature review of mucoepidermoid carcinoma following ALL, 11 out of 14 cases received radiation therapy for the initial treatment of ALL, but 3 cases had no radiation therapy. The parotid gland carcinoma as a secondary malignancy following ALL in childhood is rare, but it highlights the need for concern about the secondary malignancy in patients with painless parotid swelling after chemoradiotherapy.

Human papillomavirus seropositivity and risks of head and neck cancer.

We examined antibody response to VLP HPV-16, HPV-16 E6 and E7 antibodies as potential seromarkers of HPV-related head and neck cancer (HNC). The study included 204 HNC cases and 326 controls evaluated for HPV presence in sera using ELISAs for anti-HPV VLP antibodies and HPV-16 E6 and/or E7 antibodies, and in tumor tissue using PCR and DNA sequencing. Anti-HPV-16 VLP was detected in 33.8% of cases and 22.4% of controls, anti-E6 in 20.6% of cases and 0.9% of controls and anti-E7 in 18.6% of cases and 0.6% of controls. HPV-16 DNA was detected in 26.1% of tumors. The adjusted risk of HNC was elevated among those seropositive for HPV-16 VLP (odds ratio (OR) = 1.7, 1.1-2.5), E6 (OR = 32.8, 9.7-110.8) or E7 (OR = 37.5, 8.7-161.2). Compared to HPV DNA-negative/seronegative cases, tumor HPV-16 cases had increased risk of detection with anti-VLP antibodies (OR = 6.8, 3.1-14.9). The odds were more pronounced among cases seropositive for E6 (OR = 69.0, 19.3-247) or E7 (OR = 50.1, 14.7-171). Antibodies against E6 or E7 were associated with risk of cancer in the oral cavity (OR = 5.1, 1.2-22.4) and oropharynx (OR = 72.8, 16.0-330), and with disease characteristics: stage, grade and nodal status. Anti-E6 and/or E7 antibodies were found in 74% of tumor HPV-16 positive cases but in only 5% of tumor HPV-negative cases (K =0.7, 0.6-0.8) suggesting good correlation between the serologic marker and HPV tumor status. Antibodies to HPV-16 E6 and/or E7 represent a more specific biomarker than anti-HPV-16 VLP of an HPV-related HNC. Because of the survival advantage of HPV-related HNC, HPV-16 E6/E7 detection may be useful in therapy targeted for HPV-related tumors.

Salivary mucoepidermoid carcinoma: revisited.

Mucoepidermoid carcinoma (MEC) is a malignant epithelial neoplasm composed of varying proportions of mucous, epidermoid, intermediate, columnar, and clear cells and often demonstrates prominent cystic growth. MEC is usually subclassified as low, intermediate, or high grade on the basis of its histologic features, including the presence of cystic spaces, cellular differentiation, proportion of mucous cells, growth pattern, type of invasion, and cytologic atypia. Because even low-grade neoplasms may metastasize, the term mucoepidermoid tumor is inappropriate. The 3-level grading approach to tumor classification has found general acceptance among pathologists; differences in biologic behavior can be demonstrated even though clinical stage has become a better prognosticator. However, in the case of MEC, no universal agreement exists regarding which histologic grading criteria are most the useful, and grading has varied. These issues have led to the investigation of more subjective systems. We describe these new schemes, the histologic variants of MEC, and the ancillary methods that allow for further stratification of patients with MEC, especially for patients with grade 2 tumors, which have a variable and unpredictable clinical course.

Mucoepidermoid variant of adenosquamous carcinoma arising in ovarian dermoid cyst: a case report and review of the literature.

A 40-year-old woman with mucoepidermoid variant of adenosquamous carcinoma arising in dermoid cyst in left ovary is presented. The patient was staged as IC. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymph node sampling were carried out. The disease recurred in postoperative 12th month. To our best knowledge, this is 12th case of adenosquamous carcinoma in dermoid cyst and third case of mucoepidermoid variant of adenosquamous carcinoma in the literature.

[Primary intraosseous carcinoma of the jaws: case report and review of the literature].

Because of lacking characteristic symptoms, primary intraosseous carcinoma of the jaws can't be easily diagnosed early. A case of intraosseous mucoepidermoid carcinoma of the maxilla was reported and relevant literature was reviewed. The possible etiology, clinical symptoms, radiology, histopathology, diagnosis and treatments were discussed.

[Bronchial mucoepidermoid carcinoma in a 22 year-old cannabis smoker]. / Carcinome bronchique muco-épidermoïde chez un fumeur de cannabis âgé de 22 ans.

INTRODUCTION: Bronchial mucoepidermoid carcinoma represents less than 0.5% of malignant bronchopulmonary cancers. The factors of risk have not been clearly established. Consumption of cannabis could be incriminated, as is suggested by this case report. OBSERVATION: A 22 year-old man presented with a mucoepidermoid carcinoma of the middle bronchopulmonary lobe. This young man had consumed large quantities of tobacco and cannabis since the age of eleven. DISCUSSION: The relationship between this rare tumour and the addictions in this patient merit further discussion. The oncogenic role of cannabis smoke should be envisaged, and emphasis placed on the possible synergic effects of multiple addiction, in this case tobacco and cannabis.

[Two cases of malignant tumors of the face after hematopoietic stem cell transplantation]. / Deux cas de tumeurs malignes de la face après allogreffe de cellules souches hématopoïétiques.

INTRODUCTION: Malignant solid tumors are a complication of hematopoietic stem cell transplantation (HSCT). OBSERVATION: Two patients underwent HSCT for acute leukemia. Chronic graft-versus-host disease (GVHD) developed. At 5 years one patient developed squamous cell carcinoma of the tongue and the other mucoepidermoid carcinoma of the parotid gland. DISCUSSION: Several factors are involved in the development of secondary malignant tumors after HSCT. Pre- and post-graft immunosuppressive treatment inhibits the defence system and cell repair and can trigger chronic GVHD with chronic inflammation of the epithelial tissue leading to accelerated cell turn over and a risk of genetic anomalies favoring penetration of viral particles. Squamous cell carcinoma of the oral cavity after HSCT presents the same clinical, histological and prognostic features as in the non-grafted patient. These patients require prolonged surveillance. Improved grafting and ant-HPV vaccination techniques may reduce the risk of cancer after HSCT.

Tumores das glândulas salivares maiores: estudo restrospecitvo / Major salivary glands tumors: restrospective study

Os Tumores das Glândulas Salivares Maiores estão localizados nas Glândulas Parótida, Submandibular e Sublingual e correspondem a aproximadamente 3 a 5 porcento de todas as neoplasias do segmento cabeça e pescoço. O objetivo do presente trabalho é demonstrar o comportamento dos Tumores Benignos e Malignos das Glândulas Salivares Maiores de pacientes atendidos e tratados no Serviço de Cirurgia de Cabeça e Pescoço do Centro de Oncologia (CEON) do Hospital Universitário Oswaldo Cruz (HUOC) - Universidade de Pernambuco (UPE), no período de Janeiro de 1975 a Janeiro de 2003 (28 anos). Em um total de 153 casos (100 porcento), o sexo feminino foi mais prevalente (61,5 porcento), bem como a 4ª e 5ª décadas de vida. Os tipos histológicos benigno e maligno predominantes foram o adenoma pleomórfico (58,2 porcento) e o carcinoma mucoepidermóide (7,8 porcento), respectivamente. A complicação cirúrgica pós-operatória mais freqüente foi a parestesia do ramo mandibular facial (41,9 porcento), seguida da síndrome de Frey (20,8 porcento). Através de um estudo retrospectivo, foram analisados aspectos etiológicos, clínicos, histopatológicos, diagnóstico diferencial, tratamento e prognóstico, e compararam-se os referidos indicadores com os apresentados na revisão da bibliografia consultada. Demonstram, ainda, sua experiência com a referida patologia, e suas conclusões do material estudado

[Mucoepidermoid carcinoma of nasopharynx: a report of twelve cases].

BACKGROUND & OBJECTIVE: Mucoepidermoid carcinoma of nasopharynx, a kind of primary adenocarcinoma of nasopharynx, is rare, and has seldom been reported. This article was to summarize the pathogenesis, clinical features, and treatment outcomes of this disease according to our experiences. METHODS: From Jan. 1975 to Dec. 2003, 12 patients with pathologically confirmed primary mucoepidermoid carcinoma of nasopharynx were treated in our hospital. We analyzed retrospectively their clinical data with literature review. RESULTS: The 12 patients with mucoepidermoid carcinoma of nasopharynx accounted for only 0.026% of all nasopharyngeal cancer patients diagnosed simultaneously in our hospital. Age of getting disease was 20 to 60 years old with male to female ratio of 2:1. Positive rates of Epstein-Barr virus serological tests (VCA-IgA, EA-IgA, and DNA enzyme ratio) were very low [50.0% (6/12), 11.1% (1/9), and 20.0% (1/5)]. Of the 11 patients with follow-up data, 4 received chemotherapy, 4 received surgery plus radiotherapy, and 3 received radiochemotherapy. The 5-, and 10-year survival rates of the 12 patients were 27.3%, and 9.0%. CONCLUSIONS: Mucoepidermoid carcinoma of nasopharynx is a special type of nasopharyngeal carcinoma with specific pathogenesis features. Surgery-predominant of complete lumpectomy combined treatment strategy is possibly accommodating.

Mucoepidermoid carcinoma of the parotid gland in a child previously treated for acute lymphoblastic leukemia.

Occurrence of second cancers is a major concern for the care of children cured of cancer. Children treated for acute lymphoblastic leukemia (ALL) have an increased risk for developing mucoepidermoid carcinomas (MEC) of the parotid gland. The latent period ranges from 5 to 16 years. A 3-year-old boy presented with pre-B ALL. Treatment included multidrug chemotherapy and prophylactic intrathecal injections of methotrexate and prednisolone. Low-grade MEC of the left parotid gland was diagnosed at the age of 7 years, only 1 year after completing treatment. Local lymph nodes were not metastatic, and course was favorable 8 years after complete surgical excision. This case report is remarkable for the early diagnosis of second cancer, only 4 years after diagnosis of ALL, and its occurrence in parotid gland without previous head and neck irradiation. It highlights the need for concern about second cancers of the parotid gland in children treated for ALL.