Louise J. Clark

Squamous cell carcinoma of the thyroid gland: primary or secondary disease?

OBJECTIVE To review the aetiopathogenesis, clinical characteristics, immunohistochemical profile, prognosis and treatment options for primary thyroid squamous cell carcinoma, and to compare it with squamous cell carcinoma metastatic to the thyroid, thus providing the reader with a framework for differentiating primary and secondary disease. METHOD Review of English language literature from the past 25 years. SEARCH STRATEGY A search of the Medline, Embase and Cochrane databases (April 1984 to April 2009) was undertaken to enable a comprehensive review. RESULTS After applying strict criteria for the diagnosis of primary thyroid squamous cell carcinoma, 28 articles were identified reporting 84 cases. When reviewing secondary thyroid squamous cell carcinoma, we only analysed cases of squamous cell carcinoma metastatic to the thyroid gland, and found 28 articles reporting 78 cases. CONCLUSION It is possible to differentiate between primary and secondary thyroid squamous cell carcinoma, on the basis of combined evidence from clinical examination and endoscopic, pathological and radiological evaluation. Such differentiation is important, as the prognosis for primary squamous cell carcinoma is uniformly poor irrespective of treatment, and the most suitable option may be supportive therapy. Treatment for secondary squamous cell carcinoma of the thyroid varies with the site and extent of spread of the primary tumour.

Telomerase inhibition and the future management of head-and-neck cancer

Telomeres are tandem repeats of DNA associated with specific proteins. These structures cap eukaryotic chromosomes and maintain the integrity of the chromosome ends. In the germline, telomeres are maintained by the enzyme telomerase, but in normal somatic cells the enzymes activity is low or undetectable. Human tumours, including squamous-cell carcinoma of the head and neck (SCCHN), need telomerase to maintain telomere function; inhibition of the enzyme can lead to apoptosis. Furthermore, because most tumour cells have very short telomeres, they are more likely to succumb to telomerase inhibition than normal cells. Telomerase is therefore a potential selective anticancer target. The telomere is also involved in the repair of DNA double strand breaks, and telomere dysfunction provokes radiosensitivity. In this review we consider whether manipulation of telomere function may selectively sensitise SCCHN to radiotherapy and discuss the possible pitfalls. We also assess how some conventional treatments may affect the subsequent use of telomerase inhibitors.

Human mesenchymal stem cells isolated from olfactory biopsies but not bone enhance CNS myelination in vitro

Spinal cord injury (SCI) is a devastating condition with limited capacity for repair. Cell transplantation is a potential strategy to promote SCI repair with cells from the olfactory system being promising candidates. Although transplants of human olfactory mucosa (OM) are already ongoing in clinical trials, the repair potential of this tissue remains unclear. Previously, we identified mesenchymal‐like stem cells that reside in the lamina propria (LP‐MSCs) of rat and human OM. Little is known about these cells or their interactions with glia such as olfactory ensheathing cells (OECs), which would be co‐transplanted with MSCs from the OM, or endogenous CNS glia such as oligodendrocytes. We have characterized, purified, and assessed the repair potential of human LP‐MSCs by investigating their effect on glial cell biology with specific emphasis on CNS myelination in vitro. Purified LP‐MSCs expressed typical bone marrow MSC (BM‐MSC) markers, formed spheres, were clonogenic and differentiated into bone and fat. LP‐MSC conditioned medium (CM) promoted oligodendrocyte precursor cell (OPC) and OEC proliferation and induced a highly branched morphology. LP‐MSC‐CM treatment caused OEC process extension. Both LP and BM‐MSCs promoted OPC proliferation and differentiation, but only myelinating cultures treated with CM from LP and not BM‐MSCs had a significant increase in myelination. Comparison with fibroblasts and contaminating OM fibroblast like‐cells showed the promyelination effect was LP‐MSC specific. Thus LP‐MSCs harvested from human OM biopsies may be an important candidate for cell transplantation by contributing to the repair of SCI.

Transforming growth factor-β directly induces p53-up-regulated modulator of apoptosis (PUMA) during the rapid induction of apoptosis in myc-driven B-cell lymphomas.

Background: TGF-β induces apoptosis in Burkitts lymphoma cells. Results: PUMA is a direct target gene of TGF-β signaling and is required for rapid apoptosis. Conclusion: TGF-β-mediated direct induction of PUMA contributes to apoptosis in human and murine c-Myc-driven lymphomas. Significance: These studies link TGF-β signaling and transcriptional activation of PUMA, two factors with critical roles in regulating B-cell survival. c-Myc transformed human Burkitts lymphoma (BL) cells are highly sensitive to TGF-β-induced apoptosis. Previously we demonstrated that TGF-β-mediated cell death in BL cells is regulated via the mitochondrial intrinsic apoptosis pathway, which is dependent on the activation of BAX and/or BAK. TGF-β directly induces transcription of the BH3-only protein BIK and represses expression of the pro-survival factor BCL-XL but has no effect on the direct BAX/BAK “activators” BIM or BID (tBID). Here we show that TGF-β induces the BH3-only activator PUMA to aid induction of the intrinsic cell death pathway. TGF-β also induced PUMA in normal germinal center CD77-positive centroblasts isolated from human tonsil tissue. PUMA was a direct TGF-β target gene in B-cells, and we identify a putative Smad-binding region within the human PUMA promoter that recruits Smad3 and Smad4 in cells in response to TGF-β signaling. Constitutive activity of the isolated Smad-binding region in luciferase reporter assays was dependent on Smad consensus sequences and was partially dependent on endogenous TGF-β signaling and Smad4. Knockdown of PUMA in BL cells using lentiviral shRNA resulted in slower kinetics of the TGF-β-mediated apoptotic response. Analysis of Eμ-Myc cell lines demonstrated that c-myc-driven murine lymphomas are also sensitive to TGF-β-mediated apoptosis. Moreover, Puma−/− Eμ-Myc lines demonstrated significantly delayed kinetics of the apoptotic response when compared with wild type lymphomas. TGF-β therefore induces a polygenic response in Myc-driven lymphomas involving transcription of PUMA, which is necessary for the rapid induction of cell death.

Gamma tubulin: A promising indicator of recurrence in squamous cell carcinoma of the larynx

Objective: Centrosome amplification as detected by gamma tubulin (GT) immunostaining is associated with genetic instability and tumor aggressiveness. We assessed GT for its ability to predict recurrence of squamous cell carcinoma of the larynx (SCCL). Study Design: Case series with chart review. Materials and Methods: Five micron sections of 35 archival SCCL samples were subjected to antigen retrieval and immunostaining with antibody to GT. The keratin antibody CK5 served as a positive control for antigen retrieval, and tonsillar tissue was used as a negative control. Results: Of the 35 tumors analyzed, 22 were associated with recurrence(R) and 13 were not (NR). Fourteen of the 22 R tumors, but 0 of 13 of the NR tumours had a GT staining score of 2+ or 3+ (P < 0.0002). GT was also related to recurrence in node-negative tumors (P < 0.006) but was unrelated to T stage (P = 0.726). Conclusions: GT staining appears to be a better predictor of tumor recurrence than T stage and also predicts recurrence in N0 tumors.

Fine needle aspiration cytology versus frozen section in branchial cleft cysts

BACKGROUND Branchial cleft cysts occur because of a failure of involution of the second branchial cleft. However, as well-differentiated squamous cell carcinoma can mimic branchial cleft cysts, there is a lack of consensus on the appropriate management of cystic neck lumps. OBJECTIVE To report our experience of fine needle aspiration cytology and frozen section examination in the management of cystic neck lumps. METHOD Retrospective case note review of patients managed in the Southern General Hospital, Scotland, UK. RESULTS The sensitivity of fine needle aspiration cytology and frozen section for detecting branchial cleft cysts was 75 per cent and 100 per cent respectively. Two patients who did not undergo intra-operative frozen section examination were either over- or under-treated, which is discussed. CONCLUSION Adult patients subjected to surgical excision of a suspected branchial cyst should undergo intra-operative frozen section analysis regardless of clinical suspicion for malignancy. This part of management is critical to ensure patients are offered appropriate treatment.

Emergency department care of a patient after a total laryngectomy.

Patients who have undergone a total laryngectomy have altered anatomy and physiology. This results in unique and specific issues that must be recognized in order to ensure that this group of patients experience appropriate care. This article looks at the current literature and attempts to highlight specific areas of concern, so that emergency care providers can deliver an equally high standard of care to this patient group as they do to others. A Medline and Google scholar search was conducted using phrases associated with the complications of total laryngectomy. The results were analyzed to identify the most relevant articles that meet our objective. Articles were then organized into the different subheadings used within the article and reviewed. The most up-to-date articles or those that were in the opinion of the authors the most appropriate to convey our objective were included in our review.

Hypopharyngeal foreign body masquerading as malignancy.

Foreign body ingestion in dental and ENT practice is a commonly encountered emergency. In most cases, particularly in adults, there is a definite history of its ingestion, the nature of the foreign body is usually identifiable and the patient almost always presents immediately. We report an unusual case of an elderly patient with a six month history of progressive dysphagia referred to us by the physicians after investigations which were highly suggestive of a hypopharyngeal malignancy. Surprisingly when a biopsy was attempted, the hypopharyngeal mass turned out to be a dental plate. Dentists and otolaryngologists should be aware that pharyngeal foreign bodies can present without a positive history and can have a clinical presentation mimicking malignancy. A history of head injury, dementia, alcohol and drug abuse should be specifically excluded. A routine examination of a patient with dysphagia should include eliciting a specific history of wearing dentures and examination of teeth. In future designs for dental plates, bridges and crowns the use of a radio opaque material should be considered.

Head drop syndrome secondary to multimodality treatments for head and neck cancer

Five patients under follow-up for head and neck squamous cell carcinoma (SCC) at Southern General Hospital Glasgow presented with a fixed flexion deformity of the neck. These cases are characterized by the onset of severe weakness and atrophy of the neck extensor muscles and anterior fibrosis forcing the mandible to the chest wall. This causes considerable morbidity with communication, feeding, and appearance. This is a rare complication with no curative treatments that has not been reported previously by a UK center and is likely to become important with the increased use of multimodality treatments for head and neck SCC.Five patients under follow‐up for head and neck squamous cell carcinoma (SCC) at Southern General Hospital Glasgow presented with a fixed flexion deformity of the neck. These cases are characterized by the onset of severe weakness and atrophy of the neck extensor muscles and anterior fibrosis forcing the mandible to the chest wall. This causes considerable morbidity with communication, feeding, and appearance. This is a rare complication with no curative treatments that has not been reported previously by a UK center and is likely to become important with the increased use of multimodality treatments for head and neck SCC.

Hemoglobin Monitoring in Head and Neck Cancer Patients Undergoing Radiotherapy

Objectives Anemia is a well-recognized factor for local recurrence and decreased survival in cancer patients undergoing radiotherapy. Additionally, lower hemoglobin (Hb) levels have a negative impact on radiotherapy efficacy and response rates. The objective of this audit was to investigate how frequently Hb levels were observed in head and neck cancer patients receiving radiotherapy within a multidisciplinary team setting. Methods We performed a retrospective first-cycle audit in a university hospital in Glasgow that is a tertiary referral center for head and neck cancer. Included were 78 patients with head and neck cancer who were undergoing radiotherapy. Online laboratory services and clinical case sheets were checked for each patient to monitor the frequency of observation of Hb levels before, during, and after radiotherapy. Results Of these 78 patients, only 49 had their Hb level checked before radiotherapy treatment, only 9 during radiotherapy, and only 27 after completion of radiotherapy treatment (p < 0.0001). Of the 49 patients with preradiotherapy Hb levels available, 24% were found to be anemic; none of these patients had their Hb monitored during radiotherapy, and only 4 had Hb levels recorded after completion of treatment. Conclusions This audit has highlighted that despite evidence emphasizing that anemia in cancer is an independent prognostic factor for recurrence, there is no formal protocol for Hb monitoring in head and neck cancer patients undergoing radiotherapy. The audit has also demonstrated that Hb monitoring is infrequently performed and that subsequent observation of the Hb level is suboptimal.