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Primary squamous cell carcinoma (SqCC) of the thyroid gland is an extremely rare, highly aggressive malignancy associated with locally advanced disease and frequent metastases to regional lymph nodes and distant sites. There are no standardized guidelines for treating primary thyroid SqCC because of its rarity, but some investigators have recommended staging and treating it as a variant of anaplastic thyroid carcinoma. Prognosis, however, remains poor with minimal response to treatment and an estimated median survival of 6 to 14 months. We report a case of primary SqCC of the thyroid that was successfully treated with aggressive locoregional resection followed by concurrent radical dose radiotherapy and cisplatin-based chemotherapy. The patient remains free of disease more than 4 years after surgery and adjuvant chemoradiation. Because of potential prognostic and management implications, it is crucial to make an accurate pathologic diagnosis of primary SqCC of the thyroid and distinguish it from metastatic squamous carcinoma and other primary thyroid malignancies with squamous features. A thorough clinicopathologic diagnostic workup including immunohistochemistry, computed tomography scan, and endoscopy is mandatory. In this case, treatment similar to the standard management used for patients with locally advanced mucosal head and neck squamous cancer led to a successful outcome.

Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab—an antibody against the epidermal growth factor receptor—can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.

Squamous cell carcinoma (SCC) of the orbit is almost uniformly the result of local invasion from a cutaneous primary, extension by perineural invasion, or the result of metastasis. This is owed to the lack of native squamous epithelium in the orbit. After review of the literature, to date, only 6 reports of 8 patients with primary orbital SCC exist. Of those cases, only 2 reported non-apical orbital SCC. There are 2 reports of orbital SCC after retina surgery with proposed transplanted conjunctival epithelium and subsequent malignant transformation of a conjunctival cyst. The initial signs and symptoms can be vague and lead to delay in diagnosis. We present a case of primary orbital SCC and discuss the workup, imaging, and multidisciplinary management of this rare condition.

IMPORTANCE: Late toxic effects are common after definitive radiotherapy and chemoradiotherapy for oropharynx cancer and are considered a significant contributor to decreased quality of life for survivors. The incidence of severe late toxic effects may be reduced by modern narrow-margin image-guided intensity-modulated radiotherapy (IG-IMRT), current supportive care improvements, and the changing epidemiology of oropharynx cancer. OBJECTIVE: Assess the incidence of severe late toxic effects after modern definitive non-operative treatment for oropharynx cancer. DESIGN, SETTING, AND PARTICIPANTS: For this single-institution retrospective review, 156 patients with stage I-IVB squamous cell carcinoma of the oropharynx treated between April 2009 and February 2015 at a tertiary-referral academic multidisciplinary head and neck practice were recruited. INTERVENTIONS: Definitive narrow-margin IG-IMRT to a dose of 66 Gy (to convert milligray to rad, multiply by 0.1) or higher with or without concurrent cisplatin. MAIN OUTCOMES AND MEASURES: The primary outcome was the prospectively collected 2-year cumulative incidence of severe late toxic effects (Common Terminology Criteria for Adverse Events grade 3 or higher) occurring 3 months or more after radiotherapy. Toxic effect end points investigated included esophageal stricture requiring dilation, aspiration pneumonia hospitalization, vocal dysfunction, delayed feeding tube insertions, and osteoradionecrosis. Feeding tube dependence at 1 year was also considered a severe late toxic effect. Secondary outcomes collected include physician-reported grade 2 or higher neck fibrosis and xerostomia. The competing risks of recurrence and death were accounted for using the Gray method. RESULTS: One-hundred fifty-six patients (median [range] age, 58 [37-96] years) were identified; 130 patients (83%) were HPV positive. Concurrent cisplatin was delivered in 131 patients (84%) and 5 patients (3%) underwent an adjuvant neck dissection. The median (range) follow-up for survivors was 22 (4-73) months from diagnosis. The projected 2-year locoregional control was 93% (95% CI, 88.4%-97.6%) and overall survival was 88% (95% CI, 82.2%-94.0%). Thirty-eight patients (23%) required a feeding tube during treatment. The cumulative incidence of severe late toxic effects adjusted for competing risks at 2-year posttreatment was 2.3% (95% CI, 0%-5.6%). One patient required free-flap reconstruction for grade 3 osteoradionecrosis at 47 months. At 1 year, 2 patients (1%) experienced grade 2 neck fibrosis and 38 patients (23%) experienced grade 2 xerostomia. CONCLUSIONS AND RELEVANCE: These results suggest that severe late toxic effects after modern definitive IG-IMRT, with or without cisplatin, for oropharynx cancer is likely uncommon. The importance of late toxic effect reduction in current and future investigational strategies, including clinical trials, should be considered.

IMPORTANCE: Nonsurgical treatment of advanced supraglottic laryngeal cancer is widely used as part of a larynx preservation protocol. However, recent studies have suggested that nonsurgical treatment may be associated with inferior survival. Furthermore, it is not clear whether preservation of the larynx provides superior voice or swallowing function in the long term. OBJECTIVE: To test the hypothesis that surgical treatment of advanced-stage squamous cell carcinoma of the supraglottic larynx is associated with superior overall survival (OS), freedom from recurrence (FFR), and noninferior voice and swallowing function. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of patients treated for stage III or IV squamous cell carcinoma of the supraglottic larynx between January 1990 and June 2013 at a tertiary referral center: 97 patients underwent surgical treatment and 138, nonsurgical treatment. Exclusion criteria included prior definitive treatment for laryngeal cancer or evidence of distant metastatic disease at presentation. The median follow-up for all 235 patients was 63 months. INTERVENTIONS: Surgical or nonsurgical therapy. MAIN OUTCOMES AND MEASURES: Freedom from recurrence (FFR), OS, larynx preservation, voice graded from 1 to 5, and swallowing graded from 1 to 6 using our voice and swallowing function scales. RESULTS: Surgical treatment was associated with superior FFR (5-year FFR: 75% vs 55%; P = .006) but not OS (5-year OS: 52% vs 52%; P = .61). The larynx was preserved in 83% of patients in the nonsurgical group vs 42% of patients in the surgical group (P < .001). Voice function was superior in the nonsurgical group at all time points through 5 years after treatment (mean voice score, 3.8 vs 2.6; P < .001). Swallowing function was comparable between surgical and nonsurgical groups. Multivariable analysis revealed that advanced age (hazard ratio [HR], 1.43 per 10-year increment; 95% CI, 1.19-1.72) and clinical N stage (HR, 1.17 per 1-level increment; 95% CI, 1.05-1.30) were associated with worse OS, while treatment with chemotherapy was associated with superior OS (HR, 0.61; 95% CI, 0.41-0.92). CONCLUSIONS AND RELEVANCE: Compared with surgical treatment, nonsurgical treatment as part of a larynx preservation protocol is associated with a higher likelihood of recurrence but has similar OS and should continue to be viewed as a viable alternative for the treatment of advanced supraglottic laryngeal cancer.

IMPORTANCE: Important differences exist in the pattern and timing of distant metastases between human papillomavirus–initiated (HPV+) and HPV− oropharyngeal squamous cell carcinoma (OPSCC). However, our understanding of the natural history of distant metastases in HPV+ OPSCC and its implications for surveillance is limited. OBJECTIVE: To investigate the rate, pattern, and timing of distant metastases in advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective review, we identified 291 patients with pathologically diagnosed stages III to IVB OPSCC and known HPV status from a tumor registry at the Cleveland Clinic. Patients were treated from January 1, 1996, through December 31, 2013. Details of treatment failure and the natural history of the disease were retrieved from the electronic medical records. INTERVENTIONS: All patients were treated with definitive concomitant chemoradiotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate and timing of distant metastases. Secondary outcomes included the pattern of distant failure and survival after distant metastases. RESULTS: Thirty-seven patients developed distant metastatic disease after definitive treatment, including 28 of 252 patients with HPV+ disease and 9 of 39 patients with HPV− disease. The 3-year projected distant control rate was higher in the HPV+ group (88% vs 74%; P = .01). The median time to develop distant metastases was also longer after the completion of treatment for HPV+ disease compared with HPV− disease (16.4 vs 7.2 months; P = .008). We detected a trend in patients with HPV+ disease for more distant metastatic sites involved than in those with HPV− disease (2.04 vs 1.33 sites; P = .09). Although the lung was the most common distant site involved in HPV+ and HPV− disease (HPV+ group, 23 of 28 patients [82%]; HPV− group, 7 of 9 patients [78%]), the HPV+ group had metastases to several subsets atypical for head and neck squamous cell carcinoma, including the brain, kidney, skin, skeletal muscle, and axillary lymph nodes in 2 patients each and in the intra-abdominal lymph nodes in 3 patients. The rate of 3-year overall survival was higher in the HPV+ group (89.9% vs 62.0%; P < .001), as was the median survival after the occurrence of distant metastases regardless of additional treatment (25.6 vs 11.1 months; P < .001). CONCLUSIONS AND RELEVANCE: This retrospective review suggests that distant metastases in patients with HPV+ OPSCC occurs significantly later after completion of chemoradiotherapy than in patients with HPV− disease. Human papillomavirus–initiated OPSCC also appears to involve a greater number of subsites and metastatic sites infrequently seen in head and neck squamous cell carcinoma. Distant metastatic disease in HPV+ OPSCC has unique characteristics and a natural history that may require alternative surveillance strategies.

Salivary gland malignancies are a rare and heterogeneous group of tumors with considerable variability in their natural history. Historically they have been treated with surgery and radiation therapy. It is only recently that there has been any growth in our understanding of these diseases and their management, and this progress will be reviewed.

Several different approaches have been tested in an effort to integrate chemotherapy into definitive non-operative management of squamous cell head and neck cancer. In phase III randomized trials and in meta-analyses, the concomitant use of chemotherapy and radiation has proven to be the most consistently successful, and to produce both locoregional control and survival benefits, when compared to radiation therapy alone. Large, multi-institutional and cooperative group studies have now established high-dose single-agent cisplatin and concurrent radiation therapy as the standard of care for patients with advanced nasopharynx cancer, for patients with unresectable head and neck tumors, and as a postoperative adjuvant for patients with high-risk pathologic features. This same treatment regimen also has been demonstrated to be the most effective multi-modality treatment strategy for larynx preservation. Future investigation will focus on optimizing the concomitant chemotherapy and radiotherapy schedules used, integrating targeted agents into these established treatment schedules, addressing the problem of distant metastases, minimizing both acute and late toxicities, and identifying the most appropriate patient populations for this kind of aggressive treatment.

OBJECTIVE To report our experience using the neck examination, computed tomography (CT), and positron emission tomography (PET) to clinically evaluate node-positive patients with head and neck squamous cell cancer for residual neck node disease after definitive chemoradiotherapy. DESIGN Retrospective review of all Cleveland Clinic patients with head and neck squamous cell cancer and N2 or N3 neck node involvement at presentation who were treated with definitive concurrent chemoradiotherapy and who underwent clinical restaging after treatment using the neck examination, CT, and PET. SETTING Tertiary care referral institution. PATIENTS Forty-eight patients with 72 positive necks at diagnosis were followed up for a median of 20 months. MAIN OUTCOME MEASURES Palpable nodes on examination, nodes larger than 1 cm, nodes with central necrosis on CT, or any hypermetabolic lymph nodes on PET were considered clinical evidence of residual nodal disease. The true rate of pathologic involvement was determined by histologic examination after planned neck dissection or if regional recurrence developed. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for all 3 clinical assessment tools. RESULTS Planned neck dissection was performed in 33 necks and was positive for residual neck node disease in 5 necks. A delayed neck dissection was performed in 5 necks and was positive in 3 necks. The positive predictive value was low for all 3 clinical assessment tools. The addition of PET did not significantly improve the negative predictive value or positive predictive value of CT and the clinical examination. CONCLUSIONS Residual neck node disease after definitive chemoradiotherapy was infrequent and was not well predicted by PET. A positive PET finding in this setting is of little utility. Although a negative PET finding was highly predictive for control of neck disease after chemoradiotherapy, it added little to the clinical neck examination and CT.Arch Otolaryngol Head Neck Surg. 2007;133:435-440 --

To evaluate the effects of induction concurrent chemoradiotherapy (cCRT) on pulmonary function and postoperative acute respiratory complications (PARCs).

Squamous cell head and neck cancer is a relatively uncommon malignancy in North America. Nonetheless, it has been of considerable interest to medical oncologists because of its remarkable sensitivity to systemic chemotherapy. Even in patients with relapsed or metastatic disease, meaningful tumour shrinkage can be achieved with systemic therapy. This has led to the performance of carefully conducted clinical trials exploring the role of systemic chemotherapy, not only in the palliative setting, but as part of definitive multi-modality treatment. Chemotherapy has been used as the initial (or induction) treatment, as an adjuvant treatment after definitive surgery and/or radiation, and concurrent with both definitive and adjuvant radiation therapy. Evidence-based conclusions have been drawn from these clinical trials and have led to significant changes in the current standards of care for this disease. In this article, the available data supporting the use of systemic chemotherapy as palliative treatment, and as part of the definitive management for this disease will be reviewed.

The role of neck dissection (ND) after definitive chemoradiotherapy for squamous cell head and neck cancer is incompletely defined. We retrospectively reviewed 109 patients with N2–N3 disease treated with chemoradiotherapy to identify predictors of a clinical complete response in the neck (CCR-neck), pathologic complete response after ND (PCR-neck), and regional failure. All patients were given 4-day continuous infusions of 5-fluorouracil (1000 mg/m²/d) and cisplatin (20 mg/m²/d) during the first and fourth weeks of either once daily (n = 68) or twice daily (n = 41) radiation therapy. ND was considered for all patients after completion of chemoradiotherapy and was performed in 32 of the 65 patients achieving a CCR-neck after chemoradiotherapy and in all 44 patients with residual clinical evidence of neck disease. CCR-neck, PCR-neck, and regional failure were then correlated with potential predictors, including T, N, largest lymph node size (<3 cm, ≥3 cm), primary tumor site, and radiation fractionation schedule. Achievement of a CCR-neck was predicted by N, N2 vs N3 (53 of 80 vs 12 of 29, p = .019) and by largest lymph node size, <3 cm vs ≥3 cm (19 of 25 vs 46 of 84, p = .06). Achievement of a PCR-neck could not be predicted by any clinical parameter. Regional failure occurred both in patients undergoing ND and those not dissected (5 of 76 vs 4 of 33, p = .33) and proved more likely only in the ND patients with residual positive pathology compared with those achieving a PCR-neck (5 of 25 vs 0 of 51, p < .001). Primary site was not a useful predictor of CCR-neck, PCR-neck, or regional failure. Most importantly, CCR-neck (vs <CCR-neck) did not predict either a PCR-neck (24 of 32 vs 27 of 44, p = .21) or regional failure (5 of 65 vs 4 of 44, p = .80). After chemoradiotherapy, clinical parameters do not identify those patients with residual neck node disease or those at risk for regional failure, suggesting that ND be considered for all N2–N3 patients. © 2003 Wiley Periodicals, Inc. Head and Neck 25: 791–798, 2003

There are over 200,000 cases of brain metastases (BrM) every year, but very few are from esophageal cancer primaries. In order to determine predictors for outcome of these patients, the authors conducted a retrospective review of twenty-seven patients with BrM from esophageal carcinoma diagnosed at the Cleveland Clinic Foundation between 1991 and 2001. For the entire cohort, median follow-up and median survival was 3.6 months and 3.6 months, respectively. On univariate analysis, patients with Karnofsky Performance Status (KPS) ≥ 70, low recursive partitioning analysis score, single BrM, no systemic disease, and aggressive treatment [surgery, stereotactic radiosurgery (SRS) + whole brain radiation (WBRT), SRS + surgery + WBRT, surgery + WBRT)] had a significantly improved survival. In a multivariate model, patients with higher KPS and aggressive treatment had improved survival. The 1-year survival for the WBRT alone group and the aggressive treatment group was 6%, and 36% respectively. We conclude that based on the data presented here, patients with BrM from esophageal cancer have poor outcome. Aggressive treatment and favorable KPS are associated with longer survival for selected patients. We recommend esophageal cancer patients with BrM be enrolled in clinical trials to better delineate the role of treatment and potentially improve results.

Objective:Cancer staging is dynamic, reflecting accrual of knowledge and experience in treatment. The objectives of this study were to assess current esophageal cancer staging and to determine whether refinements of classification and stage grouping are necessary. Methods:From 1983 through November 2000, 480 patients underwent esophagectomy without induction therapy. Depth of tumor invasion (T), regional lymph node status (N), distant status (M), number of metastatic regional lymph nodes, and histopathologic type and grade were subjected to survival-tree analysis, multivariable Cox and hazard function analysis, and residual misclassification risk analysis. Results:Inhomogenity of survival was found within and lack of distinction was found between current American Joint Committee on Cancer staging groups, supporting the need for refinement. T1 and N1 were redefined on the basis of survival differences. T1a is intramucosal cancer, T1b is submucosal cancer (P= .008), N1 is 1 or 2 metastatic regional lymph nodes, and N2 is 3 or more metastatic regional lymph nodes (P= .01). Current subclassification of M1 is not warranted (P= .9). Histopathologic type (P= .17) and grade (P= .3) minimally refined staging. Reassignment of staging groups constrained by American Joint Committee on Cancer definitions of stages 0 and IV produced less monotonic, distinctive, and homogeneous survival than free assignment of staging groups. Conclusions:Current American Joint Committee on Cancer staging of esophageal cancer is inadequate. Refinement requires redefinition of T1, N1, and M1 classifications. Stage grouping within the constraints of American Joint Committee on Cancer definitions produces less accurate prognosis than free assignment based on survival data.