Hitomi Shinomiya

First bite syndrome - An 11-year experience.

OBJECTIVE First bite syndrome is the development of pain in the ipsilateral parotid region after the first few bites of food and can be seen after surgery of the upper cervical region. The aim of this study is to highlight the etiology of this potentially debilitating chronic pain syndrome. MATERIALS AND METHODS Retrospective review of 53 patients undergoing surgery of the upper neck between 2002 and 2013. RESULTS FBS developed in 16 patients (30%). Partial resolution of FBS symptoms occurred in 69% and complete resolution in 12%, whereas 15% had no change. FBS was most common in the patients who had tumor arising from deep lobe of parotid gland in comparison with other sites (50% vs 18%, p=0.017). FBS developed in 57% of patients undergoing external carotid artery (ECA) ligation and in 12.5% of patients in whom ECA was preserved (p=0.0008). Among the patients in whom ECA was preserved, FBS developed in 43% of the patients in whom sympathetic chain was sacrificed and in 4% of the patients in whom sympathetic chain was preserved. CONCLUSION Present results further support the role of sympathetic chain in the development of FBS.

Expression of amphiregulin in mucoepidermoid carcinoma of the major salivary glands: a molecular and clinicopathological study

In mucoepidermoid carcinoma (MEC), CRTC1-MAML2 fusion indicates a favorable prognosis. Amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, has been shown to be a downstream target of CRTC1-MAML2 fusion, and to play a role in tumor growth and survival in CRTC1-MAML2-positive MEC cell lines. The aim of this study was to characterize the AREG and EGFR expression in the fusion-positive and fusion-negative MEC of the major salivary gland. The AREG and EGFR expression were studied by immunochemistry in 33 MEC cases of the major salivary glands. CRTC1-MAML2 fusion was tested by reverse-transcription polymerase chain reaction (23 CRTC1-MAML2 fusion-positive, 10 fusion-negative). Of 23 fusion-positive cases, AREG and EGFR overexpression were detected in 17 (73.9%) and 14 (60.9%) cases, respectively. Of 10 fusion-negative cases, AREG and EGFR overexpression were detected in 1 (10%) and 3 (30.0%) cases, respectively. There was a positive correlation between CRTC1-MAML2 fusion and AREG overexpression (P < .01), but not between CRTC1-MAML2 fusion and EGFR overexpression. The AREG overexpression was associated with a longer disease-free survival of the MEC patients (P = .042), but EGFR overexpression was not. In this study, we showed that AREG overexpression was detected more frequently in the CRTC1-MAML2 fusion-positive tumors than in fusion-negative tumors. Detection of AREG expression may be useful for identifying CRTC1-MAML2-positive MECs and as a marker for favorable prognosis.

Patterns of lymph node metastasis of parotid cancer

OBJECTIVE To define the incidence and pattern of spread of lymph node metastasis from parotid cancers and to clarify the risk factors and appropriate extent of neck dissection (ND) for individual patient with parotid cancer. METHODS A total of 72 patients with parotid gland cancer treated by surgery between 1994 and 2013 were analyzed retrospectively by reference to medical records. In line with our protocol, patients with clinically positive lymph nodes and/or cT3/T4 disease were generally selected to undergo ND. RESULTS Pathological examinations revealed mucoepidermoid carcinoma in 23 patients, carcinoma ex pleomorphic adenoma in 11, adenoid cystic carcinoma in 9, salivary duct carcinoma in 9, acinic cell carcinoma in 8, squamous cell carcinoma in 5, adenocarcinoma NOS in 4, epithelial myoepithelial carcinoma in 2, and basal cell carcinoma in 1. Thirty-three patients underwent neck dissection: modified radical ND (MRND) in 13, and elective ND (END) in 20. Postoperative RT (PORT) was performed in 33 patients. Among 13 cN+ patients, 10 were pN+ and lymph node metastasis was distributed mainly in levels I, II, III and V. Among 59 cN- patients, clinical T1, T2, T3 and T4 classifications accounted for 10, 24, 10 and 15 patients, respectively. The incidence of occult lymph node metastasis was 22%. Occult lymph node metastasis was mostly seen in the intraparotid, levels I and II of patients with cT4 disease. Among the ND group, 12 necks were pathologically negative for cancer (pN0). Relapse of neck lymph node metastasis occurred only in two patients treated by MRND with pathologically positive lymph nodes (pN+). These patients developed local and distant metastasis within 1 year after neck lymph node recurrence, and subsequently died of the cancer. pN+ was found in 19/30 high grade (63%), 1/10 intermediate grade (10%), and 3/32 low grade (9.4%). Among 33 patients who received PORT, only 1 patient relapsed neck lymph node. CONCLUSION For patients with clinically positive lymph nodes, ipsilateral modified radical neck dissection (levels I-V) is recommended. Elective neck dissection is strongly recommended for patients with T3N0 or T4N0 disease, and the extent of ND should include at least level I/II. PORT for patients with high-risk features may improve the outcome of good neck control.

Mutation analysis of the EGFR pathway genes, EGFR, RAS, PIK3CA, BRAF, and AKT1, in salivary gland adenoid cystic carcinoma

Adenoid cystic carcinoma (AdCC), one of the most common salivary gland carcinomas, usually has a fatal outcome. Epidermal growth factor receptor (EGFR) pathway gene mutations are important in predicting a patients prognosis and estimating the efficacy of molecular therapy targeting the EGFR pathway. In this study of salivary gland AdCC (SAdCC), we looked for gene mutations in EGFR, RAS family (KRAS, HRAS, and NRAS), PIK3CA, BRAF, and AKT1, using a highly sensitive single-base extension multiplex assay, SNaPshot. Out of 70 cases, EGFR pathway missense mutations were found in 13 (18.6%): RAS mutations in 10 (14.3%), EGFR in one (1.4%), and PIK3CA in 5 (7.1%). None of the cases showed an EGFR deletion by direct sequencing. Concurrent gene mutations were found in three cases (4.3%). EGFR pathway mutations were significantly associated with a shorter disease-free (p = 0.011) and overall survival (p = 0.049) and RAS mutations were as well; (p = 0.010) and (p = 0.024), respectively. The gene fusion status as determined by a FISH assay had no significant association with mutations of the genes involved in the EGFR pathway. In conclusion, EGFR pathway mutations, especially RAS mutations, may be frequent in SAdCC, and associated with a poor prognosis for the patient.

Postoperative hypoparathyroidism after total thyroidectomy for thyroid cancer

OBJECTIVES Postoperative hypoparathyroidism (HPT) is one of the most common complications in total thyroidectomy for thyroid carcinoma. Parathyroid glands (PTGs) are at risk of being damaged during total thyroidectomy and central neck dissection mainly due to inadvertent removal, interruption of the blood supply or hematoma formation. The purpose of this study was to evaluate the efficacy of our surgical procedure to preserve for parathyroid function retrospectively and to clarify the risk factors of HPT after total thyroidectomy for thyroid cancer. PATIENTS AND METHODS Sixty-five patients undergoing total thyroidectomy with central neck dissection for thyroid cancer were enrolled in this retrospective study. Cancers were diagnosed as stage I in 15 patients, stage II in 24 patients, stage III in 19 patients, and stage IV in 7 patients. Lateral neck dissection and upper mediastinal dissection were simultaneously performed in 47 patients and one patient, respectively. Parathyroid glands (PTGs) were preserved in situ in 34 patients. Among 31 patients in whom PTG could not be preserved in situ, two or more PTGs were autotransplanted in 9 patients and one PTG was autotransplanted in 18 patients. PTG was not autotransplanted in 4 patients, since it could not be identified during the surgery. RESULTS Postoperative transient HPT and permanent HPT were observed in 44 (68%) patients and in 12 (18%) patients, respectively. Among 34 patients in whom PTGs were preserved in situ, transient HPT and permanent HPT were observed in 17 (50%) patients and in 6 (2%) patients, respectively. Among 31 patients in whom PTG were not preserved in situ, postoperative permanent HPT was observed in all 4 patients without PTG autotransplantation, and 6 (33%) out of the 18 patients who had one PTG autotransplantation. On the other hand, none of the 9 patients who had two or more PTG autotransplantation at the time of thyroidectomy developed permanent HPT (P=0.04). The patients with large tumor (≥40mm) and/or gross extra glandular invasion had a significantly higher risk of permanent postoperative HPT compared with the patients without these pathological features (P<0.01). CONCLUSIONS Two or more PTG should be autotransplanted in case where PTG is not preserved in situ to prevent postoperative HPT after total thyroidectomy with central neck dissection, especially in cases of large tumor and/or gross extrathyroidal extension.

A case of nasopharyngeal clear cell carcinoma diagnosed by molecular analysis

Abstract Clear cell carcinoma (CCC) in the salivary gland is a rare malignant neoplasm and is hardly located in the nasopharynx. An 18-year-old female presented with a 3-year history of nasal congestion. Endoscopic examination revealed a reddish round-shaped mass with a smooth surface in the posterior wall of the nasopharynx. An en bloc resection of the tumor was performed by endoscopic surgery. Preliminary pathological diagnosis made by histopathological examination was mucoepidermoid carcinoma. However, FISH analysis for MAML2-split was negative but that for EWSR1-split was positive. In addition, EWSR1-ATF1 fusion transcript was detected in the RT-PCR analysis. The final pathological diagnosis of CCC was made on the basis of these findings. Since EWSR1-ATF1 fusion is not observed in other salivary gland tumors, identifications of this unique fusion gene by FISH and RT-PCR are useful tools to confirm the diagnosis of CCC.

Prognostic value of ALDH2 polymorphism for patients with oropharyngeal cancer in a Japanese population

Background Half of Japanese possess a polymorphism of aldehyde dehydrogenase 2(ALDH2), while few white individuals possess this mutation. The purpose of this study was to investigate the possibility of ALDH2 polymorphism as a prognostic factor for oropharyngeal cancer (OPC) among Japanese population. Methods We analyzed 82 Japanese patients with OPC treated between 2006 and 2011. The median observation period was 50 months. P16-staining and ALDH2 polymorphisms were investigated. To examine the frequencies of second primary pharyngeal and esophageal cancers (SPPEC),37 Japanese patients with OPC treated at Tokyo University Hospital were included for statistical analysis. Results Statistically significant differences were noted in OS among sex, age, N classification, and p16 (p = 0.045, 0.024, 0.020, 0.007, respectively). In addition, OS and DSS rates of the patients with heterozygous ALDH2 tended to be worse than those of the patients with homozygous ALDH2 (p = 0.21, 0.086, respectively). Of note, OS and DSS of the patients with p16-negative OPC and heterozygous ALDH2 was significant poorer than those of the patients with p16-positive OPC (p = 0.002, 0.006, respectively), while there was no significant difference in OS and DSS between patients with p16-positive OPC and patients with p16-negative OPC and homozygous ALDH2. Conclusions ALDH2 polymorphism might be a promising prognostic factor for Japanese patients with p16-negative OPC.

Hearing Dysfunction in Xpa-Deficient Mice

Xeroderma pigmentosum (XP) is a rare recessive heredity disease caused by DNA repair impairment characterized by photosensitivity and neurologic symptoms in half of the cases. There are eight subtypes of XP: XP-A–XP-G and XP variant. Among eight subtypes, XP complementation group A (XP-A) display the lowest DNA repair ability and the severest cutaneous and neurologic symptoms. While its pathogenesis of skin symptoms have been well-studied, that of neurological symptoms, including sensorineural hearing loss (SNHL) remains unknown. Basic studies have suggested that SNHL may be caused by inner ear damage, including damage to the spiral ganglion neurons and organ of Corti, and that the XP-A is associated with most severe form of SNHL in humans. Here, we report the occurrence of SNHL in Xpa-deficient mice. Xpa-deficient mice and wild-type mice underwent measurements for auditory brainstem response, and the results revealed that Xpa-deficient mice exhibited significantly greater (p < 0.01) ABR thresholds at 4, 8, and 16 kHz than the wild-type mice. Furthermore, the number of spiral ganglion neurons was reduced in Xpa-deficient mice compared with that in wild-type mice, indicating that hearing loss may be related to spiral ganglion neuron deficiency, consistent with the few reports published in human patients with XP. These results provide important insights into the pathogenesis of SNHL in patients with XP-A.