Digestive Reconstruction After Pharyngolaryngectomy with Total Esophagectomy.

BACKGROUND: Pharyngolaryngectomy with total esophagectomy (PLTE) is often indicated for patients with synchronous head and neck cancer and thoracic esophageal cancer or those with head and neck cancer extending to the upper mediastinum. A long conduit is required for the reconstruction, and the blood flow at the tip of the conduit is not always sufficient. Thus, reconstructive surgery after PLTE remains challenging, and optimal reconstruction methods have not been elucidated to date. METHODS: This analysis investigated 65 patients who underwent PLTE. The short-term outcomes among the procedures were compared to explore the optimal digestive reconstruction methods. RESULTS: We used a simple gastric conduit for 7 patients, a gastric conduit with microvascular anastomosis (MVA) for 10 patients, an elongated gastric conduit with an MVA for 20 patients, a gastric conduit combined with a free jejunum transfer (FJT) for 25 patients, and other procedures for 3 patients. Postoperatively, 17 (26.2%) of the patients experienced severe complications, classified as Clavien-Dindo grade 3b or higher, including graft failure for 3 patients (6.2%). Anastomotic leakage was found in six patients (9.2%), and all leakages occurred at the pharyngogastric anastomosis. The reoperation rate was 15.4% (n = 10), and three patients (4.6%) died of massive bleeding from major vessels. The patients who underwent simple gastric conduit more frequently had graft failure (P = 0.04), anastomotic leakage (P < 0.01), and reoperation (P = 0.04) than the patients treated with the other reconstructive methods. CONCLUSION: Additional procedures such as MVA, gastric tube elongation, and FJT contribute to improving the outcomes of reconstruction after PLTE.

[Total Glossolaryngectomy of an Advanced Oropharyngeal and Tongue Squamous-Cell Carcinoma: A 29-Case Series Study].

We report herein on 29 patients with advanced oropharyngeal and tongue squamous-cell carcinoma who underwent a total glossolaryngectomy at the Cancer Institute Hospital of the JFCR between July 2005 and June 2013. In this study, we tried to evaluate associations between several variables of the primary tumor and prognosis in these 29 patients. The cause-specific 5-year survival rate with the Kaplan-Meier method was 45% in all patients. Tumor recurrence occurred in 15 patients. Four patients had recurrence in the primary site, 11 patients in neck lymph nodes or in the lungs or bone. The multivariate analysis revealed that the number of neck lymph node metastases, age and alcohol drinking were poor prognostic markers for patients undergoing a total glossolaryngectomy. Cause-specific survival was compared between patients with salvage surgery and initial surgery using Kaplan-Meier survival curves with log-rank tests. There was no significant association with survival (log-rank test: p = 0.13). The overall local control rate was 69% in all patients. Regarding salvage surgery, 9 of 16 patients had no recurrence in the primary site or neck lymph nodes. The limitations of this study include the small number of patients especially regarding the prognosis study and may have included a selection bias regarding undergoing a total glossolaryngectomy.

Predictive Factors for Completion of TPF Induction Chemotherapy in Patients With Locally Advanced Head and Neck Cancer.

BACKGROUND: Induction therapy with docetaxel, cisplatin and fluorouracil (TPF) is a treatment option for locally advanced head and neck cancer (LAHNC), but it is not known which patients are appropriate for TPF. PATIENTS AND METHODS: We retrospectively reviewed the records of patients with LAHNC who underwent induction TPF, and evaluated factors predictive of the completion of TPF treatment (defined as ≥3 cycles administered). RESULTS: Of the total 93 enrolled patients, 73 (78.5%) achieved therapy completion. In a multivariate analysis, hypolaryngeal/ laryngeal primary tumor site was a negative predictive factor (hazard ratio(HR)=0.32, 95% confidence interval(CI)=0.11-0.96, p=0.041) and body mass index ≥22 kg/m2 was a positive predictive factor (hazard ratio=3.51, 95% confidence intervaI=1.04-11.83, p=0.043) of TPF completion. CONCLUSION: For patients with LAHNC, oropharyngeal primary tumor site and high body mass index can be used to predict TPF completion and may contribute to decisions on the indications for TPF in terms of safety and tolerability.

Incidence and risk factors of interstitial lung disease of patients with head and neck cancer treated with cetuximab.

BACKGROUND: Interstitial lung disease (ILD) is known as a potentially severe adverse event associated with epidermal growth factor receptor (EGFR)-targeted therapy. The incidence and risk factors of ILD in patients with head and neck squamous cancer (HNSCC) treated with cetuximab, an anti-EGFR monoclonal antibody, have not been established. METHODS: We retrospectively reviewed patients with HNSCC who received cetuximab from December 2012 to December 2016 at our institute and evaluated the incidence and risk factors of ILD. RESULTS: Of the 201 patients with HNSCC, ILD was observed in 9 patients (4.5%), 8 of whom had grade 3 or higher. High Krebs von den Lungen-6 (KL-6) and ≥50 pack-years of smoking were significantly predictive of associated with ILD (P = 0.00011 and 0.05, respectively). CONCLUSION: The incidence of ILD in patients with HNSCC treated with cetuximab was <5%, but most of the ILD cases were severe. High KL-6 and smoking histories might be predictive for ILD among patients with HNSCC.

Three cases of bilateral chylothorax developing after neck dissection.

Only 16 cases of bilateral chylothorax following neck dissection have been reported within 10 decades. In this paper, three cases of bilateral chylothorax which developed after neck dissection are reported. In all cases, conservative treatment resulted in resolution of the condition. Diagnosis may be delayed in those who are on total parenteral nutrition, and therefore particular attention should be paid to those patients. It may be difficult to treat cases of chylothorax that develop following neck dissection performed after radiotherapy.

Two Cases of Ectopic Hamartomatous Thymoma Masquerading as Sarcoma.

Ectopic hamartomatous thymoma (EHT) is an extremely rare benign tumor. EHTs are difficult to differentiate from sarcomas, especially synovial sarcomas. We encountered two cases of EHT that were referred from other hospitals because sarcoma was suspected. In these cases, fusion gene detection via polymerase chain reaction or fluorescence in situ hybridization was useful for differentiating EHT from synovial sarcoma. EHT requires accurate diagnosis before surgery to avoid excessive treatment. Both tumor location and the presence of fat inside the tumor are important imaging findings for EHT, and confirmation of spindle cells, epithelial cells, and mature adipose cells in the tumor is an important pathological finding. It is important to exclude synovial sarcoma from the differential diagnosis via fusion gene analysis.

Indwelling voice prosthesis insertion after total pharyngolaryngectomy with free jejunal reconstruction.

OBJECTIVES: Total pharyngolaryngectomy with free jejunal reconstruction is often performed in patients with hypopharyngeal carcinoma. However, postoperative speechlessness significantly decreases patient quality of life. We investigated whether Provox® insertion could preserve speech after total pharyngolaryngectomy with free jejunal reconstruction. STUDY DESIGN: Retrospective chart review. METHODS: A total of 130 cases of secondary Provox® insertions after total pharyngolaryngectomy with free jejunal reconstruction were analyzed. Communication outcomes were compared using the Head and Neck Cancer Understandability of Speech Subscale. Outcomes and complications associated with insertion site (jejunal insertion vs. esophageal insertion) and adjuvant irradiation therapy were also evaluated. RESULTS: Provox® insertion had favorable communication outcomes in 102 cases (78.4%). Neither the insertion site nor irradiation affected the communication outcome. Complications were observed in 20 cases (15.4%). Local infection was the most common complication. Free jejunal insertion, in which the resection range was enlarged, had a lower complication rate than did esophageal insertion, and its complication rate was unaffected by previous irradiation. For all patients, the hospitalization duration and duration of speechlessness were 13.4 days and 14.6 months, respectively. Patients receiving jejunal insertions had a significantly shorter hospitalization duration than did those receiving esophageal insertions. Unlike Provox®2, Provox®Vega significantly reduced the complication rate to zero. CONCLUSION: For jejunal inserson of a Provox® prosthetic, a sufficient margin can be maintained during total pharyngolaryngectomy and irradiation can be performed, and satisfactory communication outcomes were observed. Provox® insertion after total pharyngolaryngectomy with free jejunal reconstruction should be considered the standard therapy for voice restoration. LEVEL OF EVIDENCE: 4.

A comparison of weekly paclitaxel and cetuximab with the EXTREME regimen in the treatment of recurrent/metastatic squamous cell head and neck carcinoma.

BACKGROUND: The effectiveness of the combination chemotherapy of weekly paclitaxel and cetuximab has not yet been compared to that of the current standard regimen, EXTREME (combination of 5-fluorouracil, cisplatin and cetuximab). METHODS: We retrospectively reviewed the clinical records of R/M SCCHN patients who received cetuximab-containing chemotherapy as a first-line therapy; from these, patients receiving a weekly paclitaxel and cetuximab regimen (cohort A) and the EXTREME regimen (cohort B) were extracted. The responses, prognoses and adverse events of these two cohorts were evaluated. RESULTS: A total of 86 patients were included (cohort A, 49; cohort B, 36). Patients with histories of platinum-based chemotherapy were more frequently given the cohort A treatment. Though the response rates were similar in the two cohorts (45% in cohort A and 51% in cohort B; p=0.83), the progression-free survival (PFS) was significantly more favorable in cohort A by the log-rank test (6.0monthsvs 5.0months; p=0.027). In the Cox-regression hazard analyses, male gender (hazard ratio [HR]=2.1, p=0.010), older age (≥ 70 yo) (HR=5.0, p=0.018), PS 0 (HR=2.2, p=0.027), no history of platinum chemotherapy (HR=3.2, p=0.003) and the presence of a tracheostomy (HR=2.3, p=0.039) were favorable factors within cohort A. CONCLUSION: In selected R/M SCCHN patients, the combination of weekly paclitaxel and cetuximab could be the better treatment option than the EXTREME regimen.

Predictive factors of head and neck squamous cell carcinoma patient tolerance to high-dose cisplatin in concurrent chemoradiotherapy.

Although high-dose cisplatin is the standard regimen of concurrent chemoradiotherapy (CCRT) for locally advanced head and neck squamous cell carcinoma (HNSCC), varying levels of patient tolerance towards cisplatin have been reported, and the predictive factors of cisplatin tolerance remain to be elucidated. The present study retrospectively reviewed newly diagnosed HNSCC patients who received CCRT. Cisplatin (80 mg/m2) was administered every 3 weeks. The proportion of high-dose cisplatin-tolerant patients (cumulative cisplatin dose, ≥200 mg/m2) was determined, and the predictive factors of cisplatin tolerance were analyzed in a logistic regression analysis. Between June 2006 and March 2013, a total of 159 patients were treated with CCRT. The median follow-up time was 36.7 months. A total of 73 patients (46%) tolerated a cumulative cisplatin dose ≥200 mg/m2; male gender [odds ratio (OR), 25.00; P=0.005] and high body surface area (BSA) (>1.80 m2; OR, 2.21; P=0.032) were significantly predictive of high-dose cisplatin tolerance. The high-dose cisplatin-tolerant patients had a significantly higher complete response (CR) rate (82 vs. 67%, P=0.045); however, there were no significant between-group differences in the 3-year OS (79.5 vs. 81.2%, P=0.59) or PFS (70.4 vs. 44.6%, P=0.076) by cisplatin tolerance. In clinical practice, approximately one-half of the patients tolerated high-dose cisplatin in CCRT. Male gender and high BSA could be predictive of cisplatin tolerance.

Combination chemotherapy of carboplatin and paclitaxel for advanced/metastatic salivary gland carcinoma patients: differences in responses by different pathological diagnoses.

BACKGROUND: A standard chemotherapy for recurrent/metastatic salivary gland cancers has not been established. Combination chemotherapy of carboplatin and paclitaxel should be evaluated as a treatment option. METHODS: This study retrospectively reviewed salivary gland cancer patients who received combination chemotherapy of carboplatin and paclitaxel. The differences in objective responses and in the prognoses according to the different pathological diagnoses were evaluated. RESULTS: A total of 38 patients were enrolled in the study; of them, 18 had salivary duct carcinomas (SDCs), nine had adenoid cystic carcinomas (ACCs), and 11 had other pathological diagnoses. Objective responses were observed in 15 (39%) patients. The median progression-free survival (PFS) was 6.5 months, and the median overall survival (OS) was 26.5 months. ACC patients had relatively low response rates (9%), but there were no significant differences in PFS or OS compared to other sub-types. The treatment was well tolerated, with few adverse events. CONCLUSION: Salivary gland cancer patients showed a moderate clinical response to the combination chemotherapy of carboplatin and paclitaxel. The objective response rates differed according to the pathological diagnoses, but there were no significant differences in prognoses.

[Usefulness and limitations in ultrasonography for diagnosing neck lymph node metastases in patients with hypopharyngeal squamous cell carcinoma: comparison with pathological findings following neck dissection].

We evaluated the usefulness and limitations in ultrasonography (US) for diagnosing neck lymph node metastases in patients with hypopharyngeal cancer by comparing the results of preoperative US examinations with postoperative pathological findings following neck dissection. Seventy-five previously untreated patients with hypopharyngeal squamous cell carcinoma underwent a curative procedure that included neck dissection. Preoperatively, all patients were examined by palpation, computed tomography (CT), and US. Postoperatively, all dissected neck lymph nodes were submitted for pathological examination. Results of pre-and postoperative examinations were then compared. US accuracy for each lymph node was 93.9%, while sensitivity was 78.0%, since hypopharyngeal cancer metastasizes early and easily to the neck lymph nodes, and it is difficult to detect small, pathologically positive nodes. Nine of 75 cases showed latent neck recurrence, and two of these were underestimated by US. The major cause for neck recurrence was considered to be the high rate of metastases in such cases, rather than a reduced dissection field. It is not rare to find very small, pathologically positive lymph nodes that US cannot detect in hypopharyngeal cancer. Efforts must therefore be expanded to improve the accuracy of US diagnosis. Care must also be taken when selecting cases for no or limited neck dissection.

A Clinical Study of Pharyngolaryngectomy with Total Esophagectomy: Postoperative Complications, Countermeasures, and Prognoses.

OBJECTIVE: Patients with advanced hypopharyngeal or cervical esophageal cancer have a comparatively high risk of also developing thoracic esophageal cancer. Pharyngolaryngectomy with total esophagectomy is highly invasive, and few reports about it exist. We examined the postoperative complications and respective countermeasures and prognoses of patients who underwent pharyngolaryngectomy with total esophagectomy. STUDY DESIGN: Case series with chart review. SETTING: Department of Head and Neck Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Japan. SUBJECTS AND METHODS: We examined the postoperative complications and respective countermeasures and prognoses of 40 patients who underwent pharyngolaryngectomy with total esophagectomy in our hospital. RESULTS: Postoperative complications were observed in 23 patients (57.5%) and consisted of 8 groups: tracheal region necrosis in 5 patients; neck abscess formation/wound infection in 5; fistula in 4; tracheostomy suture leakage in 2; ileus in 2; lymphorrhea in 2; pulmonary complications in 2; and other complications, including hemothorax, tracheoinnominate artery fistula, temporary cardiac arrest due to intraoperative mediastinum operation, methicillin-resistant Staphylococcus aureus enteritis, and sepsis, in 1 patient each. A lethal complication-brachiocephalic vein hemorrhage due to tracheostomy suture leakage and hemorrhagic shock due to tracheoinnominate artery fistula-occurred in 2 (5%) patients. The crude 5-year survival rate was 48.6%. CONCLUSIONS: Serious postoperative complications were related to tracheostomaplasty. Although pharyngolaryngectomy with total esophagectomy is highly invasive, we believe that our outlined treatment method is the most appropriate for cases of advanced hypopharyngeal or cervical esophageal cancer that also requires concurrent surgery for esophageal cancer.

[Basic studies on mutation analysis of K-ras codon 12 by use of three-dimensional microarray system].

A next-generation DNA microarray system, FD10 has been developed. It is based around the PamChip, a custom-made microarray, which consists of a solid three-dimensional structure that facilitated the incorporation of probe molecules. We applied this microarray system on a detection of K-ras mutation at codon 12 in some cancer cell lines. The PCR products amplified by use of FITC labeled primers were applied onto probe-absorbed microarray. After hybridization, the signal was imaged by CCD camera and analyzed by the exclusive software. We confirmed the microarray results by PCR-SSCP and sequencing analyses. Ten, two and three out of 15 cell lines were homozygous for wild type allele, heterozygous for wild and mutant allele, and homozygous for mutant alleles, respectively. Signals hybridized with antisense probes were stronger than those with sense probes, without PSN1 cell line. The system had a good reproducibility. Essentially, the microarray results were consistent with PCR-SSCP and sequencing results. In conclusion, the FD10 microarray system was easy to operate and short to get results. It might be useful for a focused array applicable for specific purposes. The K-ras mutation detection system worked well and will be applied to clinical specimens soon.

[Squamous carcinoma of the posterior oropharyngeal wall].

We treated 9 patients with squamous cell carcinoma of the posterior oropharyngeal wall at the Cancer Institute Hospital, Tokyo. All were men averaging 64.1 years of age. One patient each was stage I, stage II or stage III, and 6 were stage IV. Cervical lymph node metastasis was seen in 6 at initial diagnosis. Retropharyngeal lymph nodes were involved in 4, while 5 had second primary cancer such as esophageal, gastric, head and neck cancer. Radical radiotherapy was done for 3 and surgery as initial treatment in 6. Five-year local control was 50% and 5-year disease-free survival was 22%. Total laryngectomy was done for 4 patients. Six died of oropharyngeal cancer and 1 of second primary cancer. Cancer of posterior pharyngeal wall is relatively rare and the prognosis is considered poorer than other types of oropharyngeal cancer for necessitating study to determine which modality may improve treatment results.

[Prophylactic neck dissection for submandibular gland cancer].

The indication and preferred dissection field for prophylactic neck dissection for submandibular gland cancer are controversial and have not been standardized. We reviewed 27 patients who underwent a definitive operation for previously untreated submandibular gland cancer. The 27 patients consisted of 13 patients with adenoid cystic carcinoma, 6 patients with mucoepidermoid carcinoma, 6 patients with adenocarcinoma, and 2 patients with squamous cell carcinoma. The diagnostic accuracies of malignancy and histology with fine needle aspiration cytology were 86% and 56%, respectively. In sixteen out of 21 cases without neck lymph node metastasis, a prophylactic neck dissection was performed and pathological neck lymph node metastases were detected in five cases. On the other hand, in five cases that did not receive a prophylactic neck dissection, latent neck lymph node metastasis was observed in 2 cases. In both cases of neck lymph node metastasis, pathological positive lymph nodes were observed in only level 2 or level 3. The rates of occult neck lymph node metastasis according to the T stage were 0% in T1, 33.3% in T2, 57.1% in T3 and 100% in T4. The rates of occult neck lymph node metastasis according to the histopathology were 46.2% in adenoid cystic carcinoma, 50% in mucoepidermoid carcinoma, 50% in adenocarcinoma, and 50% in squamous cell carcinoma. In conclusion, we believe that supraomyohoid neck dissection is suitable for N0 cases of submandibular gland cancer because of four reasons: 1) rate of occult neck lymph node metastasis in submandibular gland cancer is high, 2) pathological neck lymph node metastasis in N0 cases and latent neck lymph node metastasis were observed in level 2 and level 3, 3) the prognosis of cases with neck lymph node metastasis was poor, and 4) same skin incision can be used not only for the primary resection but also for the neck dissection.

Occult functioning vagal paraganglioma in the infrahyoid carotid sheath.

Paragangliomas are highly vascular tumors that arise from chief cells in extra-adrenal paraganglia of the autonomic nervous system. Vagal paragangliomas occur along the vagal nerve, usually located in the rostral portion of the vagus nerve in the vicinity of the gangliom nodosum. Actively functional vagal paragangliomas are rare. We report a patient with functioning vagal paraganglioma located in the infrahyoid carotid sheath. The patient had no history of hypertension and catecholamines were not measured before surgery. The findings of diagnostic imaging workup, including computed tomography, ultrasonography and magnetic resonance, were suggestive of paraganglioma. The blood pressure and pulse rates increased sharply intraoperatively during tumor manipulation, together with spikes in noradrenaline and dopamine. The tumor was removed with successful preservation of the vagus nerve trunk. The blood catecholamine levels returned to normal immediately after surgery. Head and neck surgeons should be aware of occult functioning paragangliomas and patients with such tumors should undergo full hormonal assessment.

A family of multiple endocrine neoplasia type 2A (MEN 2A) with Cys630Tyr RET germline mutation: report of a case.

Since the majority of multiple endocrine neoplasia type 2A (MEN 2A) patients have missense mutations at codon 634 and those with the Cys630 RET genotype mutations are extremely rare, limited clinical information is available about this rare type. We report here three members of one Japanese MEN 2A family with the Cys630Tyr genotype. A 67-year-old woman presented a firm thyroid nodule, and preoperative examination revealed medullary thyroid carcinoma with primary hyperparthyoidism and no pheochromocytoma. At surgery, bilateral medullary thyroid carcinomas and parathyroid adenoma were found. No lymph node metastasis was identified. Computed tomography scans and laboratory examination of blood have shown no evidence of tumor recurrence and no abnormality of parathyroid function during the 4 years after surgery. A 40-year-old man, the proband's son, was shown to have the same RET mutation, underwent total thyroidectomy prophylactically, and only microscopic foci of medullary thyroid carcinoma were found. A 10-year-old boy, the proband's grandson also having the same RET mutation, showed normal basal serum calcitonin level and has been followed up conservatively. To our knowledge, 18 patients of 6 families with the Cys630 mutations have been reported so far. This is only the second reported case with primary hyperparathyroidism. RET 630 mutations might be associated with lower penetrance of primary hyperparthyoidism and pheochromocytoma.

Treatment results for 84 patients with base of tongue cancer.

CONCLUSIONS: For T2 tumors, surgery was indicated if functional preservation was possible. For T3/T4 tumors, the rate of primary disease control was not high and surgery frequently involved total laryngectomy. Points that surgeons must heed when performing such surgery were delineated. OBJECTIVES: Because tumors originating from the base of the tongue are rare, few large-scale studies of such tumors have been performed. We reviewed treatments and outcomes at our department to establish effective future therapeutic plans. PATIENTS AND METHODS: From 1971 to 2000, 84 patients with previously untreated and resectable squamous cell carcinoma of the base of the tongue were treated at the Head and Neck Department of the Cancer Institute Hospital, Tokyo. Treatment selection and results were investigated. RESULTS: The main treatment options were radiotherapy for primary lesions < or = T2 and surgery for primary lesions > or = T3. Overall disease-specific 5-year cumulative survival rate was 59.8%, but there was no significant difference in survival rate at each stage between the two treatments. Among patients who died of the primary disease, the area that was most difficult to control was the superior margin of the lateral wall of the oropharynx (n=7). The incidence of contralateral or retropharyngeal lymph node metastasis was low if tumors neither crossed the midline nor infiltrated the lateral wall. While total laryngectomy was performed on 48 patients, the larynx was operatively preserved in 5 T3 patients and one T4 patient.

Three-dimensional microarray compared with PCR-single-strand conformation polymorphism analysis/DNA sequencing for mutation analysis of K-ras codons 12 and 13.

BACKGROUND: We developed a rapid, precise, and accurate microarray-based method that uses a three-dimensional platform for detection of mutations. METHODS: We used the PamChip microarray to detect mutations in codons 12 and 13 of K-ras in 15 cell lines and 81 gastric or colorectal cancer tissues. Fluorescein isothiocyanate-labeled PCR products were analyzed with the microarray. We confirmed the microarray results with PCR-single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. RESULTS: We could correctly identify wild-type, heterozygous, and homozygous mutant genotypes with the PamChip microarray in <3.5 h. The array data were consistent with those of PCR-SSCP analysis and DNA sequencing. All 15 cell lines and 80 of 81 clinical cancer specimens (98.8%; 95% confidence interval, 96.4-100%) were genotyped accurately with the microarray, a rate better than that of direct DNA sequencing (38.9%) or SSCP (93.8%). Only one clinical specimen was misdiagnosed as homozygous for the wild-type allele. Densitometric analysis of SSCP bands indicated that the content of the mutant allele in the specimen was approximately 16%. The PamChip microarray could detect mutant alleles representing more than 25% of the SSCP band proportions. Therefore, the limit for detection of mutant alleles by the PamChip microarray was estimated to be 16-25% of the total DNA. CONCLUSIONS: The PamChip microarray is a novel three-dimensional microarray system and can be used to analyze K-ras mutations quickly and accurately. The mutation detection rate was nearly 100% and was similar to that of PCR-SSCP together with sequencing analysis, but the microarray analysis was faster and easier.