Post-treatment surveillance of thyroid cancer.

An increased incidence of differentiated thyroid cancer (DTC) has resulted in an increased population of thyroid cancer survivors requiring ongoing disease surveillance. Our institution's risk-adapted surveillance strategy is based on a contemporary understanding of disease biology, guided by analysis of prognostic factors and balanced application of available surveillance modalities. The goal of this strategy is to detect recurrent disease early, identify patients who would benefit from further treatment and reduce over investigation of low-risk patients. This article describes our center's risk-stratified approach to the postoperative surveillance of patients with differentiated thyroid cancer with reference to the recent 2015 American Thyroid Association management guidelines.

Haemorrhage following transoral robotic surgery.

BACKGROUND: To report our experience of postoperative haemorrhage in patients following transoral robotic surgery (TORS). METHODS: Data were collected on patients having TORS. Postoperative haemorrhage within 30 days was graded using the Mayo Clinic grading system. RESULTS: Transoral robotic surgery operations were performed on 122 patients. There were 23 bleeding events classified as minor to severe following 19 operations (16%). Haemorrhage requiring a return to the operating room occurred after 7 operations (6%). The odds of an emergent haemorrhage were 5.19 times greater in patients who had a staged neck dissection after TORS (P = .05). The odds of a postoperative bleeding event were 2.6 times greater in patients receiving a larger resection (P = .107). There were no haemorrhage events in the 36 patients who received a synchronous neck dissection with transcervical ligation of the external carotid artery. CONCLUSIONS: Surgical intervention for TORS haemorrhage occurred in 6% patients. No haemorrhage occurred in patients who had ligation of the external carotid artery.

Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx.

OBJECTIVE: The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC. METHODS: Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases. RESULTS: A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort. CONCLUSIONS: Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

Outcomes for patients with papillary thyroid cancer who do not undergo prophylactic central neck dissection.

BACKGROUND: The role of prophylactic central neck dissection (CND) in the management of papillary thyroid cancer (PTC) is controversial. This report describes outcomes of an observational approach in patients without clinical evidence of nodal disease in PTC. METHODS: All patients who had surgery between 1986 and 2010 without CND for PTC were identified. All patients had careful clinical assessment of the central neck during preoperative and perioperative evaluation, with any suspicious nodal tissue excised for analysis. The cohort included patients in whom lymph nodes had been removed, but no patient had undergone a formal neck dissection. Recurrence-free survival (RFS), central neck RFS and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. RESULTS: Of 1798 patients, 397 (22.1 per cent) were men, 1088 (60.5 per cent) were aged 45 years or more, and 539 (30.0 per cent) had pT3 or pT4 disease. Some 742 patients (41.3 per cent) received adjuvant treatment with radioactive iodine. At a median follow-up of 46 months the 5-year DSS rate was 100 per cent. Five-year RFS and central neck RFS rates were 96.6 and 99.1 per cent respectively. CONCLUSION: Observation of the central neck is safe and should be recommended for all patients with PTC considered before and during surgery to be free of central neck metastasis.

Outcomes in patients with poorly differentiated thyroid carcinoma.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) accounts for only 1-15% of all thyroid cancers. Our objective is to report outcomes in a large series of patients with PDTC treated at a single tertiary care cancer center. METHODS: A total of 91 patients with primary PDTC were treated by initial surgery with or without adjuvant therapy at Memorial Sloan-Kettering Cancer Center from 1986 to 2009. Outcomes were calculated by the Kaplan-Meier method. Clinicopathological characteristics were compared for PDTC patients who died of disease to those who did not by the χ(2) test. Factors predictive of disease-specific survival (DSS) were calculated by univariate and multivariate analysis using the log rank and Cox proportional hazards method, respectively. RESULTS: With a median follow-up of 50 months, the 5-year overall survival and DSS were 62 and 66%, respectively. The 5-year locoregional and distant control were 81 and 59%, respectively. Of 27 disease-specific deaths, 23 (85%) were due to distant disease. Age ≥ 45 years, pathological tumor size >4 cm, extrathyroidal extension, higher pathological T stage, positive margins, and distant metastases (M1) were predictive of worse DSS on univariate analysis. Multivariate analysis showed that only pT4a stage and M1 were independent predictors of worse DSS. CONCLUSIONS: With appropriate surgery and adjuvant therapy, excellent locoregional control can be achieved in PDTC. Disease-specific deaths occurred due to distant metastases and rarely due to uncontrolled locoregional recurrence in this series.

Anaplastic thyroid carcinoma: a 25-year single-institution experience.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors accounting for 1-5 % of primary thyroid malignancies. In this retrospective review, we aim to evaluate the prognostic factors, treatment approaches, and outcomes of patients with ATC treated at a single institution. MATERIALS AND METHODS: We retrospectively identified 95 patients with ATC from an institutional database between 1985 and 2010. A total of 83 patients with sufficient records were included in this study. Patient, tumor, and treatment characteristics were recorded. Disease-specific survival (DSS) was determined by the Kaplan-Meier method, and factors predictive of outcome were determined by univariate and multivariate analysis. RESULTS: Of the 83 patients, 41 were male and 42 were female. The median age at presentation was 60 years (range 28-89 years) with a median survival of 8 months. The 1- and 2-year DSS were 33 and 23 %, respectively. On univariate analysis, age less than 60 years, clinically N0 neck, absence of clinical extrathyroidal extension (cETE), gross total resection, and multimodality treatment were statistically significant predictors of improved survival. On multivariate analysis, absence of cETE, multimodality therapy, and gross total resection were predictors of improved outcome. CONCLUSIONS: In patients with locoregional limited disease, multimodality treatment with gross total surgical resection and postoperative radiotherapy with or without chemotherapy offers the best local control and DSS.

Incidence and location of positive nonsentinel lymph nodes in head and neck melanoma.

BACKGROUND: The complex lymphatic drainage in the head and neck makes sentinel lymph node biopsy (SLNB) for melanomas in this region challenging. This study describes the incidence, and location of additional positive nonsentinel lymph nodes (NSLN) in patients with cutaneous head and neck melanoma following a positive SLNB. METHODS: A retrospective review was performed using a single institution prospective database. Patients with a primary melanoma in the head or neck with a positive cervical SLNB were identified. The lymphadenectomy specimen was divided intraoperatively into lymph node levels I-V, and NSLN status determined for each level. RESULTS: Of 387 patients with melanoma of the head and neck who underwent cervical SLNB, 54 had a positive SLN identified (14%). Thirty six patients (67%) underwent immediate completion lymph node dissection (CLND) of whom eight patients (22%) had a positive NSLN. The remaining 18 patients (33%) did not undergo CLND and were observed. Half of positive NSLNs (50%) were in the same lymph node level as the SLN and 33% were in an immediately adjacent level; only two patients were found to have NSLNs in non-adjacent levels. The only factor predictive of NSLN involvement was the size of the tumor deposit in the SLN>0.2 mm (p = 0.05). Superficial parotidectomy at CLND revealed metastatic melanoma only in patients with a positive parotid SLN. CONCLUSIONS: A positive NLSN was identified in 22% of patients undergoing CLND after a positive SLNB. The majority of positive NSLNs are found within or immediately adjacent to the nodal level containing the SLN.

Risk stratification in medullary thyroid cancer: moving beyond static anatomic staging.

OBJECTIVES: Much progress has been made over the last 10 years with regard to risk estimation in non-medullary differentiated thyroid cancer with risk of recurrence systems and response to therapy re-evaluation approaches being used to augment initial risk estimates obtained using standard anatomic staging systems. Furthermore, risk stratification is being increasingly viewed as an active, evolving, dynamic process that requires re-evaluation during follow-up rather than a single static risk estimate predicted by initial staging. As with differentiated thyroid cancer, multiple clinico-pathologic factors have been demonstrated to correlate with the risk of disease specific mortality, risk of death, likelihood of disease progression, likelihood of cure with initial therapy, and likelihood of cure with additional therapy in medullary thyroid cancer. MATERIALS AND METHODS: In this review, we re-examine the clinically important initial risk factors in medullary thyroid cancer and then re-evaluate how some of these risk factors can be used to alter risk estimates over time as they reflect the response to therapy and the clinical course of the disease. RESULTS AND CONCLUSIONS: We demonstrate that the same response to therapy nomenclature that we have proposed and validated in differentiated thyroid cancer (excellent response, biochemical incomplete response, structural incomplete response, indeterminant response) can be easily applied to medullary cancer and used to guide on-going clinical management.

Thyroid cancer: surgery for the primary tumor.

Surgery is the mainstay of therapy for most patients who present with thyroid cancer. The surgeon must select an appropriate procedure based upon pre operative factors such as tumor histology, extent of primary disease, the presence of regional or distant metastases, associated disease in the contralateral thyroid lobe and the potential for post operative adjuvant therapy. Preservation of the vital structures in the central neck, including the recurrent and superior laryngeal nerves and the parathyroid glands is critical as is the maintenance of absolute hemostasis. In this review article we describe the management of Well Differentiated Thyroid Cancer (WDTC) presenting as a solitary nodule, WDTC in a background of multinodular disease and the management of WDTC presenting as advanced local disease. We go onto discuss the impact that regional and distant metastases have on the choice of surgical approach. The focus of this article is WDTC, however the principles of management of the primary in medullary and anaplastic carcinoma are also discussed.

Diagnostic utility of freehand core-needle biopsy in head and neck masses.

OBJECTIVE: To review our experience with freehand core-needle biopsy in the assessment of unexplained head and neck masses. METHODS: A total of 770 patients with head and neck masses (referred over a 22-month period) were evaluated. A retrospective chart review was performed on 53 of those patients who underwent core-needle biopsy for an unexplained mass. RESULTS: Correct sampling of the target tissue was achieved in all 53 patients (100 per cent) using a freehand core-needle biopsy technique. The diagnostic accuracy for providing adequate tissue samples for histopathological diagnosis was 96 per cent; the test sensitivity was 92 per cent. Four patients (7 per cent) required open surgical biopsy prior to commencing definitive treatment. CONCLUSION: Out-patient freehand core-needle biopsy can be carried out safely on select patients with head and neck masses, and provides high quality histopathology specimens with high diagnostic utility.

The role of sentinel lymph node biopsy in the management of head and neck desmoplastic melanoma.

BACKGROUND: Desmoplastic melanoma (DM), a variant of spindle cell melanoma, has a higher propensity for local recurrence and a lower incidence of nodal metastasis. In this retrospective review, we evaluated the risk for regional nodal metastases and the need for sentinel lymph node biopsy (SLNB) in patients with head and neck DM. METHODS: We identified 103 patients with DM from an institutional database of patients with head and neck melanomas treated between 1985 and 2009. Forty-seven patients had their primary treatment at Memorial Sloan-Kettering Cancer Center, and 56 patients were treated for recurrent or metastatic disease. RESULTS: Of the 47 study patients, 27 were men and 20 were women with a median age of 71 years. All patients underwent wide excision, and 21 (44 %) underwent SLNB. None of the patients who underwent SLNB had positive nodes. The mean Breslow thickness for the 45 reported patients was 6.1 mm, with 84 % of tumors >2 mm in thickness and 55 % >4 mm. All known Clark thickness levels (n = 40) were IV or V. The overall survival was 73 %, with disease-specific survival of 84 %, local recurrence-free survival of 75 %, and neck recurrence-free survival of 97 % at 5 years. CONCLUSIONS: Although DM is diagnosed at higher Breslow thickness and Clark level, neck metastases are rare and prognosis is favorable compared to conventional melanoma. The low incidence of lymphovascular invasion, high frequency of histopathologically negative sentinel lymph nodes, and low neck recurrence rates indicate that staging of neck disease by SLNB is not necessary in patients with pure DM of the head and neck.

Spontaneous cervical lymphocoele: case reports and management decisions.

INTRODUCTION: Neck lumps in young adults are not uncommon, and most represent benign, reactive lymphadenopathy. Cystic swellings are less common. Spontaneous cervical lymphocoeles are very rare, and present as fluctuant, asymptomatic, cystic swellings in the neck in otherwise fit individuals. CASE REPORTS: We report two healthy young women who presented with spontaneous cervical lymphocoeles and who were treated successfully with surgical excision. The timing of surgical intervention was influenced in both cases by their imminent wedding celebrations. CONCLUSIONS: Whilst sclerotherapy has been advocated by some authors, we found it unhelpful; however, surgery provided definitive treatment.

Cervical extraskeletal Ewing's sarcoma: case report demonstrating radiological features and management.

BACKGROUND: Extraskeletal Ewing's sarcoma is a rare tumour of mesenchymal origin, which is histologically similar to primary osseous Ewing's sarcoma. The majority of cases have been reported in the lower limb and paravertebral region, with a few cases reported in the neck. METHODS: We report a patient with extraskeletal Ewing's sarcoma presenting with a right-sided neck mass, vocal fold palsy and T1 nerve root involvement. The detection of characteristic features on computed tomography and magnetic resonance imaging scans, in conjunction with histological analysis, was required to make the diagnosis. RESULTS: Radiological imaging demonstrated that the tumour was infiltrating through the neural exit foramina of the lower cervical nerve roots, with encasement of the vertebral artery. The patient was managed with combination chemotherapy for systemic control and irradiation for local control. CONCLUSION: Extraskeletal Ewing's sarcoma has a propensity to occur in a paravertebral location, being found rarely in the cervical region, and has a predilection to infiltrate through neural exit formina. Computed tomography and magnetic resonance imaging are helpful in the diagnosis of this rare tumour.

Cytotoxic effects of the oncolytic herpes simplex virus HSV1716 alone and in combination with cisplatin in head and neck squamous cell carcinoma.

CONCLUSIONS: HSV1716 alone and combined with cisplatin was efficacious in destroying head and neck squamous cell carcinoma (HNSCC) cells. Combination treatment with HSV1716 and cisplatin gave additive efficacy. These results indicate that HSV1716 in combination with cisplatin could be of therapeutic value in HNSCC and warrants further investigation. OBJECTIVES: HSV1716 is a replication competent herpes simplex virus which selectively replicates and lyses actively dividing cells but not normal or terminally differentiated cells. The objective of this study was to determine the efficacy of HSV1716 alone and in combination with cisplatin in HNSCC. MATERIALS AND METHODS: Three HNSCC cell lines were studied; UM-SCC 14C, UM-SCC 22A and UM-SCC 22B. The permissivity of HSV1716 in these cell lines was determined using multicycle growth experiments. In vitro, cytotoxicity of HSV1716 and cisplatin was determined using an MTS proliferation assay. Isobologram analysis was used to determine the interaction between HSV1716 and cisplatin combination treatment. RESULTS: The three HNSCC cell lines studied were permissive for HSV1716 replication. Cytotoxicity increased in a dose-dependent fashion in all three cell lines. Cisplatin was non-toxic to the virus. Isobologram analysis showed additive cytotoxicity when HSV1716 was combined with cisplatin in all three cell lines.

Replication and cytolysis of an E1B-attenuated adenovirus in drug-resistant ovarian tumour cells is associated with reduced apoptosis.

Therapeutic approaches which are effective in tumour cells resistant to conventional chemotherapy would be of value. An E1B 55 kDa-deleted adenovirus (ONYX-015) induces lysis in cells with mutant p53, although the specificity of these observations for different cell types is unclear. We have used a matched set of drug-resistant human ovarian tumour cell lines to examine the potential of ONYX-015 for preferential replication and lysis of drug-resistant ovarian tumour cells with documented alterations in p53 function. Marked preferential replication of ONYX-015 is observed after infection of mutant p53 transfectant and cisplatin-resistant derivatives, compared to the wild-type p53 expressing parental A2780 line. Infection causes increased cytopathic effects in vitro and inhibition of tumour growth in vivo of the drug-resistant derivatives, but not the parental line. In apparent contrast, increased apoptosis and reduced clonogenic survival is induced by ONYX-015 infection of the chemosensitive parental cell line. ONYX-015 induces increased pro-apoptotic BAX and reduced anti-apoptotic BCLX(L) in parental cells, but not in the resistant derivative A2780/cp70. We propose that induction of apoptosis is one factor which prevents ONYX-015 spread and cytolysis after infection of chemosensitive cells, while it is the failure to engage apoptosis in drug-resistant cells that allows preferential viral replication, spread and cytolysis.

Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer.

PURPOSE: To determine the safety, humoral immune response replication, and activity of multiple intratumoral injections of ONYX-015 (replication selective adenovirus) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: This phase II trial enrolled patients with SCCHN who had recurrence/relapse after prior conventional treatment. Patients received ONYX-015 at a dose of 2 x 10(11) particles via intratumoral injection for either 5 consecutive days (standard) or twice daily for 2 consecutive weeks (hyperfractionated) during a 21-day cycle. Patients were monitored for tumor response, toxicity, and antibody formation. RESULTS: Forty patients (30 standard and 10 hyperfractionated) received 533 injections of ONYX-015. Standard treatment resulted in 14% partial to complete regression, 41% stable disease, and 45% progressive disease rates. Hyperfractionated treatment resulted in 10% complete response, 62% stable disease, and 29% progressive disease rates. Treatment-related toxicity included mild to moderate fever (67% overall) and injection site pain (47% on the standard regimen, 80% on the hyperfractionated regimen). Detectable circulating ONYX-015 genome suggestive of intratumoral replication was identified in 41% of tested patients on days 5 and 6 of cycle 1; 9% of patients had evidence of viral replication 10 days after injection during cycle 1, and no patients had evidence of replication > or = 22 days after injection. CONCLUSION: ONYX-015 can be safely administered via intratumoral injection to patients with recurrent/refractory SCCHN. ONYX-015 viremia is transient. Evidence of modest antitumoral activity is suggested.

Insular carcinoma of thyroid presenting as cervical cord compression.

Insular carcinoma of thyroid is a very rare subtype of thyroid carcinoma which is characterized by its advanced stage at presentation and aggressive clinical course. We describe a case of insular carcinoma of the thyroid presenting in an unusual fashion with cervical cord compression at initial presentation. Cord compression is shown to be due to spinal metastases from vascular spread of the tumour and this typifies the high metastatic potential of this tumour subtype.

Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial.

ONYX-015 is an E1B-55kDa gene-deleted adenovirus engineered to selectively replicate in and lyse p53-deficient cancer cells. To evaluate the selectivity of ONYX-015 replication and cytopathic effects for the first time in humans, we carried out a Phase II clinical testing of intratumoral and peritumoral ONYX-015 injection in 37 patients with recurrent head and neck carcinoma. Patients received ONYX-015 at a daily dose of 1 x 10(10) plaque-forming units (pfu) via intratumoral injection for 5 days during week 1 of each 3-week cycle (n = 30; cohort A), or 1 x 10(10) pfu twice a day for 10 days during weeks 1 and 2 of each 3-week cycle. Posttreatment biopsies documented selective ONYX-015 presence and/or replication in the tumor tissue of 7 of 11 patients biopsied on days 5-14, but not in immediately adjacent normal tissue (0 of 11 patients; P = 0.01). Tissue destruction was also highly selective; significant tumor regression (>50%) occurred in 21% of evaluable patients, whereas no toxicity to injected normal peritumoral tissues was demonstrated. p53 mutant tumors were significantly more likely to undergo ONYX-015-induced necrosis (7 of 12) than were p53 wild-type tumors (0 of 7; P = 0.017). High neutralizing antibody titers did not prevent infection and/or replication within tumors. ONYX-015 is the first genetically engineered replication-competent virus to demonstrate selective intratumoral replication and necrosis in patients. This agent demonstrates the promise of replication-selective viruses as a novel therapeutic platform against cancer.

a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer.

ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.

Current role of gene therapy in head and neck cancer.

Our increasing knowledge of cancer molecular biology has led to the development of new genetic therapies for the treatment of cancer. Such therapies are advantageous in that they can selectively target tumour tissue leaving normal tissue relatively unaffected. In squamous cell cancer of the head and neck, such therapies may be beneficial in the treatment of loco-regional recurrence, minimal residual disease and in the treatment of distant metastatic disease. This article describes the principles of cancer gene therapy reviews some early clinical trials of gene therapy in head and neck cancer.