It has been reported that high-risk human papillomavirus (HPV) is a causative agent of a subgroup of oropharyngeal carcinomas. In these tumors, the presence of the transcriptionally active HPV has ...been proved through the identification of HPV E6 or E7 messenger RNA (mRNA) transcripts. The aim of the study was to assess the HPV-active transcription in a series of sinonasal carcinomas, in correlation with the HPV DNA identification and the p16 immunohistochemistry. Seventy patients with squamous cell carcinomas of the sinonasal tract were included in the survey. The main clinicopathological characteristics were recorded. All tumors were investigated for HPV through the HPV DNA detection by PCR, using the SPF10 primers and by in situ hybridization, using the high-risk GenPoint probe (Dako, Glostrup, Denmark). HPV16 E7 mRNA transcripts detection was performed by RT-PCR in 27 cases. The immunostaining for p16 was performed in all cases. Fourteen carcinomas (20%) were positive for high-risk HPV by PCR: 13 HPV16 and one HPV35. In situ hybridization showed a dotted nuclear positivity in all these cases. HPV16 E7 mRNA was detected in seven tumors harboring HPV16; in the remaining HPV-positive cases, RNA did not reach the quality for analysis. Strong, diffuse positivity for p16 was observed only in the HPV-positive cases. The 14 HPV-positive squamous cell carcinomas were non-keratinizing or scarcely keratinizing tumors. No significant differences were found in terms of gender, age, or staging at diagnosis between HPV-positive and HPV-negative tumors. However, differences in disease-free survival and overall survival between both groups of patients were significant (P=0.004 and P=0.028, respectively). In conclusion, we have shown that HPV is the etiological agent of a subset of sinonasal carcinomas demonstrating the transcriptionally active HPV in these tumors. Immunostaining for p16 can be used as a surrogate marker to identify these tumors.
Squamous intraepithelial lesions (SILs) of the larynx, clinically usually defined as leukoplakia and chronic laryngitis, have remained the main controversial topic in laryngeal pathology for decades ...as regards classification, histological diagnosis and treatment. SILs are caused by smoking and alcohol abuse. There is also mounting evidence that gastroesophageal reflux is a potential aetiological factor. Human papillomavirus infection seems to play little if any role in laryngeal carcinogenesis.
Histological classification of SILs is the central disputed aspect of these lesions. There are as yet no generally accepted criteria for histological grading of laryngeal SILs. Three currently used classifications of SILs are reviewed here: the dysplasia system, the Ljubljana classification and the binary system of squamous intraepithelial neoplasia. One of the most important issues of SILs is the risk of malignant transformation. Data in the literature are controversial because of inconsistent use of morphological criteria in different classifications. It is often difficult for clinicians to agree on the most appropriate therapeutic option for a particular grade of SIL that has been diagnosed. Transition from normal epithelium to SILs and squamous cell carcinoma is related to progressive accumulation of genetic changes leading to a clonal population of transformed epithelial cells. Despite extensive research into these genetic changes in laryngeal carcinogenesis, reliable genetic markers with diagnostic and prognostic value are still lacking.
Aims
To verify the applicability, reproducibility and predictive value of a proposed unified classification (amended Ljubljana classification) for laryngeal squamous intraepithelial lesions (SILs).
...Methods and results
Six internationally recognized experts and three pathologists from Ljubljana contributed to this study by evaluating a set of laryngeal SILs using the new system: low‐grade SIL, high‐grade SIL, and carcinoma in situ (CIS). The overall agreement among reviewers was good. Overall unweighted and weighted κ‐values and 95% confidence intervals were 0.75 (0.65–0.84) and 0.80 (0.71–0.87), respectively. The results were stratified between the international reviewers and the Ljubljana pathologists. The former had good overall agreement, and the latter had very good agreement. Kaplan–Meier survival curves showed a significant difference (P < 0.0001) between patients with low‐grade and high‐grade SILs; 19 of 1204 patients with low‐grade SILs and 30 of 240 patients with high‐grade SILs progressed to malignancy in 2–15 years and in 2–26 years, respectively.
Conclusions
The proposed modification to the Ljubljana classification provides clear morphological criteria for defining the prognostic groups. The criteria facilitate better interobserver agreement than previous systems, and the retrospective follow‐up study demonstrates a highly significant difference in the risk of malignant progression between low‐grade and high‐grade SILs.
Summary MicroRNAs are small, noncoding RNAs that regulate gene expression by posttranscriptional regulation of target genes. miR-200 family and miR-205 have been shown experimentally to regulate ...epithelial-mesenchymal transition. As epithelial-mesenchymal transition is the postulated pathogenetic mechanism in spindle cell carcinoma, we analyzed the expression of these microRNAs in spindle cell carcinoma of the head and neck in comparison to conventional squamous cell carcinoma of similar location and stage. We also analyzed the expression of classic and desmosomal cadherins, which are believed to be important targets during epithelial-mesenchymal transition. Forty-five cases of spindle cell carcinoma and 45 cases of squamous cell carcinoma of the head and neck were analyzed using real-time polymerase chain reaction for microRNAs, and immunohistochemistry for classic cadherins (E- and N-cadherins) and desmosomal cadherins. We found a significant down-regulation of the miR-200 family and miR-205 , loss of desmosomal cadherins, and an altered expression of classic cadherins in spindle cell carcinoma in comparison to squamous cell carcinoma. Down-regulation of the miR-200 family and miR-205 strongly supports the postulated role of epithelial-mesenchymal transition in spindle cell carcinoma. These microRNAs act on transcription repressors that were also up-regulated in our cases of spindle cell carcinoma, both on mRNA and on protein levels. The result is not only an altered expression of classic cadherins in adherens junctions but also a complete loss of desmosomal cadherins.
The current state in the field of classifying oral and laryngeal precursor lesions, as proposed in the WHO 2005 Blue Book is not ideal. The results of various inter-observer studies have shown that ...the currently used grading systems, with different basic concepts and different terminology, cannot continue to be reliably used in the future. The different etiology of cervical and head and neck precursor lesions requires a classification designed to cater to the specificities of the head and neck region. Trying to harmonize different classifications of the oral and laryngeal precursor lesions, we have proposed four crucial steps to set up a unified classification of squamous intraepithelial lesions (SILs): (a) the classification should contain two grades, low-grade and high-grade lesions and, specifically for the larynx, an additional grade—carcinoma in situ (CIS) which must be separated from high-grade laryngeal SILs; (b) the terminology should be unified; our preference is for the term SIL over squamous intraepithelial neoplasia; (c) all leading morphological criteria for low- and high-grade lesions, as well as for CIS, should be clearly defined; (d) agreement between clinicians and pathologists should be achieved on the most appropriate choice of treatment of different grades of SILs in separate head and neck areas.
The differential diagnosis of neuroendocrine neoplasms of the larynx is broad and includes lesions of epithelial, mesenchymal, and neuroectodermal origin. These lesions have overlapping clinical and ...pathologic aspects and must be carefully considered in the differential diagnosis of laryngeal neoplasms. The prognosis and treatment are also different among these tumor types, which necessitates making these distinctions clinically. The current literature was reviewed to provide updated information regarding the epithelial-derived tumors, including carcinoid, atypical carcinoid, small cell neuroendocrine carcinomas, large cell neuroendocrine carcinoma, and squamous cell carcinoma with neuroendocrine component. These tumors are compared and contrasted with non-epithelial-derived tumors such as paraganglioma and nonmucosal tumors, such as medullary thyroid carcinoma. The morphologic and cytologic features are discussed, along with helpful immunohistochemical and ancillary investigations.
Mucins are glycoproteins normally synthesized by a variety of secretory epithelial cells. The aim of this study was to investigate the expression of mucins (MUC1, MUC2, MUC4, MUC5AC, MUCB, MUC6, ...MUC7) in mucoepidermoid carcinomas, the most frequent malignant tumor of salivary glands. Forty mucoepidermoid carcinomas and twenty-two normal salivary glands were studied for these mucins by immunohistochemistry from formalin-fixed and paraffin-embedded material. Normal salivary glands frequently expressed MUC1 and MUC4, mainly in ductal cells; MUC5B and MUC7 stained mucous and serous acini respectively of submandibular and minor salivary glands; and MUC5AC and MUC2 were poorly detected in excretory ducts. All mucoepidermoid carcinomas expressed MUC1, and 38/40 tumors expressed MUC4. Both membrane-bound mucins stained membranes and cytoplasm of all cell types (epidermoid, intermediate, mucous, clear and columnar). MUC5AC and MUC5B stained glandular differentiated cells in most tumors (29/40 and 33/40 cases, respectively). MUC6 was positive in 13/40 tumors, and both MUC2 and MUC7 in only 2/40 tumors. The high expression of MUC1 was related to high histologic grades, high recurrence and metastasis rates and a shorter disease-free interval (P < 0.05). Conversely, MUC4 high expression was mainly related to low-grade tumors, lower recurrence rates and a longer disease-free interval (P < 0.05). In conclusion, mucoepidermoid carcinomas of salivary glands usually express MUC1, MUC4, MUC5AC and MUC5B; less frequently MUC6; and rarely MUC2 and MUC7. This mucin expression pattern can be useful for diagnostic purposes. Therefore, MUC1 expression is related to tumor progression and worse prognosis, whereas MUC4 expression is related to a better prognosis.
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