Sherif Said

Tumor-Associated Lymphocytes and Increased FoxP3+ Regulatory T Cell Frequency Correlate with More Aggressive Papillary Thyroid Cancer

CONTEXT Ten to 30% of patients with papillary thyroid cancer (PTC) develop recurrent disease and may benefit from innovative adjuvant therapies. Immune-based therapies are under investigation to treat many types of cancer. The role of the immune system in PTC is poorly understood. OBJECTIVE We investigated whether tumor-associated lymphocytes (TAL), in the absence of background thyroiditis (LT), contribute to disease severity. We hypothesized that the type of lymphocytes associated with PTC would correlate with parameters of disease. DESIGN This retrospective study analyzed archived PTC samples for the presence of TAL and/or LT. A group of patients with TAL was evaluated for lymphocyte subsets by immunohistofluorescence. PATIENTS AND SETTING One hundred PTC patients were analyzed for LT and TAL, and 10 PTC patients with TAL were assessed for lymphocyte subsets at University of Colorado Hospital. MAIN OUTCOME We assessed correlations between disease and the presence of TAL, LT, and lymphocyte subset frequency. RESULTS Patients with TAL exhibited higher disease stage and increased incidence of invasion and lymph node metastasis compared with patients without lymphocytes or with LT. CD4(+) T cell frequency correlated with tumor size (r = 0.742; P = 0.017). FoxP3(+) regulatory T cell (Treg) frequency correlated with lymph node metastases (r = 0.858; P = 0.002), and CD8 to Treg ratio correlated inversely with tumor size (r = -0.804; P = 0.007). CONCLUSIONS TAL and high Treg frequency in primary thyroid tumors correlates with more aggressive disease. Future prospective studies may identify Treg frequency as a predictive factor in PTC, and the suppressive effects of Treg should be considered in the design of immune-based therapies.

Suppression of radiation-induced salivary gland dysfunction by IGF-1

Background Radiation is a primary or secondary therapeutic modality for treatment of head and neck cancer. A common side effect of irradiation to the neck and neck region is xerostomia caused by salivary gland dysfunction. Approximately 40,000 new cases of xerostomia result from radiation treatment in the United States each year. The ensuing salivary gland hypofunction results in significant morbidity and diminishes the effectiveness of anti-cancer therapies as well as the quality of life for these patients. Previous studies in a rat model have shown no correlation between induction of apoptosis in the salivary gland and either the immediate or chronic decrease in salivary function following γ-radiation treatment. Methodology/Principal Finding A significant level of apoptosis can be detected in the salivary glands of FVB mice following γ-radiation treatment of the head and neck and this apoptosis is suppressed in transgenic mice expressing an activated mutant of Akt (myr-Akt1). Importantly, this suppression of apoptosis in myr-Akt1 mice preserves salivary function, as measured by saliva output, three and thirty days after γ-radiation treatment. In order to translate these studies into a preclinal model we found that intravenous injection of IGF1 stimulated activation of endogenous Akt in the salivary glands in vivo. A single injection of IGF1 prior to exposure to γ-radiation diminishes salivary acinar cell apoptosis and completely preserves salivary gland function three and thirty days following irradiation. Conclusions/Significance These studies suggest that apoptosis of salivary acinar cells underlies salivary gland hypofunction occurring secondary to radiation of the head and neck region. Targeted delivery of IGF1 to the salivary gland of patients receiving head and neck irradiation may be useful in reducing or eliminating xerostomia and restoring quality of life to these patients.

Programmed Death-1+ T Cells and Regulatory T Cells Are Enriched in Tumor-Involved Lymph Nodes and Associated with Aggressive Features in Papillary Thyroid Cancer

CONTEXT Recurrent metastatic lymph node (LN) disease is common in patients with papillary thyroid cancer (PTC). Novel prognostic markers may be helpful in guiding a therapeutic approach. Our previous studies revealed that immune suppression is evident in PTC and associated with more severe disease. OBJECTIVE To characterize the immune response to metastatic PTC, we assessed CD4(+) T cell polarization in LN. In addition, we investigated the role of programmed death-1 (PD-1) and T cell exhaustion. DESIGN Uninvolved (UILN) and tumor-involved lymph nodes (TILN) were sampled ex vivo by fine-needle biopsy. T cell subsets were identified by flow cytometry. In parallel, archived TILN specimens were characterized by immunofluorescence. SETTING The study was conducted at the University of Colorado Hospital. PATIENTS Data were collected on 94 LN from 19 patients with PTC undergoing neck dissection. MAIN OUTCOME T cell subset frequencies were compared in UILN and TILN and assessed for correlation with recurrent disease and extranodal invasion. RESULTS Regulatory CD4(+) T cells (Treg) were enriched in TILN compared with UILN and further elevated in TILN from patients with recurrent disease. PD-1(+) T cells were present at high frequency in TILN and markedly enriched in TILN that showed evidence of extranodal invasion. In TILN, Treg frequency correlated with PD-1(+) T cell frequencies. Although PD-1(+) T cells produced interferon-γ, they failed to fully down-regulate CD27 and were not actively proliferating. CONCLUSIONS Increased Treg and PD-1(+) T cell frequencies in LN may be indicative of aggressive recurrent PTC. Future prospective studies are necessary to determine the prognostic and therapeutic value of these findings in PTC.

Clear cell chondrosarcoma of the larynx

described as a distinct neoplastic entity by Unni et al1 in 1976. This rare malignant tumor has since been described in a number of anatomic sites and has shown a particular predilection to involve the epiphyses of long bones.1,2 In the head and neck, however, only 1 case of clear cell chondrosarcoma has been reported in the larynx.3 In this report, we describe a second case of clear cell chondrosarcoma that involved the thyroid cartilage of the larynx.

Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression

BackgroundMetastatic melanoma has a high mortality rate and suboptimal therapeutic options. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid × receptor selective agonist, and thiazolidinediones (TZD), PPARγ selective ligands, as novel treatments.ResultsMouse xenograft models with human melanoma cell lines [A375(DRO) or M14(5–16)] were treated for 4 weeks with daily vehicle, RXR agonist (rexinoid, LGD1069, 30 mg/kg/d), PPARγ agonist (TZD, rosiglitazone, 10 mg/kg/d) or combination. A375(DRO) tumor growth was significantly inhibited by either ligand alone and the combination had an additive effect. M14(5–16) tumors only responded to LGD1069 100 mg/kg/day. A375(DRO) sublines resistant to rexinoid, TZD and combination were generated and all three sublines had reduced PPARγ expression but preserved RXR expression. shRNA knockdown of PPARγ or RXRγ attenuated the rexinoid, TZD and combination ligand-mediated decreased proliferation in A375(DRO) cells. Rexinoid (LGD1069) and retinoid (TTNPB) treatment of M14(5–16) cells resulted in decreased proliferation that was additive with combination of both rexinoid and retinoid. shRNA knockdown of RXRγ resulted in a decreased response to either ligand.ConclusionA375 (DRO) melanoma cell growth is inhibited by rexinoid and TZD treatment, and this response is dependent on RXR and PPARγ receptor expression. M14 (5–16) melanoma cell growth is inhibited by rexinoid and retinoid treatment, and this response is dependent on RXR expression. These findings may help guide molecular-based treatment strategies in melanoma and provide insight for mechanisms of resistance to nuclear receptor targeted therapies in certain cancers.

Vesiculobullous Eruptions of the Oral Cavity

The spectrum of vesiculobullous eruptions of the oral cavity is wide and rich, with different disease entities that encompass different etiologies, pathogenesis, clinical manifestations, treatment plans, and prognostic ends. Trying to present all these entities in a comprehensive fashion is challenging, but in this article, most of the important entities pertaining to this topic have been encompassed in a concise manner.

Estrogen and Progesterone Receptor and p53 Gene Expression in Adenoid Cystic Cancer

Objectives The current study examined the role of estrogen receptors (ER), progesterone receptors (PR) and p53 expression in adenoid cystic carcinoma (ACC) to determine if simple expression or possible overexpression of these products might influence the development and natural course of this cancer. Study Design ER and PR status and p53 overexpression were retrospectively evaluated utilizing immunohistochemical evaluation of 47 ACC specimens. Methods Formalin-fixed paraffin-embedded tissues from 47 ACC specimens and 47 samples of normal salivary gland tissue were evaluated histochemically for the presence of ER, PR and p53. Immunoreactivity was scored using a 0 to +3 scale in which staining was either (0) negative, (+1) spotty, (+2) weakly positive, or (+3) strongly positive. Results ER was expressed in 8 of 47 tumors while PR was expressed in 4 of 47 tumors. p53 aberrations were demonstrated in 26 of 47 tumors. Tumors showed varying degrees of immunopositivity ranging from 0 to +3. Conclusions These studies suggest that p53 aberrations may be involved in ACC tumor progression and that ER and PR may play a role in ACC development.

Radiation-induced dedifferentiated chondrosarcoma with orbital invasion

Purpose: To report 2 interventional cases of dedifferentiated chondrosarcoma with orbital involvement after radiotherapy performed in childhood and to review the literature on chondrosarcoma in the orbit following radiation treatment. Methods: Retrospective analysis of medical records of 2 patients with chondrosarcoma of the orbits with review of the literature. Results: The first patient developed chondrosarcoma of the orbital and maxillary sinus 36 years after external beam radiation therapy to the OS to treat retinoblastoma. The second patient developed a large orbital chondrosarcoma 35 years after external beam radiation therapy in the treatment of craniofacial fibrous dysplasia. Conclusions: These cases highlight the risk of secondary chondrosarcoma in patients following radiotherapy and the importance of lifetime monitoring.

Papillary adenocarcinoma with oncocytic features arising from the ethmoid sinus

Objectives: We report a case of low-grade papillary adenocarcinoma with unique oncocytic features arising in the ethmoid sinus of a 72-year-old female. Methods: A review of the case history, pathological findings, and medical literature is performed. Results: A 72-year-old female presented with a 2-month history of progressive right-sided nasal obstruction. Preoperative nasal endoscopy showed a glistening, pink-red, soft mass arising from the middle meatus suspicious for inverting papilloma. Paranasal CT revealed a soft tissue density opacifing the right ethmoid sinus with ipsilateral maxillary and frontal sinus opacification. Complete endoscopic sphenoethmoidectomy was performed. Pathological examination of the surgical specimen revealed a low-grade papillary adenocarcinoma with oncocytic features. Special staining for MIB-1, p53, and Ki-67 was confirmatory. One year following surgical resection, nasal endoscopy revealed a recurrent mass in the surgical field; paranasal CT was confirmatory. A completion external and endoscopic ethmoidectomy was performed with complete removal of the neoplasm. Pathological examination revealed recurrent low-grade papillary adenocarcinoma. At 3 months postoperatively, the patient remains free from recurrent neoplasm. Conclusion: The management of ethmoid adenocarcinoma is dependent on the extent of disease and its pathological characteristics. Locally aggressive low-grade neoplasms, such as inverting papilloma, have been successfully treated with complete endoscopic resection with good rates of local control. Similarly, low-grade papillary adenocarcinoma has been successfully treated with endoscopic resection. In this case report, a rare oncocytic form of papillary adenocarcinoma is described that behaves similarly to other low-grade sinonasal papillary adenocarcinomas. Meticulous endoscopic surgical resection must be performed as local recurrence is common.

Angiogenic squamous dysplasia: Characteristics and implications

Abstract Objectives: Keith et al described angiogenic squamous dysplasia (ASD) in the lung epithelium of patients at high risk for the development of lung carcinoma. We have recently observed similar changes in the nasal epithelium of occasional patients undergoing routine sinus surgery. This retrospective study evalautes the demographic characteristics of this small group of patients and compares them to a control series of patients undergoing similar surgery to evaluate whether this lesion is premalignant. Methods: Consecutive sinus and nasal surgical pathological specimens were reviewed for the presence of ASD. Twelve patients with ASD were identified and studied in detail. Their demographic characteristics were compared to a control group found not to have ASD but undergoing similar sinus surgery for similar conditions, using a grid approach to allow consideration of clinical characteristics without violating patient confidentiality. Results: Clear demographic differences between the study and control groups were not identified, and no progression to carcinoma was observed in any patient with ASD. In 1 patient that was re-biopsied in view of other risk factors, the mucosa reverted to normal (absence of ASD). Conclusions: ASD is an identifiable histopathological change that occurs in the sinus epithelium. The presence of this lesion with chronic sinusitis suggests that these aberrent patterns of microvasculature may represent an inflammatory response in the sinus mucosa, rather than true neoplasia at risk to proceed to carcinoma, as occurs in the lung. Additional observations are indicated to evaluate this possibility in a larger group of patients.