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Abstract: GISTs originating multifocally at different GI sites, in patients lacking familial syndromes, could be interpreted as recurrent/metastatic disease. MiR-221/222 have recently been identified as regulators of KIT expression in GISTs. We report the first case of synchronous GISTs in the stomach and duodenum concomitant with an ampullary adenocarcinoma. Different CD117 expression patterns could be related to different KIT mutational status in the two lesions: gastric GIST showed a dot-like pattern and lacked KIT mutations; duodenal GIST had a strong membranous expression pattern, likely due to KIT exon 9 duplication, which is associated with lower response to imatinib. MiR-221/222 were downregulated in GISTs as compared with normal tissue (p <0.05) and expressed increased levels in the gastric GIST as compared with duodenal one (p <0.05). Our data support an independent origin of the two GISTs. Determining whether these tumors are multiple primaries or recurrencies is helpful to predict their malignancy and to select proper treatment. [Copyright &y& Elsevier]

Background Solitary fibrous tumour (SFT) is quite a rare neoplasm involving the eye and the orbit. It is described as showing benign behaviour in adults, but malignant cases are exceptionally reported in this location. This report describes four new cases of SFT/ giant cell angiofibroma (GCA) of the eyelid and orbit, one in a 5-year-old child, and one with sarcomatous dedifferentiated transformation occurring 9 years after radiotherapy. Methods Four cases of ocular SFT/GCA were retrieved from the database of the Pathological Anatomy Unit, University of Padova; immunohistochemistry and RT-PCR were used to identify COL1A1-PDBGF fusion gene transcripts in all cases. Results In case 1, late relapse 9 years later was characterised by abrupt transition into a high-grade component, associated with a non-distinctive high-grade sarcomatous area. The latter component was CD34, CD99 and Bcl2 negative and smooth muscle actin positive. Molecular characterisation showed the absence of COL1A1-PDGFB fusion transcripts in cases 1, 3 and 4, excluded diagnosis of giant cell fibroblastoma in all cases. Analysis could not be performed in case 2. Conclusions An eyelid SFT/GCA in a 5-year-old child is the youngest case reported in the literature, indicating that the tumour is not exclusive to adults. The case with sarcomatous transformation, with dedifferentiated features occurring 9 years after radiotherapy, raises some questions about the choice of treatment for ocular SFT, in which excision is sometimes difficult without devastating surgery. [ABSTRACT FROM AUTHOR]

Conclusions: Nuclear nm23-H1 expression may be useful in identifying elderly patients operated for laryngeal squamous cell carcinoma (LSCC) at higher risk of recurrence. Further studies are needed to clarify the biological role of nm23-H1 in elderly patients with LSCC and to determine how to restore nm23-H1 loss of expression/function. Objectives: Nowadays more than 50% of cancer cases are elderly patients and this percentage is expected to be 70% by 2030. Despite advances in LSCC diagnosis and treatment, patient survival has not improved in the last two decades. Novel, effective strategies should rely also on receptor-mediated LSCC-targeted therapy. nm23-H1 protein is related to the tumor cells' metastatic potential, and low nm23-H1 expression in carcinomas often correlates with a poor prognosis. Methods: Immunohistochemistry and image analysis were used to investigate the prognostic value of nm23-H1 expression and subcellular localization in a series of 54 elderly patients consecutively undergoing primary surgery for LSCC. Results: On univariate analysis, the disease recurrence rate correlated inversely with nuclear nm23-H1 expression ( p = 0.014), and disease-free survival (DFS) was longer in patients whose nuclear nm23-H1 levels were ≥2.0% ( p = 0.022). On multivariate analysis, nuclear nm23-H1 expression (hazard ratio (HR) 2.77, p = 0.022) and N stage (HR 3.49, p = 0.007) were prognostically significant in terms of DFS. [ABSTRACT FROM AUTHOR]

Postoperative RT is generally recommended for laryngeal carcinomas (LSCCs) at high risk of recurrence after surgery. There are currently no clinicopathological parameters available to predict response to such adjuvant RT in LSCC, and only a few potentially predictive biomarkers have been investigated. Nm23-H1 protein is reportedly related to the tumor cells’ metastatic potential, and low Nm23-H1 expression levels in human carcinomas often correlate with a poor prognosis. The novel aim of the present preliminary study was to investigate the prognostic value of Nm23-H1 expression and subcellular localization in a series of patients given postoperative RT for LSCC. A retrospective clinicopathological investigation was conducted at an academic tertiary referral center of 28 consecutive patients given postoperative RT for LSCC. Image analysis of immunohistochemical reactions was performed to measure Nm23-H1 total and nuclear expression levels. Disease-free survival (DFS) was significantly shorter among LSCC patients with total Nm23-H1 levels <50.0 % (p = 0.03); the mean total Nm23-H1 expression was lower in patients with recurrent disease than in patients without it (statistical trend, p = 0.07). The disease recurrence rate was significantly higher (p = 0.021) and the DFS shorter (statistical trend, p = 0.052) among LSCC patients with nuclear Nm23-H1 levels\5.0 %. The locoregional recurrence- risk ratio in LSCC patients with nuclear Nm23-H1 levels <5.0 % was 9.16. Nm23-H1 warrants further investigation of its potential role as a predictive biomarker with a view to providing tailored treatments after surgery, such as combinations of chemotherapy and RT instead of RT alone, in patients whose LSCCs have low or no Nm23-H1 expression. [ABSTRACT FROM AUTHOR]

J Oral Pathol Med (2012) 41: 136-140 Background: There are currently no clinical or pathological parameters able to predict response to adjuvant radiotherapy (RT) in laryngeal squamous cell carcinoma (LSCC). Few studies have investigated the molecular pathways potentially capable of predicting said response. The mammalian target of rapamycin (mTOR) acts as a 'master switch' protein in cancer cells, modulating metabolism, the cell cycle, and apoptosis. Cancer treatment with mTOR inhibitors (rapamycin analogs, or rapalogs) has produced promising results in various malignancies (renal cell carcinoma, breast cancer, prostate cancer, leukemia, lymphoma, and melanoma). The novel aim of the present study was to ascertain the prognostic role of mTOR expression in a series of patients with LSCC treated with primary surgery followed by RT. Methods: The retrospective study involved 25 consecutive patients with LSCC given postoperative RT. Immunohistochemical mTOR expression was evaluated in primary LSCC by image analysis. Results: The locoregional recurrence rate was significantly higher in patients with LSCC whose mTOR expression was >2.5% ( P = 0.013). After postoperative RT, the locoregional recurrence risk ratio was 3.25 in LSCCs with mTOR >2.5%. The different disease-free survival was significantly shorter in cases of LSCC with mTOR >2.5% ( P = 0.029). Conclusions: mTOR should be studied as a potential predictor for identifying LSCCs at higher risk of early recurrence after postoperative RT. New therapeutic strategies should be investigated in LSCC, including the use of rapalogs associated with conventional chemotherapeutic regimens in combination with RT. [ABSTRACT FROM AUTHOR]

Patients with head and neck squamous cell carcinoma (SCC) respond very differently to radiotherapy (RT). Since clinical factors cannot accurately predict its effects, biological parameters have been investigated, including tumor hypoxia. CD105 is a hypoxia-inducible glycoprotein emerging as a potential prognostic indicator for several solid malignancies. Angiogenin is upregulated under hypoxic conditions and supports primary and metastatic tumor growth. Epidermal growth factor receptor (EGFR) activation stimulates tumor proliferation and angiogenesis. The aim of the present study was to ascertain the prognostic importance of hypoxia-inducible factors (CD105, angiogenin) and EGFR in a series of patients who underwent primary surgery followed by RT for laryngeal SCC. 25 consecutive patients with laryngeal SCC given postoperative RT have been investigated. CD105, angiogenin, and EGFR immunohistochemical expressions in primary laryngeal SCCs have been evaluated also with image analysis. The recurrence rate was significantly higher in SCC patients with a CD105 expression >10.0% ( P = 0.012) and their disease-free survival (DFS) was shorter ( P = 0.044). Neither angiogenin (in the carcinoma cells or endothelial cells) nor EGFR expression were associated with the prognosis in our patients after primary surgery followed by RT for laryngeal SCC. CD105 should be studied as a potentially predictive biomarker for identifying laryngeal SCCs at higher risk of early recurrence after postoperative RT. Targeted anti-CD105 therapy associated with RT should also be investigated in patients with laryngeal SCCs characterized by high CD105 expression. [ABSTRACT FROM AUTHOR]

Conclusion: MASPIN subcellular location can be considered a prognostic marker that is potentially useful for identifying elderly patients with laryngeal carcinoma at higher risk of early loco-regional recurrence, who may benefit from more aggressive therapy. In a targeted treatment setting, re-activated nuclear MASPIN in combination with anti-angiogenic and/or cytotoxic drugs may be effective in treating laryngeal carcinoma in elderly patients. Objectives: Aging is associated with molecular, cellular, and physiological changes that influence carcinogenesis and cancer growth. MASPIN has multifaceted anti-tumor effects and available evidence supports the hypothesis that its subcellular location influences its functions. The aim of the present study was to firstly assess the potential prognostic role of subcellular MASPIN location in elderly patients (>65 years old) with laryngeal carcinoma. Methods: MASPIN expression and location were immunohistochemically determined in 68 consecutive elderly patients with laryngeal carcinoma. Results: Nodal involvement and pathological stage correlated strongly with the prognosis for laryngeal carcinomas in elderly patients, in terms of disease recurrence rate and disease-free survival. The loco-regional recurrence rate was significantly lower ( p == 0.041) and the disease-free survival after treatment was significantly longer ( p == 0.045) in cases with a nuclear pattern of MASPIN subcellular expression. [ABSTRACT FROM AUTHOR]

Aims: To report three cases of serous cystadenoma and endocrine tumour in the same pancreas, to review the literature and to evaluate the clinicopathalogical features of the tumours. Cases: Three women (71,57 and 31 years old) were admitted to hospital, two for diseases unrelated to the pancreas and the third for increasing obstructive jaundice in von Hippel-Lindau disease. Preoperative examination showed two distinct lesions in the first patient and only cystic lesions in the other two. Results: Histological examination of the pancreas showed one serous oligocystic adenoma associated with a benign, well-differentiated endocrine tumour, one serous oligocystic adenoma associated with an endocrine microadenoma, and a yon Hippel-Lindau-related cystic neoplasm with a well-differentiated endocrine carcinoma. Conclusions: Serous cystadenoma associated with endocrine tumour shows same clinicopathological differences with respect to the two tumours considered separately, and with respect to yon Hippel-Lindau-related cases, although there is no convincing evidence at present to justify considering this association as a separate entity. [ABSTRACT FROM AUTHOR]

Clinical evidence of non-lymphatic distant metastasis has been reported in ˜10% of cases of head and neck squamous cell carcinoma (HNSCC). The lungs are the commonest site of distant metastasis of HNSCC, followed by the bones, liver and skin. A 65-year-old male underwent supraglottic laryngectomy and left modified neck dissection for a carcinoma of the laryngeal surface of the epiglottis extending to both false cords. Eight months later the patient underwent right radical modified neck dissection for hypodermal metastatic disease involving the underlying (sternocleidomastoid) muscle. Thirty-two months later, surgical excision of a lesion in the right gluteus maximus muscle was performed. Histological study diagnosed a muscular metastasis with the same morphological aspect as the laryngeal carcinoma. The patient showed no evidence of cervical or distant recurrence at follow-up after 13 months. Although skeletal muscles represent ˜50% of total body mass and receive a large proportion of total cardiac output, haematogenous metastases to skeletal muscle are extremely uncommon. Most skeletal muscle metastases are of pulmonary origin. Distant skeletal muscle metastasis from HNSCC is an extremely rare occurrence. Treatment options, depending upon the clinical setting, include observation, radiotherapy, chemotherapy and excision; these approaches rarely alter the patient outcome. The prognosis associated with skeletal muscle metastasis is thought to be poor, consistent with the fact that it generally occurs as a feature of systemic spread. [ABSTRACT FROM AUTHOR]

Although the diagnosis and treatment of sporadic vestibular schwannoma has improved in recent years, no factors capable of predicting its growth have been identified as yet. Endoglin (CD105) is a proliferation-associated protein expressed in angiogenic endothelial cells, and a potential prognostic indicator for several solid tumors. The aim of the present study was primarily to investigate the expression and role of CD105 in a series of sporadic vestibular nerve schwannomas. In 71 consecutive cases of vestibular schwannoma, vessel cross-sectional area and density were calculated from immunohistochemically assessed CD105 expression using image analysis to correlate them with: (i) tumor dimensions; and (ii) tumor growth rate measured on high-resolution contrast-enhanced MRI (ceMRI). Based on assessments of CD105 expression, a significant positive correlation was identified between vessel cross-sectional area and tumor size at the time of surgery (p = 0.0024), and between vessel density and tumor size (p = 0.013). Vessel cross-sectional area (p = 0.0006) and vessel density (p = 0.003) were significantly greater in tumors measuring ≥10 mm in size than in those <10 mm. Conversely, when tumor growth rate could be calculated from two or more ceMRI (38 cases), there was no significant correlation between tumor growth rate and cross-sectional vessel area or vessel density as assessed with CD105. Further investigations are needed to ascertain the feasibility of: (i) using circulating endoglin assay to monitor tumor growth; and (ii) targeting neoangiogenesis with anti-endoglin antibodies in sporadic vestibular schwannoma. [ABSTRACT FROM AUTHOR]

Lymphangiomas of the pancreas are very rare benign tumors of lymphatic origin, accounting for less than 1% of these neoplasms. We report a case of a 55-year-old woman who presented with a palpable mass in the left abdomen. Abdominal sonography and computed tomography showed a lobulated, hypodense mass extending from the left diaphragmto the pelvis, measuring 10×25 cm. A preoperative diagnosis of mucinous cystadenoma of the pancreas was suggested and the patient underwent laparotomy. Distal pancreatectomy with splenectomy was performed, encompassing a segment of descending colon because of close relationship to the mass. The cystic mass was histologically diagnosed as lymphangioma of the pancreas. The patient is well and free of disease 12 months after surgery. Pancreatic lymphangioma should be kept in mind when a huge, multiloculated mass is encountered in the abdomen, especially in adult women. Although lymphangioma is considered a benign tumor, involvement of adjacent organs sometimes occurs and extended resection is required to obtain a radical treatment. [ABSTRACT FROM AUTHOR]

Marioni G, Marino F, Blandamura S, D'Alessandro E, Giacomelli L, Guzzardo V, Lionello M, de Filippis C & Staffieri A (2010) Histopathology 57, 535-543 Neoangiogenesis in laryngeal carcinoma: angiogenin and CD105 expression is related to carcinoma recurrence rate and disease-free survival Aims: Angiogenin regulates angiogenesis supporting primary and metastatic tumour growth. CD105 is a proliferation-associated protein expressed in angiogenic endothelial cells. The aim of this study was to investigate for the first time angiogenin expression in laryngeal squamous cell carcinoma (LSCC) and to evaluate the relationship between angiogenin and CD105 expression, clinicopathological and prognostic parameters. Methods and results: A total of 108 consecutive operable LSCCs were studied. Angiogenin expression was determined immunohistochemically in both carcinoma cells and intratumoral vessels. CD105 expression was evaluated in endothelial cells of LSCC and calculated by a computer-based image analysis system. The percentage of the fields occupied by CD105-assessed microvessels was determined. Angiogenin expression in carcinoma cells was higher in LSCC patients who experienced loco-regional recurrence of disease ( P = 0.032). Disease-free survival (DFS) was shorter in cases with carcinoma cells showing angiogenin expression >21.0% ( P = 0.035). Angiogenin expression in carcinoma cells was correlated strongly with the angiogenin score in endothelial cells of intratumoral vessels ( P = 0.0000). Higher loco-regional carcinoma recurrence rate and shorter DFS in patients with high CD105 expression were found ( P = 0.0004, P = 0.0001). Conclusions: Angiogenin expression in laryngeal carcinoma cells and CD105 expression can be considered as potentially useful to detect LSCC patients with higher risk of disease recurrence who might benefit from more aggressive therapy. [ABSTRACT FROM AUTHOR]

Objective: Considerable evidence has confirmed that p27 protein plays a negative role in cell-cycle progression from the G1 to the S phase and is considered a tumour suppressor, p27 down-regulation was demonstrated in several malignancies. Only a few studies investigated p27's potential prognostic role in laryngeal squamous cell carcinoma (SCC). The aim of the present study was to determine the prognostic relevance of p27 expression in a cohort of laryngeal SCCs that were very homogeneous from a treatment viewpoint to avoid possible influences of treatment modalities on results; all patients underwent only partial laryngectomy on the primary lesion. We simultaneously investigated monoclonal antibody against a proliferating cell associated epitope MIB-1 expression. Design and Methods: Twenty-two cases of laryngeal SCC that had undergone exclusive supracricoid or supraglottic laryngectomies with or without neck dissection at the Department of Otolaryngology of Padova University were evaluated. Primary laryngeal SCC p27 reactivity and MIB-1 reactivity were immunohistochemically tested and evaluated by a workstation image analysis system. Main Outcome Measures: A lesion was considered p27 positive when more than 18.56% of the tumour cells showed diffuse strong staining. Samples with < 20.24% of stained cells were considered MIB-1 positive. Results: The mean p27 expression was 17% and 22% in patients with and without disease recurrence, respectively. Low p27 expression was statistically associated with disease recurrence (p = .045); on the other hand, high MIB-1 values were associated with SCC recurrence after treatment (p .045). Conclusions: The intervals of confidence analysis showed a stronger relationship of MIB-1 versus p27 in predicting disease recurrence in our cohort of patients treated only with partial laryngectomies. [ABSTRACT FROM AUTHOR]

Background: Uveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10 years from diagnosis, with the liver as the most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis. Methods: We collected a patient cohort comprising 21 metastatic UM patients. Hepatic and extra-hepatic UM metastasis samples were studied by multiplex immunofluorescence to assess the tumor immune cell composition. Quantitative analyses were performed to correlate immune cell densities with treatment response, metastasis site and patient survival. Results: Compared to patients with progressive disease, those with controlled disease had a higher intra-tumoral/peritumoral ratio of CD8 + Granzyme B+ cells, higher density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL) and an increased percentage of UM cells in close proximity to T lymphocytes, reflecting a role of tumor-killing T cells in the disease. In liver metastases (LM), the intra-tumoral densities of CD163+ tumor-associated macrophages (TAM) and of total CD8+ T cells were higher than in extra-hepatic UM metastases, but the percentage of Granzyme B+ CTL was lower. Moreover, LM displayed more UM cells adjacent to both CTL and TAM, and also more T cells in proximity to TAM, all signs of an impaired immune response. The percentage of activated CTL within the tumor represented a prognostic indicator, as patients with a higher intra-tumoral percentage of CD8 + Granzyme B+ cells had the better outcome. A temptative Immunoscore was generated and proved capable to stratify patients with improved survival. Finally, CD4 + FoxP3+ T cells appeared a crucial population for response to immunotherapy. Conclusion: The results of this study underly the clinical relevance and functional importance of composition and localization of antitumor effector cells for the progression of UM metastasis. [ABSTRACT FROM AUTHOR]

Background: Simultaneous occurrence of exocrine and neuroendocrine tumors of the pancreas is very infrequent. We report a patient with an endocrine tumor in the pancreatic-duodenal area and extensive exocrine carcinoma involving the whole pancreas. Case presentation: A 69-year-old woman was hospitalized in May 2016 for epigastric pain and weight loss. Her past medical history revealed an undefined main pancreatic duct dilation that was subsequently confirmed at CT scan (23 mm) and endoscopic ultrasound. There was no evidence of pancreatic masses, but the cephalic portion of the main pancreatic duct presented hypoechoic nodules. A diagnosis of the main-duct intraductal papillary mucinous neoplasm was made, and the patient underwent total pancreatectomy. Pathological examination showed a collision tumor constituted by a ductal adenocarcinoma involving the whole pancreas and a neuroendocrine tumor located in the duodenal peripancreatic wall and the head of the pancreas. There was one peripancreatic lymph node metastasis from the ductal adenocarcinoma and eight node metastases from the neuroendocrine tumor. These findings suggested a diagnosis of collision of neuroendocrine and ductal adenocarcinomas of the pancreas. The postoperative course was uneventful. Conclusions: The coexistence of pancreatic endocrine and exocrine tumors is very uncommon. When present, problems in differential diagnosis may arise between mixed exocrine-endocrine carcinoma or the collision of separate tumors. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article by K. Yoshizawa and colleagues on the relationship between Mammary Serine Protease Inhibitor (MASPIN) expression and clinico-pathologic features in anoral squamous cell carcinoma in a previous issue.

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon, aggressive malignancy with a poor prognosis in advanced cases. The dismal outcome is partially related to: the lack of reliable clinical or pathological prognostic factors and the largely unstandardized surgical and integrated treatments adopted. There is an undeniable need for novel diagnostic/therapeutic strategies to improve the prognosis. The purpose of this critical review was to explore the level of available knowledge concerning the molecular markers involved in the biology of TBSCC that have a prognostic potential. The Pub-Med and Scopus electronic databases were searched without publication date limits for studies investigating molecular markers in cohorts of patients with primary TBSCC. The search terms used were: 'temporal bone cancer', 'temporal bone carcinoma', 'temporal bone malignancy', 'ear cancer', 'ear carcinoma', and 'ear malignancy'. We decided preliminarily not to consider series with less than five cases. Nine retrospective case series of TBSCC were found in which different analytical techniques had been used to study the role of several biomarkers (HPV, vimentin, transforming growth factor β, CD105, RECK, matrix metalloproteinase-9, MASPIN, EBV, p16, TP53 mutation, pSTAT3, relaxin-2). CD105 expression (in tumor vessel endothelial cells) and MASPIN cytoplasmic expression (in carcinoma cells) were, respectively, found directly and inversely related with the neoplasm's recurrence rate. CD105 expression was also inversely related with disease-free survival in TBSCC. A future goal of such analyses should be to ascertain the radio- and chemo-sensitivity profiles of individual TBSCCs, enabling truly personalized therapies. A further, more ambitious goal will be to find targets for therapeutic agents that might prove crucial in improving the disease-specific survival for patients with advanced TBSCC. [ABSTRACT FROM AUTHOR]

Laryngeal squamous cell carcinoma (LSCC) recurrences are very difficult to manage in elderly patients (age ≥65 years), because treatment carries significant morbidity and mortality. The aim of this study was to develop a panel of parameters (clinicopathological variables or biomarkers) to improve our ability to detect elderly patients at higher risk of LSCC recurrence. Maspin, nm23-H1, and CD105 were investigated using immunohistochemistry on surgical specimens from 46 elderly patients treated for LSCC. After univariate analysis identified parameters associated with LSCC recurrence, a multivariate prognostic model was constructed. At univariate analysis, a higher recurrence rate was significantly associated with nm23-H1 nuclear expression in carcinoma cells ≤2.0 % ( p = 0.01), CD105 expression in intratumoral vascular endothelial cells ≥5.28 % ( p = 0.04), and pN+ status ( p = 0.04). Multivariate modeling confirmed that nuclear nm23-H1 ≤2.0 % ( p = 0.009) and CD105 ≥5.28 % ( p = 0.013) had a negative prognostic significance in terms of disease recurrence, while pN+ status showed a trend toward significance ( p = 0.05). We thus obtained a panel comprising two biomarkers and neck lymph node status that revealed an excellent discriminatory power [AUC (ROC) of 0.81] in terms of the risk of LSCC recurrence. The panel achieved a specificity of 96 % and a positive predictive value of 93 %. We identified a panel with an excellent discriminatory power in identifying elderly patients at higher risk of recurrence after treatment for LSCC. These patients would benefit from a more aggressive primary treatment. [ABSTRACT FROM AUTHOR]

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon, aggressive malignancy with a significant local recurrence rate even in patients with postoperative pathology reports of free surgical margins. This raises the question of how 'free' negative margins should be to be oncologically safe, especially in bone tissue. A potential role for relaxin-2 hormone in tumor-driven osteolysis has recently been reported. The aim of this study was to assess the prognostic role of relaxin-2 expression in TBSCC tissue specimens and pathologically negative bone margins. Relaxin-2 immunohistochemical expression was assessed in 25 consecutively operated TBSCC patients. Several pathological variables correlated with recurrence rate (pT stage, dura mater involvement), disease-free survival (DFS) (pT stage, pN status, grade, and dura mater involvement), and disease-specific survival (DSS) (pT stage, pN status, grade, and dura mater involvement). The recurrence rate, DFS, and DSS did not correlate with relaxin-2 expression in TBSCC specimens or pathologically negative bone margins. Although local recurrence in TBSCC could relate to neoplastic bone invasion not apparent on conventional pathological investigations, the present preliminary findings seem to rule out any role of relaxin-2 in mediating this local aggressiveness. Molecular mechanisms of TBSCC recurrence after curative treatment should be further investigated. [ABSTRACT FROM AUTHOR]

Aims Laryngeal squamous cell carcinoma ( LSCC) prognosis is definitely related to lymph node metastasis. Epithelial-mesenchymal transition ( EMT) allows neoplastic cells to gain the plasticity and motility required for tumour progression and metastasis. The aim of this study was to investigate the role of EMT in the prognosis of LSCC. Methods and results Immunohistochemical analysis of E-cadherin, N-cadherin, Snail, Slug, ZEB1, and ZEB2 was performed in 37 consecutive LSCC cases. Low E-cadherin levels and high Slug levels correlated with both disease recurrence ( P = 0.02 and P =0.01, respectively) and shorter disease-free survival ( DFS) ( P = 0.04 and P = 0.02, respectively). Relative expression levels of CDH1, SNAI2, miR-1 and the miR-200 family were also evaluated. CDH1, miR-200a and miR-200c down-regulation and SNAI2 overexpression were significantly associated with disease recurrence ( P = 0.03, P = 0.02, P = 0.04, and P = 0.04, respectively). Conclusions EMT increases tumour recurrence risk and shortens DFS in LSCC. E-cadherin and Slug immunohistochemical analysis could be useful for identifying patients requiring more aggressive treatment after surgery. [ABSTRACT FROM AUTHOR]

Purpose: Despite recent advances in diagnostic and therapeutic techniques, the prognosis for patients with head and neck squamous cell carcinoma (HNSCC) has not improved significantly. Novel clinical strategies are needed to identify HNSCC patients with a poor prognosis, who may benefit from a tailored therapy. Several bio-markers have been recently considered for prognostic purposes in oral carcinoma. Angiogenin (ANG) is a member of the ribonuclease superfamily and of medical interest largely because it supports the growth of primary and metastatic malignancies. ANG has recently been found involved in cancer cell proliferation as well as in tumor angiogenesis. The present study is the first to investigate the potential role of ANG in tongue carcinoma neo-angiogenesis and cancer cell proliferation. Materials and methods: ANG expression (in carcinoma cells and endothelial intratumor vessel cells), CD105-assessed micro-vessel density (MVD), and MIB-1 expression were correlated with prognostic parameters in 28 consecutively-operated pT1–T2 tongue carcinomas (SCC). Whenever feasible, a computer-based image analysis system was used for the immunohistochemical reaction analysis. Results: No significant correlations emerged between ANG expression in the tongue carcinoma cells or endothelial intratumor vessel cells and tongue carcinoma recurrence or disease-free survival (DFS). ANG expression was also unrelated to CD105-assessed MVD or MIB-1 expression. Conversely, CD105-assessed MVD correlated directly with recurrence rate (p =0.02), and DFS was significantly shorter in cases with CD105-assessed MVD>167micro-vessels/mm2 than in those with MVD⩽167micro-vessels/mm2(p=0.042). Conclusions: Our results support the hypothesis that CD105-assessed MVD would be a valuable parameter for predicting which patients with tongue SCC are at greatest risk of carcinoma recurrence. Despite our study results, the role of ANG in tongue carcinoma warrants further investigation in larger series because blocking ANG expression might have the potential not only to reduce angiogenesis in malignancies, but also to directly inhibit tumor growth. [Copyright &y& Elsevier]

. Purpose: To investigate the presence of KIT gene mutations and immunoreactivity in 85 conjunctival melanocytic tumours and to clarify the role of KIT as a potential therapeutic target in this group of patients. Methods: Eighty-five conjunctival pigmented tumours [27 melanomas, 12 primary acquired melanosis (PAMs) and 46 nevi] were immunostained for KIT. Intensity and pattern of expression were evaluated. Molecular analysis to identify KIT mutations was performed in 15 selected cases (tumour-rich areas >50%). KIT immunostaining score and pattern were statistically related to patients' age, sex, diagnostic category, presence of relapse, disease-free survival, presence of metastases, metastasis-free survival, limbal versus nonlimbal tumour location and thickness of melanomas. Results: KIT stains were documented in 48% of melanomas, 50% of PAMs and 24% of nevi. The mean score of KIT staining in the melanomas/PAMs group was significantly different from nevi (p = 0.0076). No statistically significant differences were detected between either c-kit immunostaining score or pattern and each of the other clinico-pathologic parameters considered. No KIT gene mutations were detected in melanomas and nevi. A silent mutation/polymorphism in KIT exon 13 was found in one PAM. Conclusions: Despite the high level of KIT immunostains in PAMs and melanomas, this parameter seems not to be a good predictor of the presence of molecular mutations. KIT-activating mutations should be considered an uncommon event in this tumour. [ABSTRACT FROM AUTHOR]

Aims Although it accounts for fewer than 0.2% of all head and neck tumours, temporal bone squamous cell carcinoma ( SCC) is an aggressive malignancy with a poor prognosis in advanced cases. Novel therapeutic strategies should be developed focusing on specific targeted therapies. Maspin is a serpin showing tumour-suppressing activity which has therapeutic potential. The present study is the first to investigate maspin expression in temporal bone SCCs, using a series of 29 cases. Methods and results Cytoplasmic maspin expression was significantly higher in the group of patients whose SCC did not recur than in the group experiencing recurrences ( P = 0.029), and in G1-G2 SCCs than in G3 cases ( P = 0.001). cT correlated with recurrence rate ( P = 0.05), disease-free survival ( DFS) ( P = 0.008) and disease-specific survival ( DSS) ( P = 0.0043), and pT and pathological regional lymph node status correlated with recurrence rate ( P = 0.008 and P = 0.03, respectively), DFS ( P = 0.017 and P = 0.0049, respectively) and DSS ( P = 0.008 and P = 0.0009, respectively). Conclusions Although further studies using larger series are required, our preliminary findings suggest that cytoplasmic maspin expression has promise as a prognostic indicator of disease recurrence in temporal bone SCC, and that reactivating maspin functions in association with apoptosis-inducing or anti-angiogenic chemotherapeutic agents might be an important goal in the treatment of temporal bone SCC. [ABSTRACT FROM AUTHOR]

Background Angiogenin ( ANG) is a member of the ribonuclease superfamily and of medical interest largely because it supports the growth of primary and metastatic malignancies. This study is the first to investigate the potential role of ANG in tongue carcinoma neo-angiogenesis and cancer cell proliferation. Methods Angiogenin expression (in carcinoma cells and endothelial intratumor vessel cells), CD105-assessed micro-vessel density (MVD), and MIB-1 expression were correlated with prognostic parameters in 28 primarily consecutively operated pT1-T2 tongue carcinomas (squamous cell carcinoma [SCC]). Whenever feasible, a computer-based image analysis system was used for the immunohistochemical reaction analysis. Results No significant correlations emerged between ANG expression in the tongue carcinoma cells or endothelial intratumor vessel cells and tongue SCC recurrence rate or disease-free survival ( DFS). ANG expression was also unrelated to CD105-assessed MVD or MIB-1 expression. Conversely, CD105-assessed MVD correlated directly with recurrence rate ( P = 0.02) and DFS was significantly shorter in cases with CD105-assessed MVD >167 micro-vessels/mm2 than in those with CD105-assessed MVD ≤167 micro-vessels/mm2 ( P = 0.042). Conclusions Our results support the hypothesis that CD105-assessed MVD would be a valuable parameter for predicting which patients with tongue SCC are at greatest risk of disease recurrence. Despite our study results, the role of ANG in tongue carcinoma warrants further investigation in larger series. [ABSTRACT FROM AUTHOR]

Background Clinicopathological research has focused on identifying molecular and biological prognostic factors for laryngeal carcinoma ( LSCC) treated with post-operative radiotherapy ( RT). The aim of this study was to assess the prognostic importance of anti-apoptotic proteins survivin and B-cell lymphoma-2 ( Bcl-2) in a series of patients with LSCC who had primary surgery followed by RT. Methods Thirty-three consecutive patients who underwent primary surgery followed by RT were considered. Survivin nuclear and cytoplasmic expressions and Bcl-2 expression were determined immunohistochemically. Results The loco-regional recurrence rate was significantly higher among LSCC patients with a nuclear survivin expression >10.0% ( P = 0.029), and their disease-free survival ( DFS) was shorter than in cases whose nuclear survivin expression was ≤10.0% ( P = 0.002). DFS was significantly shorter in cases with a Bcl-2 expression >2.0% than in those whose Bcl-2 expression was ≤2.0% ( P = 0.035). Conclusions Nuclear survivin expression and Bcl-2 expression warrant further investigation as potential predictive biomarkers to enable individualized treatments (e.g. post-operative chemo-radiotherapy instead of RT alone for patients whose LSCCs strongly express nuclear survivin or/and Bcl-2). This preliminary evidence justifies the design of new studies on the association of agents targeting survivin and Bcl-2 with conventional chemotherapeutic agents and RT for advanced LSCC. [ABSTRACT FROM AUTHOR]

Marioni G, Ottaviano G, Lionello M, Lora L, Lovato A, Staffieri C, Favaretto N, Giacomelli L, Stellini E, Staffieri A & Blandamura S (2012) Histopathology Nm23-H1 nuclear expression is associated with a more favourable prognosis in laryngeal carcinoma: univariate and multivariate analysis Aims: To use image analysis and multivariate analysis to investigate the prognostic significance of Nm23-H1 subcellular localization in a large cohort of laryngeal squamous cell carcinomas (LSCCs). Methods and results: Nm23-H1 total and nuclear levels were immunohistochemically determined and calculated with an image analysis system in 104 consecutively operated LSCCs. The mean follow-up was 58.3 ± 35.1 months (median 45 months). Total Nm23-H1 levels correlated only with patient stratification by pT ( P = 0.01). Mean nuclear Nm23-H1 levels were lower in patients with recurrent disease ( P = 0.01), and disease-free survival (DFS) was longer in patients whose nuclear levels of Nm23-H1 were >2.0% than in those with levels ≤2.0% ( P = 0.019). On multivariate analysis, Nm23-H1 nuclear expression [hazard ratio (HR) 2.59, P = 0.005] and N stage (HR 3.60, P = 0.0001) were prognostically significant in relation to DFS. Conclusions: In LSCC, Nm23-H1 nuclear expression may be useful for identifying patients at higher risk of recurrence after treatment and who might be considered for more aggressive therapy. Further investigations are needed before Nm23-H1 can be considered for use in targeted treatments for LSCC. [ABSTRACT FROM AUTHOR]

The expression of insulin receptor (IR), together with that of glucose transporters 1 and 4 (GLUT1-4) and of Insulin Growth Factor-I and -II (IGF-I,-II) in the endometrium of healthy and young women in both phases of menstrual cycle was assessed. Sixteen out of 20 healthy and normal menstruating volunteers were studied. Endometrial samplings were performed in every subject, twice in the same cycle, during the follicular and luteal phase respectively. The mRNA expression of IR, GLUT1-4, IGF-I and -II were evaluated by real-time quantitative RT-PCR and immunostaining reactions. Our results indicate that IR, GLUT1-4, IGF-I and -II mRNAs were expressed in both phases of the endometrial cycle: GLUT4 and IGF-I mRNA expression were significantly higher in the follicular phase and localized at the epithelial and stromal cell level, respectively, whereas IR, GLUT1 and IGF-II mRNA expression were mostly present in the secretory phase and mainly localized at the stromal level. An inverse tendency of IR and GLUT4 mRNA expression was respectively observed from follicular to luteal phase. In conclusion our data suggest that IR, glucose transporters and IGFs are significantly and differently expressed at the endometrial level throughout the menstrual cycle and that human endometrium cyclically undergoes through a transitory condition from normal to an insulin-resistance state. [ABSTRACT FROM AUTHOR]

Marioni G, Agostini M, Bedin C, Blandamura S, Stellini E, Favero G, Lionello M, Giacomelli L, Burti S, D'Angelo E, Nitti D, Staffieri A & De Filippis C (2012) Histopathology 61, 247-256 Survivin and laryngeal carcinoma prognosis: nuclear localization and expression of splice variants Aims: Aberrant survivin expression in cancer cells has been associated with tumour progression, radiation/drug resistance and shorter patient survival. The aim of the present study was to investigate survivin expression in laryngeal carcinoma (LSCC) tissue and - for the first time at this site - the expression of survivin splice variants. P53 was also studied. Methods and results: Survivin and p53 expression was determined immunohistochemically in 86 consecutive patients operated for LSCC. Survivin mRNA expression was assessed by quantitative real-time polymerase chain reaction (PCR). Hot-spot mutations in exons 5, 6, 7 and 8 of the TP53 gene were studied by sequencing analysis. A nuclear localization for survivin predominated. There was a significant association between a higher nuclear survivin expression and LSCC recurrence ( P = 0.046). Disease-free survival (DFS) for LSCC patients with a nuclear survivin expression >7.0% was shorter than in cases whose expression was ≤7.0% ( P = 0.05). Wild-type survivin correlated significantly with nuclear survivin expression ( P = 0.02). p53 expression was associated with the co-expression of wild-type survivin and survivin-2B ( P = 0.01). Conclusions: Nuclear expression of survivin appears to influence LSCC aggressiveness, a higher nuclear survivin expression correlating with a higher recurrence rate and a shorter DFS. Wild-type survivin was the most frequently detected splice variant in LSCC tissues. [ABSTRACT FROM AUTHOR]

Summary: Cancer is common in the elderly, who may also be frail, which can complicate the choice of the best therapeutic approach. We sought to examine whether the serine–threonine kinase mTOR, a “master switch” in cancer cells that modulates metabolism, the cell cycle, and apoptosis, might help in clinical decision-making. The aim of the present study was thus to assess the potential prognostic role of mTOR in elderly patients with laryngeal carcinoma (LSCC). mTOR expression was determined immunohistochemically in 54 consecutive elderly (⩾65years old) patients with LSCC. On univariate analysis, nodal involvement and pathological stage correlated strongly with the elderly LSCC patients’ prognosis in terms of disease recurrence rate and disease-free survival (DFS). Patients whose mTOR expression was >35.3% had a significantly higher recurrence rate (p =0.003) and shorter DFS (p =0.013). In the multivariate model, N status (p =0.001) and mTOR expression (p =0.026) maintained an independent prognostic significance in relation to DFS. mTOR probably influences the aggressive LSCC phenotype in elderly patients and its expression in elderly LSCC cases can be considered a prognostic marker potentially useful for identifying patients at higher risk of disease recurrence, and N0 patients at higher risk of recurrence who may benefit from more aggressive treatment. Since rapalogs (as mTOR inhibitors) might have an effect on LSCC, further investigations are needed to ascertain these agents’ role in therapeutic strategies for advanced LSCC in elderly patients. [ABSTRACT FROM AUTHOR]

Marioni G, Staffieri A, Giacomelli L, Lionello M, Guzzardo V, Busnardo A & Blandamura S (2011) Histopathology [ABSTRACT FROM AUTHOR]

Summary: Surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is controversial. Current recommendations contraindicate aggressive surgery because its results are unpredictable and may trigger disease progression. In this prospective study, we assessed the effectiveness of surgical resection of the jaws in cancer patients with BRONJ. Between June 2004 and July 2009, 30 cancer patients with refractory BRONJ underwent surgical resection of the jaws at our Units. They were followed-up weekly for the first month, at 3-month intervals up to 1year, and at 6-month intervals up to 2years. Panoramic radiographs and CT-scan were obtained at 3, 6, 12, 18 and 24months. Primary outcomes were the 24-month recurrence rate of BRONJ and the 24-month mortality rate. Secondary outcomes were post-operative complications, duration of hospital stay after surgery, time to return to oral diet, and degree of oral pain. The 30 patients had a median age of 66years and were mostly females (80%). Twenty-eight underwent a single resection and two had both jaws resected, for a total of 32 resected jaws. The cumulative recurrence rate of BRONJ in resected jaws 3.1% and 9.4% at 3 and 6months, respectively. All the jaws with recurrent BRONJ had osteomyelitis at the margins of bone resection. The cumulative incidence of death was 3%, 12% and 16% at 12, 18 and 24months. Surgical resection of BRONJ was highly effective, with few post-operative complications and were not associated with long-term mortality. [ABSTRACT FROM AUTHOR]

J Oral Pathol Med (2011) : 55-60 Basaloid squamous cell carcinoma is an uncommon variant of squamous cell carcinoma (SCC). Angiogenin (ANG), a member of the ribonuclease super-family, is essential to tumor angiogenesis, but has also been implicated in tumor consolidation and proliferation. ANG expression was first investigated in 12 head and neck basaloid squamous cell carcinomas (HNBSCCs) and compared with a control group of 24 site- and stage-matched conventional SCCs to establish whether the supposedly more aggressive biological behavior of HNBSCCs might be ANG-related. No significant differences were found between HNBSCCs, and SCCs in terms of recurrence, disease-free survival (DFS), or overall survival rates. In HNBSCC, we identified a trend toward a significant inverse correlation between endothelial ANG expression and DFS (statistical trend, P = 0.08). Endothelial ANG expression did not differ significantly in HNBSCCs and SCCs. A high ANG expression in carcinoma cells was directly associated with pT in both the HNBSCC ( P = 0.04) and the SCC (statistical trend, P = 0.07) groups. ANG expression in carcinoma cells was significantly lower in HNBSCCs than in SCCs ( P = 0.005). All the biological mechanisms investigated to date, including ANG-mediated angiogenesis or cell proliferation, have failed to confirm that HNBSCCs have a more aggressive behavior than matched SCC. [ABSTRACT FROM AUTHOR]

Conclusions: Further studies based on large series are necessary to investigate the role of MASPIN and angiogenin (ANG) in angiogenetic mechanisms of nasopharyngeal carcinoma (NPC) and their potential as prognostic markers. Objectives: NPC is a malignancy with an incidence among Caucasians of < 1 per 100 000 per year. In NPC, the aberrations of many pathways and the alteration in expression of several proteins have been reported. Tumor angiogenesis is the result of an imbalance between pro- and anti-angiogenic factors. MASPIN exerts several anti-tumor effects including inhibition of tumor-induced angiogenesis. ANG regulates angiogenesis under both physiological and pathological conditions supporting primary and metastatic tumor growth. Methods: For the first time, we preliminarily investigated by immunohistochemistry the subcellular localization and expression of MASPIN, and the expression of ANG (in both carcinoma cells and intra-tumor vessels) and Ki-67 in 15 Caucasian patients with NPC treated with the same chemo-radiotherapeutic protocol. Results: MASPIN-positive NPCs had a prevalent cytoplasmic localization pattern. A trend towards significant direct correlation between MASPIN presence and disease-free survival (DFS) ( p = 0.08) and a trend towards significant inverse correlation between ANG expression and DFS ( p = 0.07) were found. An association between MASPIN presence and lower ANG expression in carcinoma cells was disclosed (statistical trend, p = 0.10). [ABSTRACT FROM AUTHOR]

Despite advances in laryngeal squamous cell carcinoma (LSCC) treatment, patient survival has not improved in the last two decades. Novel, more effective strategies should be based on receptor-mediated LSCC-targeted therapy. The epidermal growth factor receptor (EGFR) is the most widely studied molecular target. MASPIN multifaceted anti-tumor effects have been rarely evaluated in LSCC. The aims of this study were to investigate EGFR and MASPIN expression and the role of sub-cellular MASPIN localization in LSSC. MASPIN and EGFR expression and the sub-cellular localization of MASPIN were assessed using a computerized image analysis system in 108 consecutive cases of operable LSCC. The rates of occurrence of lymph node metastases and recurrent disease were lower in patients with a nuclear pattern of MASPIN expression ( p = 0.004, p = 0.0028). As expected, the loco-regional recurrence rate was lower in N0 patients ( p = 0.009), but the disease recurrence rate was even lower in N0 patients with a nuclear localization of MASPIN ( p = 0.020). Disease-free survival was longer in cases of LSCC with a nuclear MASPIN pattern ( p = 0.003). The intensity of EGFR reactivity and the EGFR area fraction were unrelated to the clinico-pathological and prognostic parameters in LSCC. A nuclear MASPIN pattern is a promising prognostic indicator in LSCC, but further evidence is needed before elective neck dissection can be considered for cN0 LSCCs with a non-nuclear MASPIN pattern. Although a better understanding of the mechanisms behind sub-cellular MASPIN localization is mandatory, re-activating nuclear MASPIN in association with specific chemotherapeutic agents may be an important goal in the treatment of LSCC. [ABSTRACT FROM AUTHOR]

Conclusions: Our very preliminary results support the hypothesis that MASPIN expression in primary head and neck squamous cell carcinoma (HNSCC) may be a valuable parameter for predicting patients' responses to a treatment based on carboplatin plus vinorelbine combined with radiotherapy. Objectives: The roles of induction chemotherapy and combined chemoradiotherapy in the treatment of locally advanced unresectable HNSCCs have evolved rapidly. MASPIN has a unique tumour-suppressing activity. Experimental evidence has shown that MASPIN suppresses tumour growth, angiogenesis, invasion and metastasis. We investigated the potential prognostic roles of MASPIN and p53 in a series of HNSCCs treated with carboplatin plus vinorelbine combined with radiotherapy. Patients and methods: Nineteen consecutive stage III or IV HNSCC patients were recruited. The treatment plan consisted of the administration of carboplatin on day 1 and vinorelbine on days 1 and 8. Four weeks later, carboplatin was administered concomitantly with radiation therapy. Expression of MASPIN and p53 was determined immunohistochemically in HNSCC diagnostic biopsies. Results: A significant inverse relation was found between MASPIN expression and cN staging (p=0.003). From a prognostic viewpoint, MASPIN expression was directly correlated with chemoradiotherapy response (p=0.041). Moreover, the log-rank test showed a significant relationship between higher MASPIN expression and longer disease-free survival (p=0.03), overall survival (p=0.006) and disease-specific survival (p=0.007). [ABSTRACT FROM AUTHOR]

Conclusions. A large series confirmation may suggest elective neck dissection in cN0 MASPIN-negative oral squamous cell carcinomas (SCCs). Re-activated nuclear MASPIN in association with anti-angiogenic or cytotoxic drugs may be extremely effective in the treatment of laryngeal SCC. Objectives. MASPIN is a serpin showing a unique tumour-suppressing activity. Despite the significant incidence of head and neck SCC (HNSCC), a limited number of studies has considered MASPIN's role in these malignancies. This review focuses on the attempts to translate MASPIN's HNSCC suppressive properties toward a diagnostic/prognostic tool and a novel carcinoma therapy. Methods. A systematic literature review was performed to investigate available evidence about MASPIN subcellular localization and biological role in HNSCC. Results. Five studies have investigated MASPIN's expression in oral SCC. Most of them concluded that low or absent MASPIN cytoplasmic expression was more frequent in oral carcinomas with lymph node metastases. Only our group evaluated MASPIN's role in laryngeal SCC. Higher nuclear MASPIN expression was found in patients without SCC recurrence and was significantly associated with longer disease-free survival. Micro-vascular density was lower in laryngeal carcinomas with MASPIN nuclear staining. The relation between MASPIN and M30-assessed apoptosis in laryngeal SCC supports the hypothesis of an important apoptosis-sensitizing effect of nuclear MASPIN. [ABSTRACT FROM AUTHOR]

Few studies have tried to go beyond the conventional clinic-pathological prognostic factors investigating the molecular markers involved in the biology of temporal bone squamous cell carcinoma (TBSSC). Tumor budding represents a very aggressive subpopulation of cancer cells and demonstrates the heterogeneity of cancer cells residing in different locations within tumors. The main aim of this exploratory study was to investigate the role of tumor budding in primary TBSCC prognosis. We also analyzed the association between TBSCC tumor budding and: (i) loco-regional aggressiveness evaluated according to the revised Pittsburgh staging system, (ii) tumor infiltrating lymphocytes, lymphovascular invasion (LVSI), perineural invasion, pattern of invasion, and type of stroma. Thirty-two TBSCCs treated surgically were considered. The three-tier grading system recommended by the International Tumor Budding Consensus Conference was used first on TBSCC. Advanced (T3–4) TBSCC was related with high risk intra-tumoral budding (ITB) at two-tier risk grading (p = 0.0361). N + status was associated with intermediate/high budding (Bd2–3) at three-tier risk grading for peri-tumoral budding (PTB) (p = 0.0382). Disease-free survival (DFS) was related with T-stage (p = 0.0406), N-status (p < 0.0001), PTB two-tier risk grading (p = 0.0463), LVSI (p < 0.0001). Overall survival (OS) was associated with N-status (p = 0.0167), PTB absolute count (p = 0.0341), PTB three-tier risk grading (p = 0.0359), PTB two-tier risk grading (p = 0.0132), and LVSI (p = 0.0004). At the multivariate analysis, DFS was related with N-status (p = 0.0147) and LVSI (p < 0.0001), while OS resulted associated only with LVSI (p = 0.0144). Our preliminary findings suggest that tumor budding in TBSCC, regardless of its localization (the main tumor body [ITB] or invasive front [PTB]) may be a reliable predictor of neck lymph node metastasis and poor prognosis. Tumor budding and LVI could be predictive markers for precise treatment in TBSCC. Further investigations on larger prospective series should be designed to confirm this evidence both in post-operative specimens and in preoperative biopsies. [ABSTRACT FROM AUTHOR]

MASPIN, a member of serpin superfamily, has multifaceted biological functions and an unique tumour suppressing activity. Experimental evidences showed that MASPIN suppresses tumour growth, angiogenesis, invasion and metastasis. Only a very limited number of studies considered MASPIN expression in the upper aero-digestive tract carcinomas. It was recently found that nuclear localization of MASPIN was significantly associated with lower recurrence rate and longer disease-free interval in laryngeal carcinoma. The present study investigated the biological and prognostic role of MASPIN in relation to its subcellular localization in oral carcinoma. Sub-cellular pattern of distribution of MASPIN, nuclear and cytoplasmic MASPIN expressions were immunohistochemically determined in 56 consecutive cases of oral carcinoma. Statistical analysis found a significant association between pN-stage and recurrence of disease ( P = 0.032) and a significantly longer disease-free interval in pN0 patients than in pN+ ones ( P = 0.038). None of the subcellular expressions of MASPIN was significantly correlated with recurrence of disease and disease-free interval in our series of oral carcinomas. Sixty-one percent of pN0 cases was strongly MASPIN-positive in the cytoplasm of primary carcinoma cells, 33% of the pN+ cases was MASPIN-positive in the cytoplasm. Statistical analysis found a significant association between MASPIN cytoplasmic expression and pN-stage ( P = 0.032). Negative MASPIN immunoreactivity in carcinoma cells cytoplasm may be useful to identify patients at risk of disease disseminating to neck lymph nodes. Further investigations are necessary to understand the biological role of cytoplasmic MASPIN localization in oral carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Background: Osteonecrosis of the jaw is a well known potential complication of bisphosphonate treatment but its pathogenesis is poorly understood. The current management of patients with bisphosphonate-associated osteonecrosis (BON) is based on “expert recommendations” and there is a recognized need of better evidence. We report two cases where BON hid jaw metastases and use them to discuss some limitations of the current recommendations. Patients: Two patients undergoing long-term I.V. amino-bisphosphonate treatment for metastatic cancer presented with areas of intraorally exposed jawbone. Bisphosphonate-associated osteonecrosis was diagnosed on the basis of medical history, clinical and radiological features. They underwent surgical resection of the affected jaw due to unrelenting pain and lack of response to conservative treatments. Results: Histological examination of the surgical specimen revealed cancer cells at the margins of the site of osteonecrosis. Our patients did not undergo bone biopsy according to current recommendations, due to lack of clinical and radiological signs suggestive of jaw metastases. Conclusions: Our findings show that: i) patients with BON may also have jaw metastases; ii) there may not be clinical or imaging hints to this fact and; iii) that a biopsy based on careful selection of the site (with inclusion of necrotic margins) may be needed to reach the correct diagnosis. Further studies should be performed on this topic because of its very important prognostic implications. [Copyright &y& Elsevier]

There is debate about the role of human papillomavirus in the induction of rare inverted papillomas involving the temporal bone and in the higher recurrence rates and association with squamous cell carcinoma of temporal bone inverted papillomas compared with sinonasal inverted papillomas. An exhaustive review of the literature revealed that eight cases of temporal bone inverted papilloma have been analysed for human papillomavirus. None of the cases studied with in situ hybridization proved positive. Only one case was found to be positive using the more sensitive polymerase chain reaction assay. We present the first two cases of Schneiderian-type papilloma involving the temporal bone to be analysed by type-specific polymerase chain reaction methods for human papillomavirus. [ABSTRACT FROM AUTHOR]

Simple summary: The mechanism of epithelial–mesenchymal transition is fundamental for carcinogenesis, tumor progression, cancer cell invasion, metastasis, recurrence, and therapy resistance, resulting in cellular junction degradation and increased cellular motility. The same factors that drive epithelial cells toward a mesenchymal phenotype may also drive endothelial cells toward a proangiogenic phenotype. This study aimed to investigate a potential interplay between epithelial–mesenchymal transition and angiogenesis in laryngeal carcinoma. In our study, univariate Cox regression identified pN+ status and Slug expression as predictive of disease-free survival, while a trend toward significance emerged for CD105-assessed microvessel density and N-cadherin expression. In the multivariate Cox regression model, pN-status, Slug, and N-cadherin expressions retained their significant values in predicting disease-free survival. Data from our study support the hypothesis of a mutual concurrence of epithelial–mesenchymal transition and angiogenesis in the development of an aggressive phenotype in laryngeal squamous cell carcinoma. The mechanism of epithelial–mesenchymal transition (EMT) is fundamental for carcinogenesis, tumor progression, cancer cell invasion, metastasis, recurrence, and therapy resistance, comprising important events, such as cellular junction degradation, downregulation of epithelial phenotype markers, overexpression of mesenchymal markers, and increase in cellular motility. The same factors that drive epithelial cells toward a mesenchymal phenotype may also drive endothelial cells toward a proangiogenic phenotype. The aim of this exploratory study was to investigate a potential interplay between EMT and angiogenesis (quantified through CD105 expression) in laryngeal carcinoma (LSCC). CD105-assessed microvessel density (MVD) and EMT markers (E-cadherin, N-cadherin, Snail, Slug, Zeb1, and Zeb2) were assessed on 37 consecutive LSCC cases. The univariate Cox regression model identified pN+ status (p = 0.0343) and Slug expression (p = 0.0268) as predictive of disease-free survival (DFS). A trend toward significance emerged for CD105-assessed MVD (p = 0.0869) and N-cadherin expression (p = 0.0911). In the multivariate Cox model, pN-status, Slug, and N-cadherin expressions retained their significant values in predicting DFS (p = 0.0346, p = 0.0430, and p = 0.0214, respectively). Our data support the hypothesis of a mutual concurrence of EMT and angiogenesis in driving LSCC cells toward an aggressive phenotype. To better characterize the predictive performance of prognostic models based on EMT and angiogenesis, further large-scale prospective studies are required. [ABSTRACT FROM AUTHOR]

Objectives: The immune system is crucial in the evolution of head and neck cancer. Programmed cell death ligand 1 (PD-L1) seems to rely on close relations between neoplastic cells and immune cells in the tumor microenvironment. The main aim of this study was to apply univariate/multivariate analysis to investigate the prognostic significance of PD-L1, tumor-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLS) in laryngeal carcinoma (LSCC).Materials and Methods: PD-L1 (in terms of combined positive score [CPS]), TILs and TLS were assessed at pathology on 70 consecutive samples of LSCC.Results: A CPS ≥ 1 coincided with a lower recurrence rate (RR) (p = 0.007) and longer disease-free survival (DFS) than a CPS < 1 (p = 0.0027). Cases with higher TIL counts showed a lower RR (p = 0.036) and longer DFS than those with lower TIL counts (p = 0.0062). Cases revealing TLS had a lower RR (p = 0.004) and longer DFS (p = 0.0034) than those with no TLS. On multivariate analysis, the presence of TLS retained its positive prognostic value (p = 0.024), while CPS remained significant as regards disease recurrence (p = 0.050).Conclusions: PD-L1 seems to be an indirect marker of effective anti-tumor response in LSCC, possibly being expressed as a result of a greater immune pressure on cancer cells. The presence of TLS emerged as a positive prognostic factor. Further prospective studies are needed to characterize the role of PD-L1 as a marker of anti-tumor immune response and prognostic factor in LSCC, also with regard to the effectiveness of immunotherapeutic protocols. [ABSTRACT FROM AUTHOR]

Considering clinical evidence, <2% of laryngeal malignancies are distant metastases. Cutaneous melanomas are the preponderant primaries metastasizing to the larynx, followed by renal cell carcinomas, breast and lung carcinomas. Colonic adenocarcinoma metastases to the larynx are extremely rare: only 13 cases have been described since 1972. We present the first case of sigmoid colon adenocarcinoma metastasis to the larynx in a patient who developed peristomal malignancy recurrence after total laryngectomy. Patients with metastasis of colonic adenocarcinoma to the larynx usually present with disseminated disease: in view of the poor chances of long-term survival of these patients conservative palliative laryngeal treatments should be carried out to improve the quality of life. Curative treatment should be considered only in isolated laryngeal metastasis. [ABSTRACT FROM AUTHOR]