Vieri Galli

Overexpression of the Cytokine Osteopontin Identifies Aggressive Laryngeal Squamous Cell Carcinomas and Enhances Carcinoma Cell Proliferation and Invasiveness

Purpose: Osteopontin is a secreted cytokine that binds to the cell surface CD44v6 receptor. We studied osteopontin and CD44v6 expression in laryngeal squamous cell carcinomas and correlated osteopontin expression levels with clinicopathologic tumor features. Experimental Design: We used immunohistochemistry, immunoblotting, and reverse transcription-PCR to study osteopontin expression in 58 laryngeal squamous cell carcinomas. Cultured squamous carcinoma cells were treated with exogenous osteopontin or with RNA interference to knockdown osteopontin expression. Results: Osteopontin expression was higher in all the invasive carcinomas than in patient-matched normal mucosa. Its expression levels were significantly correlated with tumor stage and grade and with the presence of lymph node and distant metastases. Osteopontin positivity was negatively correlated with overall survival (P = 0.03). Osteopontin expression was paralleled by intense cell surface reactivity for CD44v6. Treatment of squamous carcinoma cells with recombinant osteopontin sharply increased proliferation and Matrigel invasion in comparison with the untreated cells parallel to activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase signaling cascade. Osteopontin knockdown by RNA interference, anti-CD44 antibodies, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibition prevented these effects. Conclusions: These results identify osteopontin as a marker and a potential therapeutic target in cases of aggressive laryngeal squamous cell carcinomas.

OPN/CD44v6 overexpression in laryngeal dysplasia and correlation with clinical outcome

Laryngeal dysplasia is a common clinical concern. Despite major advancements, a significant number of patients with this condition progress to invasive squamous cell carcinoma. Osteopontin (OPN) is a secreted glycoprotein, whose expression is markedly elevated in several types of cancers. We explored OPN as a candidate biomarker for laryngeal dysplasia. To this aim, we examined OPN expression in 82 cases of dysplasia and in hyperplastic and normal tissue samples. OPN expression was elevated in all severe dysplasia samples, but not hyperplastic samples, with respect to matched normal mucosa. OPN expression levels correlated positively with degree of dysplasia (P=0.0094) and negatively with disease-free survival (P<0.0001). OPN expression was paralleled by cell surface reactivity for CD44v6, an OPN functional receptor. CD44v6 expression correlated negatively with disease-free survival, as well (P=0.0007). Taken as a whole, our finding identify OPN and CD44v6 as predictive markers of recurrence or aggressiveness in laryngeal intraepithelial neoplasia, and overall, point out an important signalling complex in the evolution of laryngeal dysplasia.

Prognostic value of p27Kip1 expression in Basaloid Squamous Cell Carcinoma of the larynx.

BackgroundVery few reports have investigated the role of cell cycle regulators as biomarkers in Basaloid Squamous Cell Carcinoma (BSCC) of the larynx, a definite morphologic, uncommon, very aggressive variant of squamous cell carcinoma. Lower expression of Ki67/Mib-1, a proliferation marker highly expressed in the majority of tumours, and p53, a tumour suppressor protein that can induce an arrest of the G1-S transition, was related to a better prognosis in laryngeal BSCC. In the head and neck, p27kip1, a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors, has emerged as an independent prognostic factor, able to identify low-expressing tumours with unfavourable course. Up to date the role of this protein was never studied in BSCC. Aim of our study was to investigate the potential prognostic value of p27kip1 levels and their correlation with Ki67/Mib-1 and p53 expression in BSCC of the larynx.MethodsThe retrospective study group consisted of 15 male and 1 female patients, affected by laryngeal BSCC, ranging in age from 44 to 69 years (mean 58). The tumour originated from the supraglottis in thirtheen cases and from the glottis in the remaining three. Ten patients had metastatic cervical lymph nodes at presentation and were classified as N+. Post surgical stage was IV in four patients, III in nine, II in two cases and I in the remaining one. Follow-up ranged from a minimum of 5 months up to 9 years. Paraffin-embedded tissue sections of each laryngeal tumour were analyzed for p27kip, Ki67/Mib-1 and p53 expression by immunohistochemistry.ResultsThe immunohistochemical study showed p27kip1 expression in 40% of the patients with no evidence of disease (NED) and in none (0%) of the patients dead of disease (DOD), whilst p53 was expressed in 60% of patients in NED status and in 90% of patients in DOD status. Ki67/Mib-1 was positive in 80% of NED patients and in 100% of DOD patients. At multivariate analysis, performed by means of Discriminant analysis, low levels of p27kip1 expression significantly correlated with poor prognosis (P < 0.05).Conclusionp27kip1 protein has been shown to be a significant independent prognostic factor in laryngeal SCC. In our series of laryngeal BSCC the resulting data seem to confirm the clinical prognostic relevance of p27kip1 low expression, which directly correlated with biological aggressiveness and consequent shortened survival.

Inferior turbinate osteoma: a rare cause of nasal obstruction.

Osteoma of the nose is a rare and benign tumor that develops slowly with an incidence of 0.6% of all benign tumors of the nose. It is the most common benign tumor of the paranasal sinuses and is usually asymptomatic and found only on a coincidental radiographic investigation. Osteoma frequently occurs in the frontal sinus (52%) followed by ethmoid (22.0%), and maxillary sinus (5.1%), most rarely in the sphenoid (1.7%), and in the nose (0.6%). Osteomas may occur at any age but usually present in the second-to-fourth decades with a slight male:female preponderance. We present an unusual and rare case of patient with an osteoma of the inferior turbinate.

Submandibular gland myoepithelioma

Benign myoepithelioma is a very rare form of salivary gland tumor, composed entirely of myoepithelial cells. It accounts for ≈1% of all salivary gland tumors and is most frequently located in the parotid gland and in the minor salivary glands of the hard palate. We describe herein the ninth reported case of myoepithelioma of the submandibular gland. Benign myoepithelioma must be differentiated from several benign and malignant epithelial and mesenchymal tumors. Immunohistochemical staining can help differentiate between these conditions, but histopathology remains the gold standard for diagnosing this neoplastic process.

Angiolipoma of the larynx.

Angiolipoma is a benign lesion of soft tissue. It is a histologic variation of lipoma that occurs in approximately 6% to 17% of the cases of lipoma. Although lipomas are the most common soft tissue tumors, they occur in the head and neck region in 16% of cases. In particular, the cervico-facial location of angiolipoma has been presented in the literature in only 18 cases, with none in the laryngeal area. We present a unique case of angiolipoma of the larynx with a review of the literature concerning clinical, pathologic, and therapeutic aspects of angiolipomas in the head and neck. A 71-year-old man arrived to our observation with a 7-month history of a sensation of a foreign body in the throat, dysphonia, and dysphagia. Fiberoptic laryngoscopy revealed a 2-cm mass located on the left aryepiglottic plica and occupying the piriform sinus of the same side (Fig 1). This lesion was round, rosy in color, and rich in vessels; vocal cord mobility and conformation were preserved. The rest of the head and neck examination was normal. CT scan with contrast demonstrated a homogeneous, solid, round, and low-density mass occupying the left piriform sinus. Excision of the lesion was performed using a carbon dioxide laser with microscopic techniques. We incised the ipsilateral aryepiglottic plica mucosa to reach the capsule of the mass; submucosal resection of the mass was then performed. Histology revealed “mature adipose tissue with numerous vascular channels and perivascular and interstitial fibrosis (Fig 2).” Our patient presented no postoperative problems and during the follow-up of seven years no recurrences were revealed.

Clinical and prognostic aspects of laryngeal clear cell carcinoma.

Clear cell carcinoma (CCC) of the larynx is a rare pathological finding; only eight cases are described in the literature. It occurs in older adults and shows a predilection for men. We report the ninth observation of laryngeal CCC in the literature. We reviewed the literature and correlated the prognosis of the tumour according to its site of onset and treatment. The literature review showed that this neoplasm is highly aggressive, with a high recurrence rate and short mean survival time; the treatment of choice is surgery, and chemo- or radiotherapy are used mainly for the treatment of recurrences.

Activation of the ret oncogene in human thyroid carcinomas

A novel oncogene has been recently found activated in human thyroid carcinomas. This oncogene was named RET/PTC and was shown to be a chimeric gene, product of the fusion of the tyrosinekinase domain or the RET proto-oncogene to the 5’-terminal region of another gene named H4 or D10S170. A paracentric inversion (10) (q 11.2-21) was demonstrated to be responsible for the H4/RET fusion. Thyroid tumors consist of a broad range of lesions ranging from the benign follicular adenomas to the differentiated papillary and follicular carcinomas and to the fatal anaplastic carcinomas. Papillary and follicular carcinomas have different clinical behaviours and are associated with different risk factors, thus they are probably related to different genetic events. In fact the activation of RET is restricted to the papillary subtype. Here we show the activation of the RET oncogene in 2 out of 10 new cases of papillary thyroid carcinomas.RiassuntoRecentemente abbiamo individuate» 1a attivazione di un nuovo oncogene nei tumori umani tiroidei. Tale gene è stato definite» RET/PTC Esso è un gene chimerico che risulta dalla fusione del dominio tirosino-chinasi del proto-oncogene RET con 1a porzione 5’-terminale di un altro gene detto H4 o D10S170. L’inversione (10) (ql 1.2-21) è responsable della fusione H4/RET. I tumori tiroidei comprendono un vasto spettro di neoplasie che vanne» dagli adenomi, tumori benigni, ai carcinomi papilliferi e tollicolari sino agli anaplastici, tumori completamentc indifferenziati. I diversi fattori di rischio e il différente comportamento clinico indicano che i carcinomi papilliteri probabilmente hanno una base genetica diversa dai carcinomi tollicolari. L’attivazione dell’oncogene RET è limitata ai carcinomi papilliferi. In questo lavoro riportiamo due esempi di attivazione dell’oncogene RET su 10 nuovi carcinomi tiroidei papilliferi analizzati.