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Objective: Frequencies as high as 60% of overexpressed p16(INK4) were recently reported in lichen planus (LP). Because p16(INK4) overexpression may be a feature of human papilloma virus (HPV)-induced cancer, it has been postulated that LP may be somehow related to HPV. The present study is the first to evaluate both high p16(INK4) expression and HPV in patients with LP., Study Design: Thirty-five consecutive biopsy specimens from patients with LP constituted the basis of the present study. Level of p16(INK4A) expression was evaluated in each sample by immunohistochemical analysis, and the presence of HPV DNA was tested by real-time polymerase chain reaction (PCR)., Results: p16(INK4) expression was detected in 26 specimens, whereas HPV was found in 4 lesions: 3 low-risk HPV and 1 high-risk HPV. All HPV-positive lesions also indicated p16(INK4A) overexpression, whereas 22 cases of overexpressed p16(INK4A) were HPV negative (Chi square 2.6; ns)., Conclusions: p16(INK4) overexpression is not correlated with HPV in patients with LP., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chordomas are rare, slow-growing neoplasms, characterized by locally aggressive growth patterns and high local recurrence rates. To the best of our knowledge, the MGMT promoter methylation status has not been studied in a population of patients with chordomas to determine if a biologic rationale exists to support the use of temozolomide. We here show for the first time that methylation of MGMT promoter is present in a significant portion or recurring clival chordomas; on the contrary in clival chordomas without recurrence MGMT promoter was always unmethylated (p = 0.0317). Although these observations need to be confirmed in a larger study population, our results (1) indicate that methylation of MGMT promoter is present in a significant portion of recurring chordomas, and (2) prompt further investigation into the potential role of temozolomide as an adjuvant treatment of these tumors.

In the skin and breast, endocrine tumors are composed of a heterogeneous mixture of endocrine and exocrine cells. The definition of "pure" endocrine carcinomas is a matter for debate, and as a consequence, there is lack of uniform diagnostic criteria. There are no significant clinical differences in either overall or disease-free survival between matched neoplasms with endocrine and without endocrine differentiation nor between the degree of endocrine differentiation and tumor size, stage, or prevalence of vascular invasion for both sites (skin and breast). Here, endocrine tumors of the skin and breast are grouped respectively into three categories that include most of the neuroendocrine tumors of the skin and breast as seen in routine practice. It was felt that the number of different types of neuroendocrine tumors is so conspicuous that it is impossible to organize them in an orderly classification. It has been proposed therefore, for practical diagnostic routine purposes, to arrange these neoplasms into a working formulation. The latter includes heterogeneous lesions respectively of the skin and breast within the same group that have clinical features in common.

The Ki67 labelling index (LI - proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Lymph node metastasis (LNm), local recurrence (LR), and second primary tumor (SPT) after primary surgery for oral squamous cell carcinoma (OSCC) have been considered poor prognostic entities in terms of survival rate. The purpose of this study was to identify the clinicopathologic parameters significantly related to LNm, LR, and SPT. Records from 180 patients who underwent radical surgery for OSCC were retrospectively reviewed. Perineural invasion was significantly related to LNm (18% vs 8%) and LR (15% vs 5%), while the status of the surgical margin (10% in case of clear margins, 18% close margins, and 24% involved margins), namely epithelial precursor lesions (43%) was an independent factor influencing SPT. Perineural invasion proved a good prognostic factor for early events, either LNm or LR, while a surgical margin width less than 5 mm or with epithelial precursor lesions may be considered a risk factor for late events such as SPT.

Background: Histological and clinical criteria are generally used to differentiate second primary tumors (SPTs) from local recurrences. The purpose of the present study was to apply mitochondrial DNA (mtDNA) D-loop analysis to differentiate SPTs from local recurrences and to validate the clinical classification., Methods: The study population consisted of 20 consecutive patients presenting multiple oral neoplastic lesions for a total of 25 paired lesions. The mtDNA D-loop analysis was performed by direct sequencing and phylogenetic clusterization., Results: Agreement between mtDNA analysis and clinical classification was found in 19 cases. Discrepancies arose in 6 cases in which the clinical criteria based only on the spatial or temporal distance of the second lesion from the index tumor had led to a diagnosis of SPT (2 cases) or local recurrence (4 cases)., Conclusion: The present data highlight the value of mtDNA analysis in establishing the clonal relationship between the index tumor and the second neoplastic lesion., (Copyright © 2013 Wiley Periodicals, Inc.)

Ten cases of glioblastomas showing oncocytic changes are described. The tumors showed mononuclear to multinuclear cells and abundant, granular, eosinophilic cytoplasm. The cytoplasm of these same cells was filled by strongly immunoreactive mitochondria. At ultrastructure, numerous mitochondria, some of which were large, were evidenced in the cytoplasm of neoplastic cells. Finally, 9 of 10 of these cases had a significantly high mitochondrial DNA content compared with control tissue (P < .01). It seems that, for these tumors, the designation of oncocytic glioblastoma is appropriate. To the best of our knowledge, oncocytic changes have not been previously reported in such neoplasms. Oncocytic glioblastomas have to be added to the long list of various tumors that can manifest "unexpected" oncocytic changes in different organs. Albeit failing to show statistical significance (log-rank test, P = .597; Wilcoxon test, P = .233), we observed a trend for longer median survival in oncocytic glioblastomas, when compared with "ordinary" glioblastomas (median survival of 16 versus 8.7 months). Thus, it seems that the definition of neoplasms showing oncocytic changes, currently based on classic morphological parameters (ie, histology, ultrastructure, and immunohistochemistry), can be expanded by including the quantitative assessment of mitochondrial DNA content., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Myofibroblastoma is a relatively rare, benign mesenchymal tumor that typically occurs in the breast parenchyma. Unlike mammary-type myofibroblastoma, myofibroblastoma that primarily arises in the lymph nodes exhibits nuclear palisading, and the term palisaded myofibroblastoma has been proposed, accordingly. We report 2 unusual cases of myofibroblastoma of the male breast, which showed a predominant (>90% of the entire tumor) nuclear palisading and Verocay-like bodies. The present cases represent a hitherto unreported variant of mammary-type myofibroblastoma closely mimicking schwannoma. The diagnosis of myofibroblastoma was supported by immunohistochemical analyses showing a diffuse staining for desmin and CD34. In addition, the diagnosis of myofibroblastoma was confirmed in 1 case cytogenetically by the demonstration of the monoallelic loss of the FOXO1/13q14 locus by fluorescence in situ hybridization. Pathologists should be aware of this unusual variant of mammary myofibroblastoma to assure a correct diagnosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Axillary treatment of breast cancer patients is undergoing a paradigm shift, as completion axillary lymph node dissections (ALNDs) are being questioned in the treatment of patients with tumor-positive sentinel nodes. This study aims to develop a novel multi-institutional predictive tool to calculate patient-specific risk of residual axillary disease after tumor-positive sentinel node biopsy., Methods: Breast cancer patients with a tumor-positive sentinel node and a completion ALND from five European centers formed the original patient series (N = 1000). Statistically significant variables predicting nonsentinel node involvement were identified in logistic regression analysis. A multivariable predictive model was developed and validated by area under the receiver operating characteristics curve (AUC), first internally in 500 additional patients and then externally in 1068 patients from other centers. All statistical tests were two-sided., Results: Nine tumor- and sentinel node-specific variables were identified as statistically significant factors predicting nonsentinel node involvement in logistic regression analysis. A resulting predictive model applied to the internal validation series resulted in an AUC of 0.714 (95% confidence interval [CI] = 0.665 to 0.763). For the external validation series, the AUC was 0.719 (95% CI = 0.689 to 0.750). The model was well calibrated in the external validation series., Conclusions: We present a novel, international, multicenter, predictive tool to assess the risk of additional axillary metastases after tumor-positive sentinel node biopsy in breast cancer. The predictive model performed well in internal and external validation but needs to be further studied in each center before application to clinical use.

Laser excision has been used with increasing success to treat oral leukoplakia. The aim of the present study was to evaluate whether clinical healing of a leukoplakia after laser surgery is associated with a normal functional status of the new epithelium and whether pathological alterations in these parameters are related to the risk of local recurrence. The study population consisted of 13 consecutive patients with oral leukoplakia in which clinical healing was achieved after laser therapy using an Nd:YAG laser (Model 6000, Laser Sonics, Cooper Laser Sonics). At the end of the therapy, all patients underwent a second biopsy of the clinically healthy tissue. Epithelial cell turnover was evaluated before and after laser surgery by Ki67 protein expression, and positive staining of more than 20% was considered abnormal. All patients were followed on a monthly basis. Eight patients had abnormally high Ki67 values before laser therapy (mean 27.4 ± 6.2%), but the levels decreased significantly after treatment (17.6 ± 8.5%; t = 2.6, p < 0.05). High Ki67 values persisted in three patients, and local recurrences in the new epithelium was observed in two of these patients. Kaplan-Meier statistics showed that the between-group difference was statistically significant (Chi square 7.3; p < 0.01). In conclusion, this is the first prospective study to show that clinical healing of leukoplakia treated by laser surgery may be accompanied by altered cell turnover in 20% of the cases. Ki67, as a marker of proliferative status, may be a prognostic indicator in the mucosa replacing the lesion.

Aim:   To examine a group of lesions that progressed to oral squamous cell carcinoma (OSCC) to determine whether p16(INK4A) expression is an early finding during malignant transformation, and whether immunohistochemical evaluation of p16(INK4A) is an appropriate prognostic marker., Methods and Results:   Twenty cases of OSCC were investigated. All cases had had a biopsy on the same site as OSCC performed at least 1year before OSCC (range 1-11years; mean 3.15±3.1years). Twenty specimens from normal oral mucosa served as controls. p16(INK4A) expression was evaluated by immunohistochemical analysis and cases showing >5% of stained cells were defined as 'positive'. All 20 control cases were negative for p16(INK4A) . Oral lesions were p16(INK4A) -positive in nine cases and negative in 11. No significant relationship was found between p16(INK4A) positivity and the presence/absence of dysplasia. Among OSCC, nine tumours showed p16(INK4A) positivity and 11 showed negativity. A significant relationship (χ(2)=7.1; P<0.01) was found between the presence/absence of p16(INK4A) staining in OSCC and the presence/absence of p16(INK4A) staining in lesions preceding OSCC., Conclusions:   p16(INK4A) immunohistochemistry has a potential role in detecting a subset of p16(INK4A) -positive lesions with malignant potential., (© 2010 Blackwell Publishing Limited.)

Sclerosing polycystic adenosis (SPA) is a rare pathological condition affecting the salivary glands, first described by Smith etal. in 1996. Even though this lesion is being increasingly diagnosed, less than 50 cases have been published in the world literature to date. In line with numerous other pathological analogies between breast and salivary gland lesions, SPA shares with fibrocystic disease of the breast many histopathological features, i.e., fibrosis, oncocytic (apocrine) changes, hyperplasia of ductal and acinar epithelium, cystic dilation of ducts, and, often, atypical epithelial changes. Most of the described cases have followed a benign clinical course, despite the frequent possibility of atypical hyperplasia in more than 50% of the cases and of the more than occasional in situ malignant transformation. In this article, we introduce a new case occurring in the parotid gland of a 57-year-old male showing atypical epithelial hyperplasia and low-grade in situ mucoepidermoid carcinoma. Fine-needle cytology (FNC) was performed on the lesion and, when a diagnosis of SPA was prospected, the variegated cytological features of the obtained sample posed several differential diagnostic problems. The spectrum of pathological lesions entering differential diagnosis comprised sebaceous adenoma, Warthin's tumors with presence of sebaceous remnants, and low-grade mucoepidermoid carcinoma. Histopathological examination disclosed SCA with intraductal neoplastic transformation resembling noninvasive low-grade mucoepidermoid carcinoma. The cytological diagnosis of SPA should be entertained whenever a polymorphous picture is found on FNC samples comprising oncocytic/apocrine changes, sebaceous cells, cystic background, and epithelial hyperplasia with low-grade cytological atypias.

Merkel cell carcinoma (MCC) of the skin is a neuroendocrine tumor with characteristic histological and immunohistochemical features. Among various cytogenetic changes, trisomy of chromosome 6 has been reported in 47% of cases using in situ hybridization. Primary tumors, morphologically and immunohistochemically identical to MCCs of the skin, have been described in other organs, including lymph nodes. Here, a cytogenetic study of four cases of MCC of lymph nodes is presented. Four cases of primary MCCs of lymph nodes and ten cases of cutaneous MCCs were studied for chromosome 6 using fluorescent in situ hybridization (FISH). All cases showed typical features of MCC both at hematoxylin and eosin (H&E) and immunohistochemistry. FISH showed trisomy 6 in two out of the four cases ofMCCs of lymph node as well as in 6 out 10 cases of MCCs of skin. Lymph nodal and cutaneous MCCs share same histological and immunohistochemical features, as well as same cytogenetic alteration for chromosome 6. It seems that there are more similarities than differences between cutaneous and lymph nodal MCCs. Whether lymph nodal MCCs are primary tumors or metastases from regressed skin lesions is still questionable, although several findings indicate a primary origin.

This study aimed at identifying factors related to sentinel lymph node (SLN) involvement in patients with tubular, cribriform, mucinous or papillary breast carcinoma and those related to non-SLN metastases if an SLN was positive. Multivariate analyses involved logistic and stepwise regressions. The SLNs harboured metastases in 85 of 572 cases, 78 of whom underwent axillary dissection; 19 presented non-SLN positive disease. Lack of lymphovascular invasion, a tumour size < or = 10 mm and a single SLN removed were the factors predicting an SLN metastasis rate <10%, and patients with these features could be candidates for no surgical axillary staging. A positive SLN proportion of < or = 50% and no lymphovascular invasion were associated with a <10% rate of non-SLN invasion; patients with a positive SLN and these features could be candidates for the omission of completion axillary dissection. The opposite presentation of these factors would mandate SLN biopsy and axillary dissection, respectively.

A case of epithelioid hemangioendothelioma of the cauda equina is reported. The patient presented with rapidly worsening low back pain. Magnetic resonance imaging revealed a sharply demarcated intradural lumbar lesion. A bluish-red lesion, attached to the filum terminale, was removed. The patient is alive without evidence of recurrence 18 months after surgery. The tumor was composed of variously sized vessels lined by epithelioid endothelial cells with clear cytoplasm and centrally located, moderately atypical nuclei. These cells were immunoreactive for CD31 and factor VIII antibodies. Cytogenetic analysis disclosed two clones: 44-45X, - Y [cp3]/46XY[11]. Epithelioid hemangioendothelioma may arise in several sites, the most common being soft tissues. It is a borderline tumor that may recur, may metastasize, and rarely causes death. The present case appears to be the first example of epithelioid hemangioendothelioma of the spinal cord.

Three cases of lobular carcinoma of the breast showing a complex morphology that included myoepithelial cell differentiation are reported. One case was a pure in situ acinar lesion, while the other 2 cases were in situ and invasive carcinomas. Three different cell types were seen in these tumors: one was the phenotype commonly seen in the garden variety of in situ lobular carcinoma (LCIS) constituted by noncohesive round to ovoid cells with round nuclei and positivity for epithelial membrane antigen (EMA), estrogen receptor (ER), and progesteron receptor (PR). E-cadherin was negative in these cells. The second type was represented by cohesive elements with irregular nuclei. These cells were immunoreactive for smooth muscle actin, calponin, keratin 14, p63, and e-cadherin. EMA, ER, and PR were consistently negative. The third type, seen in a minority of cell population of case nos. 2 and 3, consisted of cells showing at the same time EMA and smooth muscle actin in their cytoplasm. This type was defined as "hybrid myosecretory cell" to highlight contractile and secretory properties present at the same time. Cells with hybrid features probably indicate that myoepithelial and secretory cells are strictly related and the existence of a stem cell, at least for these cases, is not necessary.

Herein we describe the case of a patient with primary diffuse leptomeningeal gliomatosis (PDLG). After surgery and ventriculoperitoneal shunt placement, due to poor general conditions, the patient was not eligible for radiotherapy. For this reason we decided to start a systemic chemotherapy treatment with Temozolomide (150 mg/m2 per day for 5 days every 4 weeks). After three cycles a partial response was achieved with a clear improvement of general conditions. In our knowledge, this is the first time that PDLG treatment with Temozolomide has been described.

The diagnosis and characterization of rhabdomyosarcoma requires the use of combined histological and immunohistochemical criteria due to the variety of its histological patterns. The identification of actin isoform expression is accepted as a useful adjunct to the diagnosis and classification of soft tissue tumors. Using a new antibody specific for alpha-cardiac actin, obtained according to a recently described strategy for the production of polyclonal antibodies against actin isoforms [9], we have analyzed a series of 17 rhabdomyosarcomas, including all histological subtypes. In addition, we have evaluated the presence in these tumors of alpha-skeletal and alpha-smooth muscle actins. All specimens examined revealed a positive immunostaining for alpha-cardiac actin. Tumoral cells of eight cases also expressed alpha-smooth muscle actin and only three cases (all embryonal subtypes) were positive for alpha-skeletal actin. Our results indicate that immunohistochemical screening for alpha-cardiac actin expression is a useful tool for the diagnosis of rhabdomyosarcoma. They also suggest that the expression of alpha-skeletal actin is valuable in determining the subtype and possibly the state of differentiation of these tumors.

The purpose of the present study is to determine the presence and distribution of epithelial and myoepithelial cells in mucoepidermoid carcinoma (MEC) of salivary glands and to compare them with normal salivary gland tissue and other primary carcinomas. This is in order to establish novel diagnostic criteria and to better understand MEC histogenesis. Formalin-fixed paraffin-embedded tissues from ten well-differentiated MECs, three adenoid cystic carcinomas (ACC), four acinic cell carcinomas (AC), and three epithelial-myoepithelial carcinomas (EMCC) of salivary glands were studied with immunohistochemistry using antibodies that recognise antigens indicative of epithelial and myoepithelial cell differentiation. An anti-mitochondrial antibody was also employed. Normal salivary tissue was present for comparative study in non-tumorous areas of the same section from 12 cases. MEC contained numerous keratin-positive cells. Anti mitochondrial antibody was diffusely positive in all ten of these tumours. Smooth muscle actin, h-caldesmon, and smooth muscle heavy chain myosin, which are indicative of myoepithelial cell differentiation, were negative. Rare cells in only one case were stained by calponin. Cytokeratin 14 (CK14) and anti mitochondrial antibody stained cells located mainly at the periphery of neoplastic nests and cystic spaces, while CK7 was mainly present in cells bordering gland lumina (zoning pattern). The immunohistochemical cell profile was similar to that seen in striated normal ducts. All others tumours studied showed a different immunohistochemical pattern, mostly consisting of a lack of mitochondrion-rich cells and the presence of myoepithelial cells in ACC and EMCC. Immunoreactivity in MEC for CK7, CK14 and mitochondrial antibodies appears as a peculiar pattern of staining, different from that of other salivary gland tumors; this seems helpful for diagnostic purposes. In addition, a differentiation of the "striated duct phenotype" is suggested.