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To report on the anti-tumor activity of a novel combination in high-risk locally advanced head and neck squamous cell carcinoma.At a fixed dose of 1500 mg every 28 days, anti PD-L1 Durvalumab was given concomitantly to Radiotherapy and Cetuximab starting from the first week of combined treatment, followed by adjuvant Durvalumab to a maximum of 6 months after completion of radiation. The primary endpoint of the study was 2-year progression-free survival (PFS). A safety run-in was planned. Due to regulatory issues which prevented from opening multiple centers, COVID-19 pandemic and withdrawal of Durvalumab from supporting company, the study was prematurely terminated in April 2021.Between July 2019 and August 2020, 9 patients were enrolled in the study. All tumors had a PD-L1 Combined Positive Score 1. Optimal drug exposure was observed, with mean relative dose intensity of 85.5% and 87.5% for Cetuximab and Durvalumab, respectively. No radiation breaks were necessary. A grade 4 mucositis lasting for 14 days corresponded to the only dose limiting toxicity we reported. At a median follow-up of 11.5 months (IQR 7.7-16.7) all surviving patients (6 out of 9) are disease-free, with 1 and 2-year PFS rates of 77.7% and 58.3%, respectively. A selective sparing of node levels in the elective volume was performed in all cases, yielding a cumulative mean dose of 37.6 Gy (SD 8.4).Albeit limited by the small sample size, our preliminary observation of anti-tumor activity and tolerability of Durvalumab in addition to Cetuximab and radiation may warrant further investigations.

Authors retrospectively analyzed possible prognostic factors in a series of patients affected by Ewing sarcoma of extremities (eEWS) and treated over a 20-year period at a single institution. Between 1997 and 2017, 88 bone eEWS were treated at our institution. Staging, age, gender, tumoral volume, local treatment, surgical margins, post-ChT necrosis were investigated for prognostic correlation with overall survival (OS) and event-free survival (EFS). Median follow-up was 74 months (1–236). Staging of disease correlated with OS (81% vs 59%, p = 0.01) and not with EFS (68% vs 57%, p = 0.28) in localized vs metastatic eEWS at presentation. Age ≥ 14 years (p = 0.002) and volume ≥ 100 cm3 (p = 0.04) were significant negative prognostic factors. No difference was found in local treatment: OS was 76% vs 63% (p = 0.33), while EFS was 68% vs 49% (p = 0.06) after surgery alone or surgery + radiotherapy, respectively. Regarding surgical margins, OS was 76% vs 38% (p = 0.14), and EFS was 65% vs 33% (p = 0.14) in adequate vs not adequate, respectively. OS was 86% and 68% in good and poor responders, respectively (p = 0.13). In eEWS, metastatic disease at presentation, age > 14 years and tumoral volume > 100 cm3 are negative prognostic factors. Intensified adjuvant ChT can improve prognosis in poor responders and metastatic patients.

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unluckily restricted to a small subgroup of patients. Much of the inter-individual variability in treatment efficacy is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. The nucleotide excision repair (NER) system is the main defense mechanism for repairing DNA damage caused by carcinogens and chemotherapy drugs. Single nucleotide polymorphisms (SNPs) of NER pathway key genes, altering mRNA expression or protein activity, can be significantly associated with response to chemotherapy, toxicities, tumor relapse or risk of developing cancer. In the present study, in a cohort of STS patients, we performed DNA extraction and genotyping by SNP assay, RNA extraction and quantitative real-time reverse transcription PCR (qPCR), a molecular dynamics simulation in order to characterize the NER pathway in STS. We observed a severe deregulation of the NER pathway and we describe for the first time the effect of SNP rs1047768 in the ERCC5 structure, suggesting a role in modulating single-stranded DNA (ssDNA) binding. Our results evidenced, for the first time, the correlation between a specific genotype profile of ERCC genes and proficiency of the NER pathway in STS.

Aims Secretory carcinoma (SC) (synonym: mammary analogue secretory carcinoma) is a low-grade salivary gland tumour that occurs in both major and minor salivary glands. SC is known for its wide morphological, architectural and immunohistochemical spectrum, which overlaps with those of several salivary gland neoplasms, including acinic cell carcinoma (AciCC) and intercalated duct-type intraductal carcinoma (IDC) in major salivary glands, and polymorphous adenocarcinoma (PAC) in minor salivary glands. These tumours share with SC some morphological features and SOX10 immunoreactivity; also, with the exception of AciCC, they all coexpress S100 and mammaglobin. Methods and results We compared MUC4 and mammaglobin expression in 125 salivary gland carcinomas (54 genetically confirmed SCs, 20 AciCCs, 21 PACs, and 30 IDCs) to evaluate the potential of these two markers to differentiate these entities. Moderate to strong diffuse MUC4 positivity was detected in 49 SCs (90.7%), as compared with none of the IDCs and PACs. In contrast, mammaglobin was frequently expressed in SCs (30 of 36 cases; 83.3%), IDCs (24/28; 85.7%), and PACs (7/19; 36.8%). Two of three high-grade SCs lost MUC4 expression in the high-grade tumour component. No significant correlation was found between MUC4 expression and the fusion variant in SC (ETV6-NTRK versus non-ETV6-NTRK). Conclusion The results of our study identify MUC4 as a sensitive (90.7%) and specific (100%) marker for SC, with high positive (100%) and negative (93.4%) predictive values. Thus, MUC4 may be used as a surrogate for SC in limited biopsy material and in cases with equivocal morphology.

Introduction This case-series is aimed to describe the natural history of epithelioid sarcoma (ES) and to provide insights into the differential clinical behaviour of its two variants (“classic-type” and “proximal-type”). The value of a subtype-adapted grading system based on pathological features is explored. Methods Data from consecutive, primary, localised, INI1-deleted ES operated at three Italian sarcoma reference centres (1995–2015) were included. Centralised pathological review was performed. Classic-type ES was broken down into “high-grade” and “low-grade”, according to number of mitoses, evidence of necrosis and nuclear atypia. Five- and 10-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were estimated. Results Fifty-two patients were included. 5- and 10-year OS estimates were 70% and 47% in the whole series, 57% and 37% in patients with proximal-type ES, 77% and 54% in patients with classic-type ES (P = 0.02). In classic-type ES, 5- and 10-year OS was higher for low-grade (95% and 72%, respectively) than high-grade tumours (P = 0.002). 5- and 10-year CCI estimates for LR were 21% and 33% in the whole series. 5- and 10-year CCI estimates for DM were 35% and 39% in the whole series, both 28% in classic-type ES, 47% and 59% in proximal-type ES (P = 0.03). Conclusions Suffering from a proximal- or a classic-type is the stronger predictor of outcome in patients with localised ES, with proximal-type ES patients having lower survival due to a higher tendency toward metastatic spreading. However, the “high-grade” classic-type ES was associated with outcomes close to proximal-type ES.

Highlights • Immunotherapy is a new option for head and neck squamous cell carcinoma. • Very limited data are available for concurrent radio-immunotherapy in recurrent disease. • Our case report adds to this very limited series, focusing on oligopression under immunotherapy., Immune checkpoint inhibitors (ICIs) represent a recently introduced class of agents active in head and neck squamous cell carcinoma (HNSCC). For a subgroup of patients with recurrent or metastatic disease, long-term benefit can be achieved: maintaining a sustained response to immunotherapy is therefore a critical factor for its efficacy at an individual level. In analogy to targeted agents, a limited pattern of progression, or “oligoprogression”, can occur. For locally recurrent HNSCC, the potential biologic interplay between the efficacy of ICIs and the design of radiation fields chosen for primary treatment is currently unknown. Here, we report on a patient who presented two subsequent oligoprogressions successfully treated with re-irradiation without interrupting Nivolumab. Both oligoprogressive lesions developed in previously unirradiated areas. We hypothesize the existence of a synergistic effect with optimal spatial cooperation between ICIs and re-irradiation for oligoprogressive disease under immunotherapy.

Recurrent salivary gland carcinomas (RSCs) are poorly characterized and their clinical features and treatment options have not yet been fully described. The goal of this study was to analyze the therapeutic strategies and oncological outcomes of RSC patients through a literature review analysis. This systematic review was performed according to the PRISMA statements. Inclusion criteria for the systematic review were based on the population, intervention, comparison, and outcomes according to (PICO) framework. Two thousand seven hundred and four records were selected and 1817 recurrences were studied. Three hundred and sixty-five patients underwent salvage surgery (20.1%) and their 5-year mortality rate, overall survival and disease-free survival were 35%, 70%, and 42%, respectively. RSCs are aggressive neoplasms with a high rate of distant metastases (28.9%). Salvage surgery can be considered in patients with limited local and/or regional recurrences, even in case of single distant relapse, appearing within the first 3 years of follow-up.

Metastatic soft tissue sarcoma (STS) patients may benefit from local ablative treatments due to modest efficacy of systemic chemotherapy. However, use of stereotactic body radiotherapy (SBRT) is controversial because of presumed radioresistance of STS.Patients treated with SBRT for oligometastatic and oligoprogressive metastatic STS were retrospectively reviewed to assess results in terms of local control (LC), disease-free survival (DFS), and overall survival (OS). Incidence and grade of adverse events were reported. Statistical analysis was performed to identify variables correlated with outcome and toxicity.Forty patients were treated with SBRT to a median biologic effective dose (BED) of 105 (66-305) Gy5 to 77 metastases. Two-year LC, DFS, and OS were 67%, 23%, and 40%. Improved LC was shown in patients receiving a BED150 Gy5 (hazard ratio [HR], 3.9; 95% confidence interval [CI], 1.6-9.7; P = 0.028). A delay24 months between primary tumor diagnosis and onset of metastases was associated with improved DFS (HR, 0.46; 95% CI, 0.22-0.96; P = 0.01) and OS (HR, 0.48; 95% CI, 0.23-0.99; P = 0.03). No toxicity grade ≥3 was observed.Stereotactic body radiotherapy is effective in metastatic STS with a benign toxicity profile. A BED150 Gy5 is required to maximize tumor control rates. Metastatic relapse24 months after diagnosis is correlated to improved survival.

Synovial sarcoma (SS) is a malignant mesenchymal soft tissue neoplasm. Despite its name, the cells of origin are not synovial cells, but rather neural, myogenic, or multipotent mesenchymal stem cells have been proposed as possible cells originators. Unlike other sarcomas, an unusual presentation of long-term pain at the tumor site has been documented, but the exact mechanisms have not been fully clarified yet. The transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel mainly expressed in primary sensory neurons, where it functions as a pain sensor. TRPA1 have also been described in multiple non-excitable cells, including those derived from neural crest stem cells such as glial cells and, in particular, Schwann cell oligodendrocytes and astrocytes. We evaluated TRPA1 expression in SS. We selected a cohort of 41 SSs, and by immunohistochemistry, we studied TRPA1 expression. TRPA1 was found in 92.6% of cases. Triple TRPA1/pS100/SOX10 and TRPA1/SLUG/SNAIL staining strongly supports a neural origin of SS. TRPA1 positivity was also observed in a subset of cases negative with pS100, SOX10 and/or SLUG/SNAIL, and these divergent phenotypes may reflect a process of tumor plasticity and dedifferentiation of neural-derived SSs. Given the functional diversity of TRPA1 and its expression in neuronal and non-neuronal multipotent neural crest stem cells, it remains to be determined whether TRPA1 expression in SSs neoplastic cells plays a role in the molecular mechanism associated with premonitory pain symptoms and tumor progression.

It has been hypothesized that the development of sinonasal intestinal-type adenocarcinoma (ITAC) occurs through intestinal metaplasia (IM) of the respiratory and/or glandular epithelium. The aim of this study was to characterize the histological, immunohistochemical, and molecular features of sinonasal IM. Histologic slides from 29 consecutive surgical specimens of ITAC were retrieved. Sections were stained for CDX2, cytokeratin 20 (CK20), MUC2, and p53. The status of TP53 gene exons 4–9 was assessed separately in areas of IM and in ITAC. Foci of IM were detected in eight cases (27.5 %). They were all positive for CK20 and CDX2, while MUC2 was detected in six cases (75 %). In six cases (75 %), the metaplastic foci showed signs of dysplasia, including nuclear enlargement with increased nucleus to cytoplasm ratio, nuclear hyperchromasia, loss of nuclear polarity, and presence of prominent nucleoli. P53 nuclear immunoreactivity was observed in four cases. TP53 gene sequencing was successfully performed in six cases and revealed the same mutation in both IM and ITAC in two cases (c.832C > T and c.215G > C), while another ITAC showed a mutation that was not present in the adjacent IM (c.536A > G). In conclusion, our study suggests a possible clonal relationship between areas of sinonasal IM and ITAC, indicating that IM may represent a precursor lesion of ITAC. Improving the knowledge on the morphological and molecular features of IM is a key step to identify reliable biomarkers to determine the risk of sinonasal ITAC development.

PLAG1 (pleomorphic adenoma gene 1) is a proto-oncogene whose overexpression is a crucial oncogenic event in salivary gland pleomorphic adenomas (PA), and in carcinoma ex-PA. The aim of the present study is to evaluate the sensitivity and the specificity of PLAG1 as a marker in the differential diagnosis of salivary gland benign and malignant tumors. We examined 101 cases, including 36 PAs, 8 myoepitheliomas, 3 basal cell adenomas, and 1 canalicular adenoma among benign tumors; 16 mucoepidermoid carcinomas, 10 adenoid cystic carcinomas, 8 acinic cell carcinomas, 8 polymorphous low-grade adenocarcinomas, 7 salivary duct carcinoma, and 4 epithelial-myoepithelial carcinoma among malignant tumors. PLAG1 was diffusely positive in 94.4% of PAs and in all myoepitheliomas, although with a lower staining intensity. Among malignant tumors, 2 (25%) polymorphous low-grade adenocarcinomas and 1 salivary duct carcinoma ex-PA were positive. In conclusion, PLAG1 is a marker with good specificity for PA and could be a useful diagnostic adjunct in the diagnosis of salivary gland tumors. In particular, this marker is negative in the most common salivary carcinomas, including adenoid cystic carcinoma, mucoepidermoid carcinoma, and acinic cell carcinoma. However, some mimickers of PA, like polymorphous low-grade adenocarcinoma, may show occasional positivity for PLAG1, thus limiting its diagnostic use. In addition, carcinoma ex-PA shows consistent positivity, and therefore should be considered as a diagnostic possibility in case of a malignant tumor with PLAG1 expression.

We have previously shown that a subset of sinonasal intestinal-type adenocarcinomas (ITAC) shows activation of the epidermal growth factor-receptor (EGFR) pathway. In this study we examine the status of the EGFR, KRAS and BRAF genes in a series of sinonasal intestinal (ITAC) and non-intestinal type adenocarcinomas (non-ITAC). Eighteen ITACs and 12 non-ITACs were studied immunohistochemically for EGFR expression. Point mutations were analyzed for EGFR exons 19 and 21, KRAS exon 2 and BRAF exon 15 by direct sequencing. Non-ITACs showed significantly higher expression of EGFR (p = 0.015). Mutation analysis revealed one ITAC with EGFR and one ITAC with KRAS mutation, while two non-ITACs presented mutation of BRAF. We conclude that a subset of sinonasal adenocarcinomas shows overexpression of EGFR, while activating mutations of the signaling cascade downstream of EGFR are rare, suggesting that these tumors could be good candidates for anti-EGFR therapies.

The oropharynx and nasopharynx are the sites of common infectious diseases, as well as a wide variety of malformative and neoplastic lesions, requiring differential diagnosis. The epidemiologic, aetiopathogenetic, morphological and molecular features of these entities are discussed. Particular emphasis is given to aspects of viral carcinogenesis, regarding both oropharyngeal and nasopharyngeal carcinomas, including the current diagnostic methods of virus detection. This chapter is a complement of Chaps. 1, 11, 12 and 13.

Franchi A, Palomba A, Fondi C, Miligi L, Paglierani M, Pepi M & Santucci M (2011) Histopathology59, 98–105 Immunohistochemical investigation of tumorigenic pathways in sinonasal intestinal-type adenocarcinoma. A tissue microarray analysis of 62 cases Aims: Sinonasal intestinal-type adenocarcinoma (ITAC) is an uncommon neoplasm morphologically similar to colorectal adenocarcinoma, with a well-recognized association with occupational exposure to wood or leather dusts. Here, we analyse several gene products with pivotal roles in tumorigenesis, including p53, p16, deleted in colon cancer (DCC), retinoblastoma, adenomatous polyposis coli, β-catenin, E-cadherin and CD10, and discuss their relation to clinical behaviour and to similar pathways in colorectal adenocarcinomas. Methods and results: Immunohistochemical analysis of 62 ITACs was conducted on a tissue microarray. Aberrant expression of p53 and p16 were the most commonly observed alterations (61.3% and 64.5% of cases, respectively). Analysis according to the histological subtype showed that p53 overexpression was less frequent in mucinous ITACs (35.3% versus 71.1%, P = 0.018), while loss of DCC and E-cadherin were observed more frequently in this subtype (76.5% versus 31.1%, P = 0.002 and 82.4% versus 31.1%, P

Franchi A, Palomba A & Cardesa A (2011) Histopathology 59, 1034–1045 Current diagnostic strategies for undifferentiated tumours of the nasal cavities and paranasal sinuses Several malignant tumours occurring in the sinonasal tract may present with an undifferentiated morphology. Overall, these lesions pose significant diagnostic difficulties for the surgical pathologist, especially in limited biopsy material, but their correct classification is becoming increasingly important for an appropriate treatment strategy. This review deals with the criteria for differential diagnosis of these neoplasms, with emphasis on recent advances in immunohistochemistry and molecular biology, as well as with previous progress in electron microscopy. Through careful microscopic examination of haematoxylin and eosin-stained sections, in the light of clinical information and imaging data, a list of differential diagnoses can be made and an appropriate panel of antibodies can be chosen to further categorize the tumour. An initial panel including cytokeratins, synaptophysin, S100 protein, desmin and CD45 may allow the classification of most lesions or may help to narrow the list of differential diagnoses. Further refinement can be obtained through second-line markers, including in-situ hybridization for Epstein–Barr virus, other neuroendocrine markers, melanocytic markers, myogenin, CD99, other lymphocyte markers, and CD138 and light chains. Finally, molecular analysis can further assist in the recognition of specific entities such as nuclear protein in testis midline carcinoma, Ewing’s sarcoma/peripheral neuroectodermal tumour, alveolar rhadbomyosarcoma, and poorly differentiated synovial sarcoma.

Neuroendocrine neoplasms represent a rare subset of tumors in the sinonasal tract. Combined tumors, with an endocrine and a non-neuroendocrine component, are exceedingly rare, and mainly consist of a combination of neuroendocrine carcinoma with adenocarcinomas. We present the clinico-pathologic and immunohistochemical features of a neuroendocrine carcinoma combined with squamous cell carcinoma, arising in the maxillary sinus. In addition, we evaluated the clonal origin of the two components through analysis of TP53 gene status. Both components were positive for cytokeratins AE1/AE3, while the squamous cell carcinoma was positive for cytokeratin 5/6 and p63, and the neuroendocrine carcinoma showed immunoreactivity for neuron specific enolase, chromogranin, synaptophysin and CD56. In situ hybridization for human papilloma virus and Epstein–Barr virus were negative in both components. A missense mutation in TP53 exon 7 (c.734G>C) and strong nuclear immunostaining for p53 were detected only in the neuroendocrine carcinoma. This suggests that the tumor either derived from one precursor cell with squamous differentiation, which underwent TP53 mutation and acquisition of a neuroendocrine phenotype, or it derived from two separate clones, one with mutated TP53 and neuroendocrine differentiation, and the other with wild type TP53 and squamous differentiation (collision tumor).

Background: Intratumoral microvessel density (MVD) could be used as a prognostic factor in colorectal cancer. We retrospectively analyzed the value of microvessel count in predicting the clinical outcome of stage I and II (Dukes A and B) rectal cancer patients. Methods: Eighty-four patients who had undergone curative resection of lymph node-negative rectal cancer were included. Tumor type and differentiation, the depth of local invasion, venous invasion, the character of the invasive margin, and the degree of lymphocytic infiltration were evaluated for each tumor specimen. Immunohistochemical staining for the CD31 endothelial antigen was performed to highlight the microvessels. Results: The median value of MVD was 45 microvessels. Low MVD (microvessels ≤45) was observed in 41 patients (48.8%), and high MVD (>45) was found in 43 (51.2%). The presence of conspicuous lymphocytic infiltration was significantly associated with increased vessel density. With uni- and multivariate survival analysis MVD did not show any prognostic significance. The character of the invasive margin was the only parameter with independent prognostic value. Conclusions: MVD does not seem to provide any additional prognostic information when compared with standard histopathological parameters in lymph node-negative rectal cancer. It is likely that the strong association between MVD and the presence of conspicuous lymphocytic infiltration may interfere with its predictive value.

We investigated the prognostic significance of microsatellite instability (MI) in 50 consecutive patients with sporadic mucinous colorectal cancer who had undergone only surgery. We evaluated MI and the pathological features with a possible prognostic value for each tumor, and the effect of the examined parameters on patients' outcome was statistically analyzed (univariate and multivariate analysis). All patients were followed-up for a minimum of 72 months or until death; in evaluating survival, only deaths of colorectal cancer were considered. DNA extracted from tumor sections and the corresponding normal tissue was analyzed by polymerase chain reaction at six microsatellite loci: D2S123, D3S1611, D3S49, D5S107, BAT26, BAT40. Alterations at two or more loci were detected in 36% of cases (MI+ tumors). MI+ and MI- cancers differed significantly in the pattern of growth, and most MI+ tumors showed an expanding type of growth (72.2%, P = .005). At univariate analysis, improved survival rate was significantly associated with MI, as well as with the following parameters: expanding cancer growth, Dukes stage, and absence of venous invasion. Nevertheless, at multivariate analysis, only the pattern of cancer growth and Dukes stage were independent prognostic factors, whereas the effect on survival of MI and venous invasion was found to be negligible. In our study, MI+ and MI- cancers differ only on the pattern of growth; therefore, our data suggest that the better survival rate in mucinous cancers with genomic instability is strictly related to their less aggressive type of growth.

We describe the clinicopathological, immunohistochemical, and molecular features of 3 primary juxtacortical myoepithelioma/mixed tumor of bone. The patients were 2 males (13 and 23 years of age) and a 15-year-old female. The juxtacortical lesions were all located in the femur, and were surgically removed, 2 with wide margins and one with marginal margins. This latter tumor recurred locally 18 months later. The 3 patients were free of disease at 6 to 17 months follow-up. Histologically, all lesions showed a prominent multinodular architecture, and were formed by epithelioid and stellate elements, organized in solid sheets, or embedded in myxoid or chondroid matrix. Areas of osteoid formation were also observed. One tumor had the appearance of classical mixed tumor, showing aspects of duct formation and focal squamous differentiation. Immunohistochemically, all cases were positive for cytokeratins, epithelial membrane antigen, and S100 protein. The expression of other myoepithelial markers, including p63, glial fibrillary acid protein and calponin was more limited. No rearrangement of Ewing sarcoma region 1 (EWSR1) and fused in sarcoma (FUS) genes was observed by fluorescent in situ hybridization. To our knowledge, this is the first report of primary myoepitheliomas of bone arising at juxtacortical sites. These lesions must be distinguished from other benign and malignant bone and cartilage-forming surface tumors, including periosteal chondroma and chondrosarcoma, juxtacortical chondromyxoid fibroma, and periosteal and paraosteal osteosarcoma. The clinicoradiologic presentation and their histological and immunohistochemical features are distinctive enough to allow the separation from these entities.

Several malignant tumours occurring in the sinonasal tract may present with an undifferentiated morphology. Overall, these lesions pose significant diagnostic difficulties for the surgical pathologist, especially in limited biopsy material, but their correct classification is becoming increasingly important for an appropriate treatment strategy. This review deals with the criteria for differential diagnosis of these neoplasms, with emphasis on recent advances in immunohistochemistry and molecular biology, as well as with previous progress in electron microscopy. Through careful microscopic examination of haematoxylin and eosin-stained sections, in the light of clinical information and imaging data, a list of differential diagnoses can be made and an appropriate panel of antibodies can be chosen to further categorize the tumour. An initial panel including cytokeratins, synaptophysin, S100 protein, desmin and CD45 may allow the classification of most lesions or may help to narrow the list of differential diagnoses. Further refinement can be obtained through second-line markers, including in-situ hybridization for Epstein-Barr virus, other neuroendocrine markers, melanocytic markers, myogenin, CD99, other lymphocyte markers, and CD138 and light chains. Finally, molecular analysis can further assist in the recognition of specific entities such as nuclear protein in testis midline carcinoma, Ewing's sarcoma/peripheral neuroectodermal tumour, alveolar rhadbomyosarcoma, and poorly differentiated synovial sarcoma.

Background Our aim was to determine whether lymphangiogenesis occurs in the early steps of cancerogenesis of the upper aerodigestive tract. Methods We assessed the number of lymphatics per unit area (lymphatic vascular density [LVD]) and the percent area occupied by the lymphatic vessels (lymphatic vascular area [LVA]) by computer-assisted morphometric analysis in 56 samples immunohistochemically stained with the lymphatic marker D2-40. The results were compared to those obtained in 63 invasive squamous cell carcinomas. Results No significant difference was observed between normal mucosa, hyperplasia/mild dysplasia, and moderate/severe dysplasia for LVD (p = .8) and LVA (p = .7). Conversely, invasive carcinomas presented a higher LVD than normal mucosa and precancerous lesions (p < .001), whereas there was no difference for LVA (p = .1). Conclusion Lymphangiogenesis does not occur in premalignant lesions of the upper aerodigestive tract and it is rather a late event associated with the development of an invasive phenotype. © 2010 Wiley Periodicals, Inc. Head Neck, 2010

Sinonasal carcinomas are rare tumors with an aggressive clinical behaviour which frequently pose a number of problems regarding the interpretation of diagnostic findings and the treatment. In addition, in comparison with other malignancies of the head and neck region, an elevated fraction of sinonasal carcinomas can be attributed to occupational exposure. This review is focused on the recent advances in the molecular and phenotypic characterization of sinonasal carcinomas, and their possible implications for the interpretation of epidemiological data, as well as for the diagnosis and treatment of these rare malignancies. The increasing knowledge on their phenotypic and genotypic features is progressively leading to a refinement in diagnosis, especially for poorly differentiated and undifferentiated lesions, as well as to the identification of markers which can be potentially useful to identify the early phases of carcinogenesis, to detect subclinical disease, to predict the response to therapy, and finally, that may represent potential targets for alternative treatments.

Background The association between intestinal-type sinonasal adenocarcinoma and the occupational exposure to leather dusts has been widely documented, but the identification of precursor lesions in exposed workers has remained controversial. The purpose of this study was to investigate the histological changes and modifications in the phenotype of epithelial cells in nasal mucosa of leather workers. Methods Biopsy specimens of the mucosa of the middle turbinate were obtained from 139 subjects who had been employed in leather factories for 10–48 years (median, 29 years). Tissue fragments were routinely processed for histological examination and immunostainings for cytokeratin 20, CDX-2, and MUC-2 were performed. Results Regarding the surface epithelium, the most common histopathological finding was the presence of squamous metaplasia (64.7%), which was associated with mild to moderate dysplasia in 37 cases (41.1%), and goblet cell hyperplasia was identified in 30 biopsy specimens (21.6%). Positivity for MUC-2 was detected in goblet cells of 20 of the 30 samples with goblet cell hyperplasia (66.6%), whereas no immunostaining was observed for cytokeratin 20 and CDX-2. Presence of goblet cell hyperplasia was significantly associated with longer occupational exposure in leather tanning activities (p = 0.03). None of the alterations observed (squamous metaplasia, dysplasia, or goblet cell hyperplasia) showed correlation with smoking habits. Similarly, there was no correlation between squamous metaplasia with or without dysplasia and type and duration of occupational exposure. Conclusion Our data identify goblet cell hyperplasia as possible work-related alterations of nasal mucosa in leather workers. Additional investigations are needed to clarify the significance of these findings in the development of sinonasal intestinal-type carcinoma.

Lymph node involvement is the most important prognostic factor for patients who have undergone radical surgery for colorectal carcinoma. An accurate examination of the surgical specimens is mandatory for the correct assessment of the lymph node status of the tumor. The risk of understaging is particularly high for patients with tumors classified as Dukes B (TNM stage II). The aim of this study was to determine if a specified minimum number of lymph nodes examined per surgical specimen could have any effect on the prognosis of patients who had undergone radical surgery for Dukes B colorectal cancer. Between 1988 and 1995 a total of 140 patients underwent radical resection of Dukes B colorectal cancer by the same surgeon (C.C.). The relation between clinicopathologic variables and survival was estimated using the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify the variables that can independently influence survival. A median of 12 lymph nodes (range 3-38) was examined per tumor specimen. The 5-year survival rate of Dukes B patients who had had eight or fewer lymph nodes examined after surgery was 54.9%, whereas the survival rate for those who had had nine or more lymph nodes examined was 79.9% (p < 0.001). Cox regression analysis identified the number of lymph nodes as the only independent prognostic factor (p = 0.01). Seventy patients with one to four metastatic lymph nodes (Dukes C patients) who had been operated on during the same period were included in the survival analysis for comparison. The 5-year survival rate of the Dukes B patients with eight or fewer lymph nodes examined was similar to that of the 70 Dukes C patients (54.9% and 51.8%, respectively). Examination of eight or fewer lymph nodes in Dukes B colorectal patients may be considered a high risk factor for missing positive lymph nodes in the surgical specimens. Our results suggest that harvesting and examining a minimum of nine lymph nodes per surgical specimen may be sufficient for reliable staging of lymph node-negative tumors.

To find out whether tumour DNA content correlates with allelic loss of p53 and other pathological features in primary colorectal carcinomas.Ongoing prospective study.University hospital, Italy.128 patients who had undergone radical resections for colorectal carcinoma.Flow cytometric measurement of tumour DNA content and detection of allelic loss on the short arm of chromosome 17 by Southern blot (restriction fragment length polymorphism) analysis in fresh tumour specimens.Correlation between DNA ploidy and deletion of p53, as well as between these two genetic events and clinicopathological variables.Interpretable DNA histograms were obtained for 122 tumour specimens. Forty-three tumours (35%) were diploid and 79 (65%) aneuploid. The diploid tumours were significantly more common in the proximal colon (from the caecum to the splenic flexure) than in the distal colon (from the descending colon to the rectum) (p = 0.002). The allelic state on the short arm of chromosome 17 was evaluated in 80 heterozygous patients. Forty-four tumour specimens (55%) showed deletion of 17p. Allelic loss of p53 was significantly more common in the distal and rectal tumours than in the proximal ones (p0.0001). Aneuploidy was more common among those tumours which had shown deletion of p53 than in those that had not (p = 0.0008).DNA aneuploidy was significantly associated with the deletion of the p53 gene. This suggests that the functional loss of p53 may favour the growth and establishment of an aneuploid cell population within tumours. Tumours of the proximal and distal colon differ in their genetic nature.

PURPOSE: The clinical significance and prognostic value of the histopathologic parameters used in both the Dukes and Jass classifications were evaluated to select those with an independent effect on survival after radical surgery for colorectal cancer. METHODS: The depth of local spread (limited to the bowel wall or extended beyond it), the number of metastatic lymph nodes (none, 1–4, more than 4), the character of the invasive margin (pushing or infiltrating), and the presence or absence of conspicuous peritumoral lymphocytic infiltration were assessed in 235 patients who had undergone radical resection for colorectal cancer. The influence of these variables on survival was studied by univariate and multivariate analysis. RESULTS: No significant difference in survival was found between patients with conspicuous peritumoral infiltrate and those without it; moreover, multivariate analysis failed to show any independent prognostic value for either lymphocytic infiltration or depth of local invasion. However, the character of the invasive margin and the number of metastatic lymph nodes were identified as the only variables with any independent importance on survival. Based on these data, a new prognostic model may be proposed; it uses the character of the infiltrative margin as a discriminating factor among patients within the lymph node-negative (Dukes A and B stages) and lymph node-positive (Dukes C1 and C2 subsets) groups. A good prognosis for Dukes A, B, and C1 patients was associated with pushing tumors; C1 and C2 patients with infiltrating tumors had a poor prognosis. On the whole, the new prognostic model has allowed for the placement of 59.6 percent of our patients into groups that provide a confident prognosis. The clinical outcome of Dukes A and B patients with infiltrating tumors is still uncertain. CONCLUSIONS: The character of the invasive margin is an important prognostic factor in colorectal cancer. The association of this parameter with the traditional Dukes classification may provide additional useful prognostic information and aid in the selection of those patients who could most benefit from adjuvant therapy.

PURPOSE: Colorectal signet-ring cell carcinoma (SRCC) is uncommon; discordant data have been previously reported about clinicopathologic features. Thirty-four cases of primary colorectal SRCC were retrospectively reviewed to clarify controversies. METHODS: Primary colorectal SRCC was diagnosed when the following criteria were satisfied: 1) the tumor was primary; 2) histologic material was adequate; 3) signet-ring cell represented more than 50 percent of the cancer. RESULTS: We identified 34 cases (1.1 percent) of 2,995 consecutive large bowel cancers collected at the Institute of Anatomic Pathology of Florence between 1985 and 1993. Patients ranged in age from 31 to 89 (mean, 63.5; median, 65) years; 19 were male, and 15 were female (male:female=1.3∶1). Fifteen tumors were located in the proximal colon, 11 in the rectum, and 8 in the distal colon. The gross shape was infiltrative in 24 cases and exophytic in 10; only 6 cases (17.6 percent) showed features of linitis plastica. Most cancers (61.8 percent) were Stage C, 29.4 percent were Stage B, and distant metastases were present in only three cases (8.8 percent). No Stage A case was found. Prognosis was extremely poor, and overall five-year survival rate was 9.1 percent. Survival was influenced significantly by tumor stage (P

Inflammatory pseudotumors have been described in many organs but they are rare in the testis.' They are ohn classified as fibrous pseudotumors or spindle cell nodules.2 Inflammatory pseudotumors represent a new category of apparently benign postoperative proliferative spindle cell lesions resembling sarcoma. Hydrocele and antecedent scrotal trauma are associated with these asymptomatic nodules in 45% of cases.3 CASE REPORT A 22-year-old man presented 2 months after scrotal trauma with an asymptomatic scrotal nodule. The nodule had a strong elastic consistency and it was separate from the testicle, epididymis, spermatic cord and corpora cavemosa. Scrotal sonography revealed a nonhomogeneous 3 x 4 x 3.7 cm. mass. Cystourethrography confirmed no relationship with the urethra. htal magnetic resonance imaging showed a nonhomogeneous nodule without hemorrhagic areas median to the crura penis that did not infiltrate the scrotal layers or Buck's fascia (fig. 1). The nodule was surgicdy removed and biopsies of adjacent areas were obtained. Histological examination revealed a polymorphous inflammatory infiltrate with neutrophils, plasma cells, lymphocytes and a small number of eosinophils, histiocytes and spindle cells. Foci of hemorrhage and hyalinized collagen were also noted but mitotic figures and atypical cells were absent (fig. 2). After 6 months there was no recurrence. DISCUSSION

Because the histopathological features of some primary adenocarcinomas of the sinonasal tract may show considerable overlap, we assessed the diagnostic value of a panel of immunohistochemical markers in the distinction between these malignancies. Paraffin-embedded tumour tissue sections from a series of 39 primary adenocarcinomas of the sinonasal tract, including 25 cases of intestinal-type adenocarcinoma (ITAC), 10 cases of salivary gland-type carcinoma and 4 cases of tubulopapillary low-grade adenocarcinoma were immunostained for CDX-2, cytokeratin 7 and cytokeratin 20. Diffuse nuclear staining for CDX-2 was identified in 80% of ITACs, while all non-ITACs were negative. Staining for cytokeratin 20 was positive in 84% of ITACs, including all cases negative for CDX-2, but negative in all other adenocarcinomas. Cytokeratin 7 was consistently positive in 88% of ITACs and in 100% of non-ITACs. Normal sinonasal epithelia expressed cytokeratin 7, but not CDX-2 and cytokeratin 20. Staining for CDX-2 and cytokeratin 20 has potential use in separating ITACs from other primary malignant glandular neoplasms of the nasal cavities and paranasal sinuses.