John D. Casler

Oropharyngeal Cancer: A Case for Single Modality Treatment With Transoral Laser Microsurgery

OBJECTIVE To demonstrate the role of transoral laser microsurgery (TLM) in the treatment of oropharyngeal cancer. DESIGN A 2-center retrospective case series analysis. SETTING Two tertiary care medical centers. PATIENTS The study population comprised 69 patients with previously untreated select T1 to T3, N0 to N2 squamous cell carcinoma of the oropharynx, of whom 44 (74%) had no indication for adjuvant RT and 25 (36%) had an indication for adjuvant RT to the neck alone but declined radiotherapy. The primary tumor sites were the tonsil (n = 28 [41%]), tongue base (n = 28 [41%]), pharyngeal wall (n = 8 [12%]), soft palate (n = 4 [6%]), and vallecula (n = 1 [1%]). INTERVENTIONS Transoral laser microsurgery in 69 patients, with neck dissection in 59 patients (83%). MAIN OUTCOME MEASURES Complications, local and regional control, overall and disease-specific survival, swallow function, and feeding tube dependence. RESULTS Over the mean follow-up period of 44 months, 66 of 69 patients had no disease recurrence at the primary site. The 5-year local control estimate was 94%. The mean duration of hospitalization was 3 days. There were no major complications relating to TLM. No patient required a permanent feeding or tracheostomy tube. For stage I, II, and III disease, the 5-year Kaplan-Meier estimates of locoregional control were 90%, 73%, and 70%, respectively. The 5-year overall survival estimate was 86%. CONCLUSIONS Transoral laser microsurgery alone with or without neck dissection is an effective approach for select T1 to T3, N0, or N1 oropharyngeal cancer. Low levels of morbidity, short treatment duration, and excellent disease control make it an attractive therapeutic strategy. The treatment option of endoscopic-assisted laser microsurgery should be discussed by the multidisciplinary team for patients presenting with tumors suitable for this approach.

Clinical and molecular features of Hürthle cell carcinoma of the thyroid

CONTEXT Hürthle cell cancer (HCC) of the thyroid remains the subject of controversy with respect to natural course, treatment, and follow-up. OBJECTIVE The objective of the study was to evaluate the clinical and molecular features associated with outcome in HCC. DESIGN The study was a review of 173 HCC cases treated at Mayo Clinic over 11 years with a median 5.8-year follow-up. RESULTS None of the patients with minimally invasive histology had persistent disease, clinical recurrence, or disease-related death. Male gender and TNM stage were independently associated with increased risk of clinical recurrence or death in widely invasive patients. The 5-year cumulative probability of clinical recurrence or death was higher in patients with TNM stage III-IV (females, 74%; males, 91%) compared with patients with TNM stage I-II (females, 0%; males, 17%). Pulmonary metastases were best identified by computed tomography, whereas radioactive iodine scans were positive in only two of 27 cases. Thyroglobulin was detectable in patients with clinical disease, with the notable exception of five patients with distant metastases. The common TERT C228T promoter mutation was detected in both widely invasive and minimally invasive tumors. TERT mRNA was below the limit of detection in all samples. CONCLUSION Widely invasive HCC with TNM stage III-IV is aggressive, with low probability of recurrence-free survival. Males have worse outcomes than females. Minimally invasive HCC appears to be considerably less aggressive. Radioactive iodine scan performs poorly in detecting distant disease. Although the TERT gene is mutated in HCC, the role of this mutation remains to be demonstrated.

Analysis of Postoperative Bleeding and Risk Factors in Transoral Surgery of the Oropharynx

IMPORTANCE With an increasing incidence of oropharyngeal carcinoma and prevalence of transoral surgical techniques, postoperative bleeding, with its associated risk factors, deserves evaluation. OBJECTIVE To classify and review postoropharyngectomy hemorrhage rates and associated risk factors. DESIGN, SETTING, AND PARTICIPANTS Single-institution, multicenter retrospective medical chart review analyzing surgical procedures in 906 patients treated with transoral surgery for oropharyngeal carcinoma at a tertiary care, academic referral center from 1994 to 2012. Tumor stage, previous treatment, resection method, and transcervical external carotid branch ligation were analyzed in relationship to postoperative hemorrhage rate, and severity. A novel classification system was created, grading bleeding episodes as minor, intermediate, major, or severe based on management method and related sequelae. RESULTS Postoperative bleeding occurred in 5.4% of patients (49 of 906) with 67.3% of these (33 of 49) requiring operative intervention. Severe bleeding episodes were very rare (1.1% of patients). Transcervical external carotid system vessel ligation was performed with the primary resection in 15.6% of patients with no overall difference in bleeding rate or severity of bleeding in patients who underwent ligation vs those who did not (P = .21 and P = .66, respectively). Vessel ligation was performed more frequently in patients with a higher T stage (P = .002). In previously treated patients, severity of bleeding was decreased if vessels were ligated (P > .05). Higher T-stage tumors had a higher bleeding rate (P = .02). Bleeding rates were similar between those treated with laser (5.6%) and robotic (5.9%) oropharyngectomy (P = .80); however, patients with significantly higher T-stage tumors were treated with laser vs robot techniques (P < .001). CONCLUSIONS AND RELEVANCE Transoral resection of oropharyngeal carcinoma is safe, and severe life-threatening hemorrhage is rare. Although transcervical vessel ligation did not result in an overall decrease in bleeding rate, there is a trend toward reduced postoropharyngectomy bleeding severity with ligation. We recommend ligation for higher T-stage tumors, primary tonsil tumors, and patients undergoing revision surgery.

Detailed Molecular Fingerprinting of Four New Anaplastic Thyroid Carcinoma Cell Lines and Their Use for Verification of RhoB as a Molecular Therapeutic Target

CONTEXT Anaplastic thyroid carcinoma (ATC) is a highly aggressive carcinoma in need of therapeutic options. One critical component of drug discovery is the availability of well-characterized cell lines for identification of molecular mechanisms related to tumor biology and drug responsiveness. Up to 42% of human thyroid cancer cell lines are redundant or not of correct tissue origin, and a comprehensive analysis is currently nonexistent. Mechanistically, RhoB has been identified as a novel molecular target for ATC therapy. OBJECTIVE The aim was to develop four ATC cell lines detailing genetic, molecular, and phenotypic characteristics and to test five classes of drugs on the cell lines to determine whether they inhibited cell proliferation in a RhoB-dependent fashion. DESIGN Four cell lines were derived from ATC tumors. Short tandem DNA repeat and mutational status of the originating tumors and cell lines were performed along with molecular and phenotypic characterizations. Compounds were tested for growth inhibition and ability to up-regulate RhoB. RESULTS Cell line authenticity was confirmed by DNA short tandem repeat analysis. Each proved unique regarding expression of thyroid markers, oncogene status, amplified and deleted genes, and proliferative growth rates. FTI-277, GGTI-286, lovastatin, romidepsin, and UCN-01 up-regulated RhoB and inhibited cell proliferation in a dose-responsive fashion with only romidepsin and FTI-277 being RhoB dependent. CONCLUSIONS Molecular descriptions of thyroid lines were matched to the originating tumors, setting a new standard for cell line characterization. Furthermore, suppressed RhoB is implicated as a molecular target for therapy against ATC because five classes of drugs up-regulate RhoB and inhibit growth dose-responsively.

RNA Sequencing Identifies Multiple Fusion Transcripts, Differentially Expressed Genes, and Reduced Expression of Immune Function Genes in BRAF (V600E) Mutant vs BRAF Wild-Type Papillary Thyroid Carcinoma

CONTEXT The BRAF V600E mutation (BRAF-MUT) confers an aggressive phenotype in papillary thyroid carcinoma, but unidentified additional genomic abnormalities may be required for full phenotypic expression. OBJECTIVE RNA sequencing (RNA-Seq) was performed to identify genes differentially expressed between BRAF-MUT and BRAF wild-type (BRAF-WT) tumors and to correlate changes to patient clinical status. DESIGN BRAF-MUT and BRAF-WT tumors were identified in patients with T1N0 and T2-3N1 tumors evaluated in a referral medical center. Gene expression levels were determined (RNA-Seq) and fusion transcripts were detected. Multiplexed capture/detection and digital counting of mRNA transcripts (nCounter, NanoString Technologies) validated RNA-Seq data for immune system-related genes. PATIENTS BRAF-MUT patients included nine women, three men; nine were TNM stage I and three were stage III. Three (25%) had tumor infiltrating lymphocytes. BRAF-WT included five women, three men; all were stage I, and five (62.5%) had tumor infiltrating lymphocytes. RESULTS RNA-Seq identified 560 of 13 085 genes differentially expressed between BRAF-MUT and BRAF-WT tumors. Approximately 10% of these genes were related to MetaCore immune function pathways; 51 were underexpressed in BRAF-MUT tumors, whereas 4 (HLAG, CXCL14, TIMP1, IL1RAP) were overexpressed. The four most differentially overexpressed immune genes in BRAF-WT tumors (IL1B; CCL19; CCL21; CXCR4) correlated with lymphocyte infiltration. nCounter confirmed the RNA-Seq expression level data. Eleven different high-confidence fusion transcripts were detected (four interchromosomal; seven intrachromosomal) in 13 of 20 tumors. All in-frame fusions were validated by RT-PCR. CONCLUSION BRAF-MUT papillary thyroid cancers have reduced expression of immune/inflammatory response genes compared with BRAF-WT tumors and correlate with lymphocyte infiltration. In contrast, HLA-G and CXCL14 are overexpressed in BRAF-MUT tumors. Sixty-five percent of tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of these newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-MUT and BRAF-WT tumors.

Sclerosing Epithelioid Fibrosarcoma: A Case Report

Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma. It is a mesenchymal neoplasm composed of round to oval cells dispersed in a nestlike or cordlike distribution on a highly collagenous tissue background and is now recognized as a distinct clinical entity. In this report we discuss the presentation, diagnosis, and treatment of SEF. We focus on the unique histologic and immunohistochemical properties of this lesion. It is essential for both the surgeon and the pathologist to be aware of SEF and include it in the differential diagnosis for atypical head and neck neoplasms. Sclerosing epithelioid fibrosarcoma is a rare neoplasm that is now listed among the low-grade neoplasms that may occur in the head and neck. However, its behavior tends to be typical of more aggressive lesions. An awareness of this characteristic of SEF is essential for clinicians and pathologists alike.

Predictors of accuracy in preoperative parathyroid adenoma localization using ultrasound and Tc-99 m-Sestamibi: A 4-quadrant analysis☆☆☆★

PURPOSE To compare the accuracy of preoperative parathyroid adenoma localization in patients with primary hyperparathyroidism (pHPT) due to a single adenoma using a detailed 4-quadrant analysis and to identify patient and tumor characteristics associated with accurate preoperative localization. MATERIALS AND METHODS Retrospective review of 203 patients who underwent parathyroidectomy for pHPT due to a single adenoma between 2008 and 2011. Results from preoperative ultrasound and Tc-99m-sestamibi were compared to operative findings to determine accuracy of localization studies. Associations between clinicopathologic features and accurate preoperative adenoma localization were evaluated. RESULTS Ultrasound was performed on 198 patients, sestamibi on 177 patients, and both on 172 patients. Accurate localization occurred significantly more often for ultrasound than sestamibi (63% vs. 41%, P<0.001). For ultrasound, accurate localization was found in patients with larger or heavier adenomas, those with adenomas located inferiorly, patients not having a reoperative procedure, and patients with higher post-operative serum calcium levels. For sestamibi, greater adenoma size or weight, adenomas located inferiorly, and patients with associated thyroid cancer on pathology were most predictive of accurate preoperative localization. CONCLUSIONS Our results provide evidence that ultrasound is more accurate in localizing parathyroid adenomas in patients with pHPT due to a single adenoma when compared to sestamibi scan using 4-quadrant location analysis and may be the preferred preoperative imaging modality in these patients. No significant preoperative patient factors were associated with accurate localization by ultrasound or sestamibi, but adenoma size, weight, and location in an inferior position were predictive of accurate preoperative localization.

Follicular Dendritic Cell Sarcoma Presenting As a Thyroid Mass

Case Report A 44-year-old white woman with a history of Hashimoto’s thyroiditis presented to her primary care physician for routine evaluation. A palpable right-sided thyroid nodule was noted. Ultrasound demonstrated heterogeneous enlargement of the thyroid with two 1 cm thyroid nodules (one hypoechoic, one isoechoic) in the lower pole of the right thyroid lobe. A 6-month follow-up ultrasound revealed a hypoechoic nodule measuring 2.7 1.7 2.2 cm (Fig 1A, gold arrow) with peripheral nodularity (Fig 1A, white arrowheads) and Doppler flow (Fig 1B)—all features of malignancy. Fine-needle aspiration suggested anaplastic thyroid carcinoma. The patient underwent a total thyroidectomy, central compartment dissection, and parathyroid reimplantation. Pathology revealed a 2.5 cm extranodal follicular dendritic cell sarcoma (FDCS) (Figs 2A and 2B, inset) in a background of a lymphocytic infiltrate. The tumor was described as high grade due to significant cytological atypia and nuclear pleomorphism. One intrathyroidal parathyroid gland was involved by tumor, as were three of 11 lymph nodes in the central compartment (Fig 2C). Surgical margins of the tumor were negative. Immunostains for CD21 (Fig 2D), CD23 (Fig 2E), vimentin, clusterin (Fig 2F), fascin, podoplanin, and CXCL13 were positive. No features of Castleman’s disease were seen within the tumor specimen or lymph nodes removed. Epstein-Barr virus (EBV) in situ hybridization was negative, as was calcitonin. Adjuvantly, our patient received parotidsparing intensity-modulated radiation therapy (IMRT) to the bilateral neck and tumor bed with 54 Gy. She did not receive adjuvant chemotherapy due to the lack of benefit in reported series. Because of the rarity of the tumor, lack of benefit with known systemic agents, and absence of genomic characterization in the literature, we analyzed the genomic profile of the tumor utilizing the Foundation One genomic analysis developed by the Broad Institute (Cambridge, MA). The assay uses next-generation sequencing to evaluate the status of 236 cancer-related genes.

MEN1 Mutations in Hürthle Cell (Oncocytic) Thyroid Carcinoma

CONTEXT AND OBJECTIVE Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation, and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of disease and thus opportunities for more effective clinical management. DESIGN AND PATIENTS Initially, two oncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing. Subsequently, 72 oncocytic thyroid carcinomas, one cell line, and five Hürthle cell adenomas were examined by targeted sequencing for the presence of mutations in the multiple endocrine neoplasia I (MEN1) gene. RESULTS Here we report the identification of MEN1 loss-of-function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma. Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these tumors. CONCLUSION Menin, a ubiquitously expressed nuclear protein, is a well-characterized tumor suppressor whose loss is the cause of MEN1 syndrome. Menin is involved in several major cellular pathways such as regulation of transcription, control of cell cycle, apoptosis, and DNA damage repair pathways. Mutations of this gene in a subset of Hürthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis.

Development of a Multidisciplinary, Multicampus Subspecialty Practice in Endocrine Cancers

OBJECTIVES Relative to more abundant neoplasms, endocrine cancers have been historically neglected, yet their incidence is increasing. We therefore sought to build interest in endocrine cancers, improve physician experience, and develop innovative approaches to treating patients with these neoplasms. METHODS Between 2005 and 2010, we developed a multidisciplinary Endocrine Malignancies Disease Oriented Group involving all 3 Mayo Clinic campuses (Rochester, Minnesota; Jacksonville, Florida; and Scottsdale, Arizona). In response to higher demand at the Rochester campus, we sought to develop a Subspecialty Tumor Group and an Endocrine Malignancies Tumor Clinic within the Division of Medical Oncology. RESULTS The intended groups were successfully formed. We experienced difficulty in integration of the Mayo Scottsdale campus resulting from local uncertainty as to whether patient volumes would be sufficient to sustain the effort at that campus and difficulty in developing enthusiasm among clinicians otherwise engaged in a busy clinical practice. But these obstacles were ultimately overcome. In addition, with respect to the newly formed medical oncology subspecialty endocrine malignancies group, appointment volumes quadrupled within the first year and increased 7 times within 2 years. The number of active therapeutic endocrine malignancies clinical trials also increased from 1 in 2005 to 5 in 2009, with all 3 Mayo campuses participating. CONCLUSIONS The development of subspecialty tumor groups for uncommon malignancies represents an effective approach to building experience, increasing patient volumes and referrals, and fostering development of increased therapeutic options and clinical trials for patients afflicted with otherwise historically neglected cancers.PURPOSE Relative to more abundant neoplasms, endocrine cancers have been historically neglected, yet their incidence is increasing. We therefore sought to build interest in endocrine cancers, improve physician experience, and develop innovative approaches to treating patients with these neoplasms. METHODS Between 2005 and 2010, we developed a multidisciplinary Endocrine Malignancies Disease Oriented Group involving all three Mayo Clinic campuses (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ). In response to higher demand at the Rochester campus, we sought to develop a Subspecialty Tumor Group and an Endocrine Malignancies Tumor Clinic within the Division of Medical Oncology. RESULTS The intended groups were successfully formed. We experienced difficulty in integration of the Mayo Scottsdale campus resulting from local uncertainty as to whether patient volumes would be sufficient to sustain the effort at that campus and difficulty in developing enthusiasm among clinicians otherwise engaged in a busy clinical practice. But these obstacles were ultimately overcome. In addition, with respect to the newly formed medical oncology subspecialty endocrine malignancies group, appointment volumes quadrupled within the first year and increased seven times within two years. The number of active therapeutic endocrine malignancies clinical trials also increased from one in 2005 to five in 2009, with all three Mayo campuses participating. CONCLUSION The development of subspecialty tumor groups for uncommon malignancies represents an effective approach to building experience, increasing patient volumes and referrals, and fostering development of increased therapeutic options and clinical trials for patients afflicted with otherwise historically neglected cancers.