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Aims Methods and Results Conclusion A subset of exceptionally rare primary renal perivascular epithelioid cell tumours (PEComas) that harbour Xp11.2 translocation have been reported, but no larger series devoted to this topic have been published.We describe the clinicopathological and molecular features of 10 renal PEComas, collected from our routine and consultation files. There were five female and five male patients aged 14–65 (median: 32 years). One patient had a history of childhood neuroblastoma, but no patients were known to have a tuberous sclerosis complex or other hereditary disorder. Complete surgical excision was the treatment for all patients. The available follow‐up in five patients indicated a favourable outcome in 4/5 cases. Tumour size ranged from 2.8 to 15.2 cm (median, 5.2 cm). Immunohistochemistry revealed consistently strong TFE3 expression in all tumours, whereas PAX8 and keratin cocktails were uniformly negative. Other positive markers included HMB45 (7/9 tumours), CathepsinK (7/9 tumours), and CD117 (KIT) (3/5 tumours). TFE3 rearrangements were detected in 8/9 tumours (by targeted RNA sequencing in seven and by FISH in one). The identified fusion partners included SFPQ (n = 2) and one tumour each with ASPSCR1, ZC3H4, MED15, RBMX, and PRCC. One tumour that lacked TFE3 rearrangement by next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH) revealed a large intrachromosomal deletion involving PKD1 and TSC2 by DNA‐based NGS.This study highlights the morphologic and genetic diversity of TFE3‐rearranged primary renal PEComas and underlines the value of surrogate TFE3 immunohistochemistry in identifying them. The lack of PAX8 and keratin expression represents the mainstay for distinguishing these tumours from MiTF‐associated renal cell carcinomas. In addition, we report rare (ZC3H4, RBMX) and novel (MED15) TFE3 fusion partners in PEComa. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess the prognostic significance of lymph node yield (LNY), lymph node ratio (LNR), and the number of lymph node metastases (LNMs) in patients affected by oral squamous cell carcinoma (OSCC). Methods: The study included patients who underwent surgical treatment for primary OSCC. Receiver operating characteristic curves were generated to determine the optimal threshold values. Kaplan–Meier curves were employed, along with the log‐rank test, for the analysis of survival. To compare the performance in terms of model fit, we computed Akaike's information criterion (AIC). Results: This study enrolled 429 patients. Prognostic thresholds were determined at 22 for LNY, 6.6% for LNR, and 3 for the number of LNMs. The log‐rank test revealed a significant improvement in both overall survival and progression‐free survival for patients with a LNR of ≤6.6% or a number of LNMs of ≤3 (p < 0.05). Interestingly, LNY did not demonstrate prognostic significance. The AIC analyses indicated that the number of LNMs is a superior prognostic indicator compared to LNY and LNR. Conclusions: Incorporating LNR or the number of LNMs into the TNM classification has the potential to improve the prognostic value, as in other types of cancers. Particularly, the inclusion of the number of LNMs should be contemplated for future N staging. [ABSTRACT FROM AUTHOR]

Aims: Soft‐tissue tumours are rare and both accurate diagnosis and proper treatment represent a global challenge. Current treatment guidelines also recommend review by specialised pathologists. Here we report on international consensus‐based datasets for the pathology reporting of biopsy and resection specimens of soft‐tissue sarcomas. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of international pathology and cancer organisations. Methods and results: According to the ICCR's guidelines for dataset development, an international expert panel consisting of pathologists, a surgical oncologist, and a medical oncologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were subspecialised soft‐tissue sarcoma experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the documents were finalised and ratified, and the datasets, which included a synoptic reporting guide, were published on the ICCR website. Conclusion: These first international datasets for soft‐tissue sarcomas are aimed to promote high‐quality, standardised pathology reporting. Their adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve patient's management. [ABSTRACT FROM AUTHOR]

Aims: The formal pathogenesis of salivary carcinosarcoma (SCS) remained unclear, both with respect to the hypothetical development from either preexisting pleomorphic adenoma (PA) or de novo and the clonal relationship between highly heterogeneous carcinomatous and sarcomatous components. Methods and results: We performed clinicopathological and molecular (targeted RNA sequencing) analyses on a large series of 16 cases and combined this with a comprehensive literature search (111 cases). Extensive sampling (average 11.6 blocks), combined with immunohistochemistry and molecular studies (PA‐specific translocations including PLAG1 or HMGA2 proven in 6/16 cases), enabled the morphogenetic identification of PA in 15/16 cases (93.8%), by far surpassing a reported rate of 49.6%. Furthermore, we demonstrated a multistep (intraductal/intracapsular/extracapsular) adenoma‐carcinoma‐sarcoma‐progression, based on two alternative histogenetic pathways (intraductal, 56.3%, versus myoepithelial pathway, 37.5%). Thereby, early intracapsular stages are identical to conventional carcinoma ex PA, while later extracapsular stages are dominated by secondary, frequently heterologous sarcomatous transformation with often large tumour size (>60 mm). Conclusion: Our findings strongly indicate that SCS (almost) always develops from PA, with a complex multistep adenoma‐carcinoma‐sarcoma‐sequence, based on two alternative histogenetic pathways. The findings from this novel approach strongly suggest that SCS pathogenetically is a rare (3–6%), unique, and aggressive variant of carcinoma ex PA with secondary sarcomatous overgrowth. In analogy to changes of terminology in other organs, the term "sarcomatoid carcinoma ex PA with/without heterologous elements" might be more appropriate. [ABSTRACT FROM AUTHOR]

Aim: To raise awareness of the existence of extrarenal renal cell carcinoma (RCC). Methods and results: We report three patients with extrarenal RCC found in the renal proximity, but unattached to the kidney. None had a history of RCC or an identifiable primary renal neoplasm at the time of the diagnosis and on follow-up. The patients included two males and one female aged 57, 77, and 63 years, respectively. One carcinoma was found in the perirenal tissue adjacent to the adrenal, one involved the adrenal gland, and one was a retroperitoneal mass found within the lymph nodes. Two extrarenal RCCs represented clear-cell RCCs and one was an unclassifiable RCC. No patient had evidence of metastases at presentation and disease progression during the follow-up. This report adds to the literature on this unusual clinical scenario and further supports the concept of extrarenal RCC, which is not a well-recognized clinical phenomenon. We also reviewed other similar reports documenting the absence of identifiable renal primaries in the setting of either disseminated metastatic disease or isolated distant metastases of presumed renal origin. Similarly, some carcinomas of apparent renal derivation have been also identified during a work-up of metastatic carcinomas of unknown primary. Conclusions: There should be an awareness of this unusual and intriguing clinical scenario that currently lacks a definitive explanation and standardized therapy strategies. Establishing a correct diagnosis may allow treatment with specific targeted therapies in selected clinical cases. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate and compare the histopathological findings in pleomorphic adenomas (PA) of the parotid and submandibular gland with emphasis on the histological subtype and capsular characteristics. Materials and Methods: The histopathological specimens of all patients with PAs of the parotid and submandibular gland between 2000 and 2020 were re‐examined by an experienced head and neck pathologist. Patients without representative slides allowing evaluation of the whole periphery of the PA were excluded from our study sample. Results: Nine hundred and thirty‐four patients formed our study sample (327 men, 607 women, male‐to‐female ratio: 0.53:1). Eight hundred and forty‐four cases had a PA in the parotid gland and the remaining 90 in the submandibular gland. Our comparative analysis showed that submandibular PAs are characterized by the consistent presence of an intact anatomical capsule, infrequent occurrence of pseudopodia and satellite nodules, and a low proportion of the high‐risk myxoid subtype. Conclusion: Our study highlights significant differences between PAs of the parotid and submandibular glands in their histopathological characteristics. Their differences likely underlie the favorable surgical outcome observed in PAs of the submandibular glands and may explain the propensity of PAs of the parotid glands for local recurrences. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: The aim of this study was to identify potential associations between epidemiologic, morphologic, and histopathologic features in pleomorphic adenomas (PAs) of the parotid gland in order to extract information about the natural course and biologic behavior of these lesions on the basis of a single‐center series of 845 cases within a period of 15 years. Study Design: Retrospective study in a tertiary academic center. Methods: For this study, an experienced head and neck pathologist critically re‐evaluated the histological slides of the pathological specimens of all patients who underwent a parotidectomy for PA of the parotid gland between 2006 and 2020. Results: A total of 845 cases made up our study sample. Our analysis showed a statistically significant association of the histologic subtype with younger age (P =.001) and maximal diameter (P =.044), with the hypocellular type being encountered more often in younger patients and in smaller lesions. The same subtype was significantly associated with an incomplete capsule (P =.001), pseudopodia (P =.006), and satellite nodules (P =.001). An incomplete capsule was associated with the presence of pseudopodia (P =.001) and satellite nodules (P =.001). Conclusion: It seems that various histologic subtypes have different capsule‐producing properties. Apparently, over the course of time, tumor material builds a finger‐like projection still inside the capsule, separates itself from the parenchyma with fibrous tissue still remaining enclosed within the capsule (pseudopodium), slowly penetrates the capsule (incomplete capsule), and leaves the main lesion taking a part of the capsule with it (satellite nodules). Laryngoscope, 132:73–77, 2022 [ABSTRACT FROM AUTHOR]

Aims: PRRX1–NCOA1‐rearranged fibroblastic tumour is a recently described, rare mesenchymal tumour. Only four cases have been previously reported. The aim of this article is to report six additional cases of this unusual mesenchymal neoplasm, with an emphasis on its differential diagnosis. Methods and results: The six cases were from three females and three males (age, 20–49 years; median, 42 years). Three tumours were located on the abdominal wall; two from the shoulder/axillary areas, and one on the lateral hip. All presented as slow‐growing subcutaneous nodules, ranging from 26 to 55 mm (median, 40 mm). The tumours consisted of circumscribed, variably cellular nodules composed of relatively bland plump spindled to epithelioid cells arranged singly, in cords, and occasionally in nests, embedded in hyalinised and collagenous stroma. Small hypocellular myxoid zones with ropey collagen fibres were present, as were irregularly dilated, gaping, crescent‐shaped or staghorn‐like thin‐walled vessels, best appreciated at the periphery. Immunohistochemistry for CD34, S100, MUC4 and STAT6 was consistently negative. RNA‐sequencing revealed PRRX1–NCOA1 fusions in all cases. Of the four cases with limited follow‐up (1.5–4 months), none recurred following local surgical excision. Conclusions: The morphological features of PRRX1–NCOA1‐rearranged fibroblastic tumour overlap with those of RB1‐deficient soft‐tissue tumours, solitary fibrous tumour, and low‐grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. This differential diagnosis can be resolved with a combination of careful morphological study and the application of a panel of immunostains, although molecular genetic study is most definitive. The natural history of PRRX1–NCOA1‐rearranged fibroblastic tumour appears to be quite favourable, although longer‐term study of a larger number of cases is warranted. [ABSTRACT FROM AUTHOR]

Aims: There is a widespread perception among clinicians and pathologists that the histomorphological assessment of minor salivary gland (MinSG) tumours is more difficult and hampered by more misdiagnoses than that of major salivary gland tumours. This is based on a vague, subjective clinical impression, lacking scientific proof. The aim of the present study was to identify and statistically verify potential reasons that could explain this difference. Methods and results: We identified 14 putative clinical, pathological and combined clinicopathological reasons that, altogether, could explain the phenomenon of the perceived greater diagnostic difficulty associated with MinSG tumours. We performed a comprehensive literature search and a statistical comparison of data from a large personal consultation series (biased for difficult cases) with cumulated data from straightforward, unselected (non‐consultation) series from the literature. By performing this comparison, we identified, with statistical significance, a comprehensive series of reasons, as well as of consequences, of the greater difficulty in diagnosing MinSG tumours. Conclusions: Among the 14 criteria, high frequencies of initial incisional biopsies and of a low‐grade category in malignant tumours emerged as the two most important reasons for enhanced diagnostic difficulty. Very rare entities, unusual locations, shortcomings in clinicopathological communication, and pecularities of the special anatomical location of the hard palate, such as tumour necrosis, mucosal ulceration, pseudoinvasion, and the peculiar phenomenon of 'tumoral–mucosal fusion', contribute to further diagnostic difficulties. The awareness of these shortcomings and pitfalls enables us to provide a series of recommendations for clinicians and pathologists that might aid in assessment and reduce the rate of misdiagnosis of MinSG tumours. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Papillary neoplasms of the middle and inner ear are rare and poorly characterised. The current World Health Organization classification divides them into two major subtypes: aggressive papillary tumours (APTs) and endolymphatic sac tumours (ELSTs). The aim of this article is to present two papillary neoplasms of the middle ear that do not fit into either the classic APT category or the classic ELST category, and compare them with three ELSTs. Methods and results: The patients were a 48‐year‐old female and a 59‐year‐old male without a history of other neoplasms. Histology showed papillary‐cystic growth of predominantly oncocytic (Case 1) or mucinous (Case 2) cells surrounded by a p63‐positive basal layer. The overall histology was reminiscent of oncocytic sinonasal papilloma (Case 1) and pancreatobiliary or salivary intraductal papillary mucinous neoplasms (Case 2). Ovarian‐type stroma, invasion and malignant features were absent. Immunohistochemistry revealed expression of cytokeratin (CK) 7, but not carbonic anhydrase IX (CAIX) or paired box gene 8 (PAX8) (except for very focal PAX8 expression in Case 1). The TST15 gene panel and HRAS sequencing revealed no pathogenic mutations in BRAF, KRAS, EGFR, AKT1, or HRAS. The TruSight RNA fusion panel revealed an MKRN1–BRAF fusion in Case 1. No fusion was detected in Case 2. The three ELSTs showed classic features of the entity, expressed CK7, epithelial membrane antigen, PAX8, and CAIX, and lacked a basal cell layer. Conclusion: These novel cases suggest that papillary tumours of the ear represent a heterogeneous spectrum of distinct neoplasms unified by a prominent papillary‐cystic pattern rather than a single entity. Future studies should clarify whether the MKRN1–BRAF fusion is a defining recurrent driver event, especially in those cases reported as sinonasal‐type middle ear papillomas. [ABSTRACT FROM AUTHOR]

Osteosarcoma is an often‐fatal mesenchyme‐derived malignancy in children and young adults. Overexpression of EMT‐transcription factors (EMT‐TFs) has been associated with poor clinical outcome. Here, we demonstrated that the EMT‐TF ZEB1 is able to block osteoblastic differentiation in normal bone development as well as in osteosarcoma cells. Consequently, overexpression of ZEB1 in osteosarcoma characterizes poorly differentiated, highly metastatic subgroups and its depletion induces differentiation of osteosarcoma cells. Overexpression of ZEB1 in osteosarcoma is frequently associated with silencing of the imprinted DLK‐DIO3 locus, which encodes for microRNAs targeting ZEB1. Epigenetic reactivation of this locus in osteosarcoma cells reduces ZEB1 expression, induces differentiation, and sensitizes to standard treatment, thus indicating therapeutic options for ZEB1‐driven osteosarcomas. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1‐mutated PEComa displaying a TFE3‐altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options. [ABSTRACT FROM AUTHOR]

Aims: Pseudosarcomatous myofibroblastic proliferations (PSMPs) of the urinary bladder are diagnostically challenging. Diagnostic difficulties are mainly due to frequent cytokeratin expression, variable ALK expression and worrisome morphological features suggestive of malignancy. Conversely, sarcomatoid urothelial carcinoma (UC) may show bland inflammatory myofibroblastic tumour (IMT)‐like morphology. TERT promoter mutations are characteristic events in urothelial cancers, but have not been studied in PSMPs. Methods and results: We compared histomorphological and immunohistochemical features and TERT promoter status in 16 PSMPs and 18 sarcomatoid UC. In a subset of PSMPs, RNA sequencing was performed. At least focal IMT‐like morphology was seen in nine of 17 sarcomatoid UC. Atypical mitoses, differentiated urothelial component and heterologous elements were the most reliable distinguishing histomorphological features of sarcomatoid UC, if present. A panel of immunohistochemistry (IHC) including ALK (clone D5F3), p53 pattern, p63 and GATA3 reliably distinguished PSMP from sarcomatoid UC. GATA3 (P = 0.001) and p53 patterns (mutant versus wild‐type; P < 0.001) were differentially expressed between PSMPs and sarcomatoid UC. Diffuse pancytokeratin staining was significantly associated with PSMPs (10 of 13) compared to four of 14 sarcomatoid UCs (P = 0.012). TERT promoter mutations were found in 17 of 18 sarcomatoid UC versus none of 16 PSMPs (P < 0.001). RNA sequencing revealed ALK genetic rearrangements in one of two ALK‐positive and one of 10 ALK‐negative PSMPs, which revealed a novel FN1/RET gene fusion. Conclusion: Careful histomorphological analysis and differential IHC reliably distinguish the majority of PSMPs and sarcomatoid UC. In equivocal cases, TERT promoter mutation analysis and/or detection of ALK expression/rearrangements are valuable additional diagnostic adjuncts, strongly supporting sarcomatoid UC and PSMP, respectively. [ABSTRACT FROM AUTHOR]

Aims: Anaplastic carcinoma arising in a mucinous tumour of the ovary and rarely in the retroperitoneum is an uncommon neoplasm with three morphological patterns; rhabdoid, sarcomatoid and pleomorphic. We investigated expression of switch/sucrose non‐fermentable (SWI/SNF) chromatin remodelling complex components and claudin‐4 expression. Methods and results: Twenty‐two ovarian and three retroperitoneal mucinous tumours were investigated using antibodies against SMARCB1, SMARCA4, SMARCA2, ARID1A and claudin‐4. Loss of nuclear staining for any SWI/SNF protein was observed in the anaplastic component of nine of 25 (36%), with retained expression within the mucinous component of all tumours. Five (56%) showed loss of more than one protein, with dual loss of SMARCA4 and SMARCA2 in two, loss of SMARCA2 and ARID1A in two and loss of SMARCB1 and SMARCA2 in one. Retained expression of claudin‐4 was seen in 39% of the anaplastic carcinomas and within the mucinous component of all tumours. Rhabdoid morphology was associated with poor prognosis [stages III or IV disease (six of six, 100% versus four of 14, 29%; P = 0.0108] and death from disease (three of four, 75% versus one of 13, 8%; P = 0.0223). Although loss of a SWI/SNF protein was not significantly associated with death from disease (three of five, 60% versus one of 12, 8%; P = 0.0525), it showed a trend in correlation with poor prognosis and was often noted in tumours with rhabdoid morphology within this small cohort. Conclusions: Our report adds to the growing list of female genital tract malignancies with loss of SWI/SNF proteins, underlining their broad differential diagnosis and the importance of careful, context‐dependent interpretation of SWI/SNF protein loss. [ABSTRACT FROM AUTHOR]

Aims: Ameloblastic fibrosarcoma (AFS) is an aggressive odontogenic neoplasm featuring malignant mesenchymal stroma in addition to an ameloblastic epithelial component, and is hence considered to be the malignant counterpart of ameloblastic fibroma (AF). AFS is exceedingly rare, with <110 cases having been reported so far. Although BRAF mutations are recognised driver mutations in ameloblastoma, the molecular pathogenesis of AFS remains elusive. Methods and results: We herein describe seven AFSs that were analysed, for the first time, for mutations in the BRAF–NRAS pathway. The patients were four females and three males aged 23–57 years (median, 26 years). Three tumours developed after one or multiple recurrences of AF (4–20 years after initial diagnosis), two showed transition from AF‐like bland areas, and two developed de novo. All patients were treated with surgery; adjuvant chemotherapy was given to one patient. At the last follow‐up, five patients were alive and well (19–344 months). The remainder were lost to follow‐up. Histological examination showed variable sarcomatous overgrowth with varying degrees of atypia and increased mitotic activity. The epithelial component varied greatly according to the degree of sarcomatous overgrowth. Molecular testing revealed BRAF V600E mutations in five cases and NRAS p.Gln61Lys mutation in one case. One tumour was wild‐type. Conclusion: To our knowledge, this is the first study on BRAF/NRAS mutations in AFS. Given the activity of RAF and MEK inhibitors across different cancers harbouring V600E mutations, our data strongly suggest that all AFS cases should be genetically tested, and that targeted treatment approaches for this extremely rare sarcoma subtype should be clinically investigated. [ABSTRACT FROM AUTHOR]

Postlaryngectomy sinonasal squamous cell carcinoma, being theoretically associated with exposure to the same risk factors or development of precancerous lesions due to altered nasal physiology, should warrant a thorough head and neck examination. [ABSTRACT FROM AUTHOR]

Aims: Despite increasing interest in the recently established immunoglobulin 4‐related disease (IgG4‐RD), its pathogenesis and aetiology remain largely unclear. Characteristic histopathological features are one of the key elements of diagnosis, including 'storiform' fibrosis, obliterative phlebitis, increased lymphoplasmacytic infiltration and increased levels of IgG4 in serum and tissue. Histopathological features of IgG4‐RD are striking but not specific, and can pose a pitfall for surgical pathologists. This paper aims to determine the actual amount of IgG4+ plasma cells in nodular‐sclerosing Hodgkin lymphoma (NSHL) and its potential to be misdiagnosed in routine clinical practice. Methods and results: IgG4+ plasma cells per high‐power field (HPF) and the ratio of IgG4+ versus IgG+ plasma cells (IgG4/IgG ratio) in lymph node biopsies of 24 patients with nodular‐sclerosing Hodgkin lymphoma (NSHL) were determined using immunohistochemistry and consensus scoring criteria as used for IgG4‐RD. Ten lymph node biopsies with reactive follicular hyperplasia were assessed for comparison. Higher numbers of IgG4+ plasma cells (P < 0.001) were observed in NSHL versus follicular hyperplasia (mean 34 versus 8 per HPF) with a mean IgG4/IgG ratio of 0.38 versus 0.18. Five cases (21%) fulfilled the consensus criteria of IgG4‐RD, with >50 IgG4+ plasma cells per HPF and an IgG4/IgG ratio of >0.4. The mean count of IgG4+ plasma cells per HPF in NSHL varied greatly (3–88) with increased numbers of IgG4+ plasma cells seen near areas of fibrosclerosis. Conclusions: Significantly higher levels of IgG4+ plasma cells are common in NSHL, emphasising the need to exclude Reed–Sternberg cells by morphology and immunohistochemistry in biopsies where IgG4‐RD is suspected. [ABSTRACT FROM AUTHOR]

Aims: Nested variant of urothelial carcinoma (NVUC) is rare, and only a few small series exist. Molecular characteristics and the classifying marker profile as well as therapeutic targets of this specific variant are mostly unknown. The aim of this study was to characterise NVUC at the molecular level in one of the largest cohorts to date. In addition, we applied an immunohistochemical marker panel in order to define the molecular subtype. Methods and results: Sixty NVUC cases were collected from different departments. TERT promoter mutation analysis was carried out in all samples using SNaPshot analysis. Targeted sequencing of 48 cancer‐related genes by next‐generation sequencing (NGS) analysis was performed in a subset of 26 cases. Immunohistochemical markers CD44, CK5, CK14, EGFR, p63, FOXA1, GATA3, CD24 and CK20 were used to elucidate the molecular subtype. A total of 62.5% of NVUC cases harboured a mutation of the TERT promoter. Additionally, TP53, JAK3 and CTNNB1 were among the most frequently mutated genes identified by NGS analysis. Subtyping revealed that all NVUC express luminal markers such as CD24, FOXA1, GATA3 and CK20. Conclusions: In summary, NVUC belong to the luminal molecular subtype. Moreover, a subset of NVUC seems to be characterised by mutations of the Wnt and inflammatory pathways, including JAK3 mutations, indicating a different biological background compared to conventional urothelial bladder cancer. [ABSTRACT FROM AUTHOR]

Aims: Primary renal well‐differentiated neuroendocrine tumour (NET) (hereafter referred to as renal NET) is rare, with ~100 cases having been reported in the literature. There are also limited data on the molecular–genetic background of primary renal NETs. Methods and results: We analysed 11 renal NETs by using next‐generation sequencing (NGS) to identify characteristic genetic aberrations. All tumours were positive for synaptophysin, and also expressed insulinoma‐associated protein 1 (10/11), chromogranin‐A (8/11), and CD56 (3/11). Cytoplasmic positivity of CD99 was present in eight of 11 cases, and strong nuclear expression of α‐thalassaemia/mental retardation syndrome X‐linked (ATRX) was retained in all 11 cases. Molecular–genetic analysis of aberration of VHL gave negative results in all cases. Loss of heterozygosity on chromosome 3p21 was found in three of nine analysable cases. NGS was successful in nine cases, showing a total of 56 variants being left after the updated filtering process, representing an average of five variants per sample. All analysable cases were negative for ATRX and DAXX (death‐domain associated protein X) mutations. The most frequently mutated genes were CDH1 and TET2, with three mutations in two cases. Mutations in AKT3, ROS1, PIK3R2, BCR and MYC were found in two cases. The remaining 41 genes were found to be mutated only in individual cases. In four cases, the mutations affected a subset of genes related to angiogenesis. Conclusions: Overall, the mutation profile of primary renal NETs is variable, and none of the studied genes or affected pathways seems to be specific for renal NET. [ABSTRACT FROM AUTHOR]

The high mortality rate of melanoma is broadly associated with its metastatic potential. Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P‐value = 0.044) and the lymphangiogenic receptor VEGFR‐3 (P‐value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing‐based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P‐value = 0.031), ANGPT2 (P‐value < 0.001), and SIX1 (P‐value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio‐ and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease. [ABSTRACT FROM AUTHOR]

Background: Despite the observed association of increased PD‐L1 expression in peripheral blood of oral squamous cell carcinoma (OSCC) patients with histomorphologic parameters, the role of the PD1 ligands—PD‐L1 and PD‐L2—is insufficiently understood. Aim of the study was to investigate whether the alterations of PD‐L1 and PD‐L2 expression in blood are associated with survival and could serve as immune monitoring parameter. Moreover, it should be analyzed if PD‐L2 is differentially expressed in tissue and blood samples of OSCC patients compared to healthy controls and if there is an association of PD‐L2 expression with histomorphologic and prognostic tumor parameters. Methods: PD‐L2 mRNA expression was analyzed in tumors and healthy oral mucosa specimens and in corresponding peripheral blood samples of 48 OSCC patients and 26 healthy controls using RT‐qPCR. A cutoff point (COP) was determined and a chi‐square test (χ2 test) was carried out. Survival analysis of PD‐L2 and previously reported PD‐L1 expression data was performed using Kaplan‐Meier analysis (Log‐rank test). Results: PD‐L2 expression in tissue samples was significantly (P < 0.001) higher in OSCC patients compared to healthy controls. A significant association of PD‐L2 expression above the COP (positive) with malignancy was ascertained (P < 0.001). A significant (P = 0.01) association of previously reported PD‐L1 expression rates in peripheral blood with survival could be shown. Conclusion: Peripheral blood PD‐L1 expression might be a prognostic marker for OSCC patients and a possible parameter to monitor immune dysfunction in malign diseases. In the peripheral blood, PD‐L1 might be more relevant for immune tolerance than PD‐L2. Local PD‐L2 expression in tissue samples might be useful as a diagnostic parameter for malignancy and could contribute to the immunosuppressive local microenvironment in OSCC. Increased PD‐L2 expression in tissue specimens could serve as diagnostic parameter for OSCC. Local PD‐L2 expression in OSCC might contribute to tumor immune escape additionally to PD‐L1. Increased PD‐L1—but not PD‐L2—in peripheral blood is associated with inferior survival in OSCC patients. [ABSTRACT FROM AUTHOR]

Abstract: A 27‐year old caucasian male was diagnosed 2.7 years after kidney transplantation with Epstein‐Barr virus (EBV)‐associated smooth muscle tumors in liver and spleen. The reduction in immunosuppression and conversion from tacrolimus to sirolimus did not lead to a regression of the tumors. Additionally, the patient developed a cellular rejection of his renal allograft, which was successfully treated. A combined approach with stereotactic radiofrequency ablation (SRFA) and surgical resection was effective in the treatment of the tumors. [ABSTRACT FROM AUTHOR]

Aims: To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC. Methods and results: We identified 28 tumours from multiple institutions. They typically showed two cell populations—larger cells with eosinophilic cytoplasm and higher‐grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5–100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39–86 years). The median tumour size was 20 mm (range 9–65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low‐grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt–Hogg–Dubé syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, α‐methylacyl‐CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus ≤1%). Negative stains included: carbonic anhydrase 9, CD117, GATA‐3, WT1, CK5/6, and CK20; CD10 and 34βE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow‐up was available for 23 patients (median 24 months, range 1–244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes). Conclusions: Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal. [ABSTRACT FROM AUTHOR]

The anatomic site-dependent expression of hematopoietic progenitor cell antigen CD34 is a feature of gastrointestinal stromal tumours (GISTs). The basis for the differential CD34 expression is only incompletely understood. This study aimed at understanding the regulation of CD34 in GISTs and clarification of its site-dependent expression. Two sample sets of primary GISTs were interrogated including 52 fresh-frozen and 134 paraffin-embedded and formalin-fixed specimens. DNA methylation analysis was performed by HumanMethylation450 BeadChip array in three cell lines derived from gastric and intestinal GISTs, and differentially methylated CpG sites were established upstream of CD34. The methylation degree was further quantified by pyrosequencing, and inverse correlation with CD34 mRNA and protein abundance was revealed. The gene's expression could be activated upon induction of DNA hypomethylation with 5-aza-2′-deoxycytidine in GIST-T1 cells. In patient samples, a strong inverse correlation of DNA methylation degree with immunohistochemically evaluated CD34 expression was documented. Both CD34 expression and DNA methylation levels were specific to the tumours' anatomic location and mutation status. A constant decrease in methylation levels was observed ranging from almost 100% hypermethylation in intestinal GISTs from duodenum to hypomethylation in rectum. CD34 was heavily methylated in gastric PDGFRA-mutant GISTs in comparison to hypomethylated KIT-mutant counterparts. Next to CD34 hypermethylation, miR-665 was predicted and experimentally confirmed to target CD34 mRNA in GIST-T1 cells. Our results suggest that CD34 expression in GISTs may undergo a complex control by DNA methylation and miR-665. Differential methylation and expression of CD34 in GISTs along the gastrointestinal tract axis and in tumours that harbour different gain-of-function mutations suggest the origin from different cell populations in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

OBJECTIVE To analyze the prognostic effect of E-cadherin expression, the growth pattern of the tumor and the regression grade in a rectal cancer cohort treated with neoadjuvant radiochemotherapy ( RCT). METHODS A total of 223 patients with rectal cancer treated with neoadjuvant RCT followed by surgery were included. Altogether 88 biopsies prior to RCT and 213 tumor resections in an average of 55 days post- RCT were investigated. Protein expression of E-cadherin and tumor growth pattern (solid glandular vs single-cell pattern) was assessed by staining tissue microarrays. The regression grade at the invasion front was determined according to the Dworak scale. RESULTS There was a significant decrease of E-cadherin expression ( P = 0.002) and a significant increased single-cell growth ( P < 0.001) at the invasion front in tumor samples after RCT compared with primary biopsies of the tumor. A low E-cadherin expression in the biopsy was related to a longer metastasis-free survival ( P = 0.033) and tumor-specific survival ( P = 0.030). Post- RCT single-cell growth at the tumor invasion front was a prognostic factor for longer tumor-specific survival ( P = 0.021). A combination of growth pattern and the Dworak regression grade was an independent prognostic parameter for tumor-specific survival ( P = 0.015). CONCLUSIONS Loss of E-cadherin protein expression in the pretreatment biopsy of rectal cancer is associated with fewer metastases and improved survival. Furthermore, the growth pattern in the post- RCT resection specimen has a prognostic value for survival. A combination of growth pattern and tumor regression score (the Reg Pat score) showed the highest discriminatory power to identify high-risk patients. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptor 1 and 3 (FGFR1, FGFR3) impact on tissue homoeostasis, embryonic development and carcinogenesis. Murine double minute protein 4 (MDM4) and mouse double minute 2 homologue (MDM2) are regulators of p53-protein and may be the origin of an apoptosis overpowering cascade. A collective of 266 carcinomas of salivary glands were investigated for MDM2, MDM4, FGFR1 and FGFR3 aberrations by fluorescence in situ hybridization (FISH). The results were matched with clinicopathological parameters and with expression of PTEN and p53. MDM2 gene amplification (n = 9) and chromosomal aberrations (trisomy, n = 47; high polysomy, n = 7) are linked to high-grade malignancy (P < 0.001), lymph node metastasis (P = 0.001), advanced tumour size (P = 0.013) and stage (P < 0.001), gender (P = 0.002) and age (P = 0.001). MDM4 gene amplification (n = 19) and chromosomal aberrations (trisomy, n = 34; high polysomy, n = 31) are correlated to high-grade malignancy (P < 0.001), lymph node metastasis (P = 0.008), advanced tumour size (P = 0.039), stage (P = 0.004) and loss of PTEN (P < 0.001). Only, high-grade malignancy (P < 0.001), lymph node metastasis (P = 0.036) and advanced tumour stage (P = 0.025) are associated with FGFR3 amplification (n = 1) or chromosomal aberrations (low polysomy, n = 61; high polysomy, n = 55) but not with MDM4 alterations. FGFR1 amplifications (n = 5) and chromosomal aberrations (trisomy, n = 38; high polysomy, n = 30) are associated with high-grade malignancy (P < 0.001), advanced tumour size (P = 0.026) and stage (P = 0.004), gender (P = 0.016) and age (P = 0.023). Aberrations of MDM2, MDM4, FGFR1 and FGFR3 correlate with aggressive tumour growth and nodal metastasis. MDM2 (P < 0.001), MDM4 (P = 0.005) and FGFR3 (P = 0.006) alterations are associated with worse overall survival of patients with salivary gland cancer. [ABSTRACT FROM AUTHOR]

Neoplasms with a myopericytomatous pattern represent a morphological spectrum of lesions encompassing myopericytoma of the skin and soft tissue, angioleiomyoma, myofibromatosis/infantile haemangiopericytoma and putative neoplasms reported as malignant myopericytoma. Lack of reproducible phenotypic and genetic features of malignant myopericytic neoplasms have prevented the establishment of myopericytic sarcoma as an acceptable diagnostic category. Following detection of a LMNA-NTRK1 gene fusion in an index case of paediatric haemangiopericytoma-like sarcoma by combined whole-genome and RNA sequencing, we identified three additional sarcomas harbouring NTRK1 gene fusions, termed 'spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern'. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. While the tumours of the adults were strikingly myopericytoma-like, but with clear-cut atypical features, the paediatric cases were more akin to infantile myofibromatosis/haemangiopericytoma. All cases contained numerous thick-walled dysplastic-like vessels with segmental or diffuse nodular myxohyaline myo-intimal proliferations of smooth muscle actin-positive cells, occasionally associated with thrombosis. Immunohistochemistry showed variable expression of smooth muscle actin and CD34, but other mesenchymal markers, including STAT6, were negative. This study showed a novel variant of myo/haemangiopericytic sarcoma with recurrent NTRK1 gene fusions. Given the recent introduction of a novel therapeutic approach targeting NTRK fusion-positive neoplasms, recognition of this rare but likely under-reported sarcoma variant is strongly encouraged. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Background The purpose of this study was to evaluate risk factors that influence overall survival (OS)/disease-free survival (DFS)/locoregional recurrence-free survival (LRFS), and distant metastases-free survival (DMFS) in patients with high-risk primary salivary gland carcinoma who underwent surgery and postoperative (chemo)radiotherapy with curative intention. Methods We reviewed data of 63 patients with high-risk primary salivary gland carcinoma in a retrospective single-center audit. Results At a median follow-up of 31 months (range, 5-145 months), cumulative OS and DFS were 91.7%, 77.6%, and 62.9%, and 82.1%, 65.6%, and 57.7%, respectively, after 1, 2, and 5 years. LRFS and DMFS were 92%, 86%, and 86%, and 83.4%, 70.4%, and 62.3% after 1, 2, and 5 years, respectively. Of all patient-related, tumor-related, and treatment-related factors, high-grade histology (G3) was the only factor in univariate and multivariate analysis that was predictive for a shorter DMFS (low/intermediate vs high-grade: 100%, 100%, and 89.4% vs 72.9%, 54.3%, and 42.8% after 1, 2, and 5 years, respectively) and a shorter DFS (low/intermediate vs high-grade: 100%, 90%, and 84.4% vs 71.2%, 50.1%, and 39.4% after 1, 2, and 5 years, respectively) and OS (low/intermediate vs high-grade: 100%, 100%, and 86.5% vs 86.5%, 63.2%, and 46.5% after 1, 2, and 5 years, respectively). Conclusion High-grade tumor histology is a highly significant predictor of a shorter DMFS, OS, and DFS in salivary gland carcinoma, irrespective of histological subtype. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2041-E2048, 2016 [ABSTRACT FROM AUTHOR]

The ability to escape apoptosis is a hallmark of cancer-initiating cells and a key factor of resistance to oncolytic therapy. Here, we identify FAM96A as a ubiquitous, evolutionarily conserved apoptosome-activating protein and investigate its potential pro-apoptotic tumor suppressor function in gastrointestinal stromal tumors (GISTs). Interaction between FAM96A and apoptotic peptidase activating factor 1 (APAF1) was identified in yeast two-hybrid screen and further studied by deletion mutants, glutathione-S-transferase pull-down, co-immunoprecipitation and immunofluorescence. Effects of FAM96A overexpression and knock-down on apoptosis sensitivity were examined in cancer cells and zebrafish embryos. Expression of FAM96A in GISTs and histogenetically related cells including interstitial cells of Cajal (ICCs), 'fibroblast-like cells' (FLCs) and ICC stem cells (ICC-SCs) was investigated by Northern blotting, reverse transcription-polymerase chain reaction, immunohistochemistry and Western immunoblotting. Tumorigenicity of GIST cells and transformed murine ICC-SCs stably transduced to re-express FAM96A was studied by xeno- and allografting into immunocompromised mice. FAM96A was found to bind APAF1 and to enhance the induction of mitochondrial apoptosis. FAM96A protein or mRNA was dramatically reduced or lost in 106 of 108 GIST samples representing three independent patient cohorts. Whereas ICCs, ICC-SCs and FLCs, the presumed normal counterparts of GIST, were found to robustly express FAM96A protein and mRNA, FAM96A expression was much reduced in tumorigenic ICC-SCs. Re-expression of FAM96A in GIST cells and transformed ICC-SCs increased apoptosis sensitivity and diminished tumorigenicity. Our data suggest FAM96A is a novel pro-apoptotic tumor suppressor that is lost during GIST tumorigenesis. [ABSTRACT FROM AUTHOR]

Aims The diagnosis of Hirschsprung's disease is currently based on the identification of aganglionosis and the presence of an increase in acetylcholinesterase-positive hypertrophic nerve fibres in the large bowel submucosa. However, acetylcholinesterase staining is laborious and requires a skilled technician. The aim of this study was to identify a method for diagnosing Hirschsprung's disease reliably using an immunohistochemical panel of recently proposed markers. Methods and results Sixty-nine specimens from 37 patients were evaluated. MAP2 and calretinin antibodies were shown to stain ganglia reliably in the submucosal and myenteric plexuses of normal tissue. By contrast, reduced staining of ganglia was observed in patients with Hirschsprung's disease. Staining for GLUT1 and S100 was used to evaluate the number and thickness of nerve fibres. Gain of GLUT1 and S100 expression was in contrast to the loss of calretinin and MAP2. Hypertrophic submucosal nerve fibres in Hirschsprung's disease develop a perineurium with a ring-like GLUT1 staining pattern similar in size and intensity to that observed in deeper subserosal tissue. Conclusions The diagnosis of Hirschsprung's disease using immunohistochemical panels could be as accurate as with conventional frozen section techniques. In particular, the use of a combination of markers for ganglia and hypertrophic nerve fibres highlighting a prominent perineurium in Hirschsprung's disease could be an alternative method. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to localization, genotype and aggressiveness. DNA methylation at CpG dinucleotides is an important mechanism for regulation of gene expression. We performed targeted DNA methylation analysis of 1.505 CpG loci in 807 cancer-related genes in a cohort of 76 GISTs, combined with genome-wide mRNA expression analysis in 22 GISTs, to identify signatures associated with clinicopathological parameters and prognosis. Principal component analysis revealed distinct DNA methylation patterns associated with anatomical localization, genotype, mitotic counts and clinical follow-up. Methylation of a single CpG dinucleotide in the non-CpG island promoter of SPP1 was significantly correlated with shorter disease-free survival. Hypomethylation of this CpG was an independent prognostic parameter in a multivariate analysis compared to anatomical localization, genotype, tumor size and mitotic counts in a cohort of 141 GISTs with clinical follow-up. The epigenetic regulation of SPP1 was confirmed in vitro, and the functional impact of SPP1 protein on tumorigenesis-related signaling pathways was demonstrated. In summary, SPP1 promoter methylation is a novel and independent prognostic parameter in GISTs, and might be helpful in estimating the aggressiveness of GISTs from the intermediate-risk category. [ABSTRACT FROM AUTHOR]

Aims Neuroendocrine middle ear adenoma ( MEA) is a rare epithelial neoplasm of uncertain histogenesis that frequently shows neuroendocrine features. To date, <120 cases have been reported. The aims of the current study were to describe our experience with neuroendocrine MEA, to assess the frequency of specific neuroendocrine differentiation, and to test these lesions for transcription factors known to be expressed in a variety of other neuroendocrine tumours. Methods and results We investigated six cases of neuroendocrine MEA, and stained them, for the first time, for the transcription factors CDX2, TTF1, PAX8, and ISL1 (islet-1). The patients were four men and two women (mean age, 39 years; range, 27-53 years). Two of four patients with extended follow-up (4.5-22 years) experienced recurrence at 92 months, and at 9 and 22 years, respectively. One case extending into the external ear coexisted with cholesteatoma. Histological examination showed trabecular, solid, acinar, glandular, cribriform, organoid, nested, diffuse non-cohesive plasmacytoid and pseudoalveolar patterns in varying combinations. Immunohistochemistry showed consistent expression of vimentin (4/4), pancytokeratin (6/6), synaptophysin (6/6), CD56 (4/4), and ISL1 (6/6). A CK7 antibody stained scattered cells in two of five cases. The myoepithelial markers and transcription factors TTF1, CDX2 or PAX8 were not expressed in any of the cases. Conclusions Middle ear adenoma is an indolent, locally recurring, but generally non-metastasizing neoplasm with uniform expression of synaptophysin and ISL1, indicating true neuroendocrine differentiation. Because of its highly varied cellular and architectural appearance, MEA should be distinguished from tympanic paraganglioma and a variety of rare benign and malignant lesions at this site. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to evaluate our experience in the diagnostic approach to inflamed benign tumors of the parotid gland at a single tertiary center. Methods A retrospective evaluation was carried out for all patients with signs of inflammation in the parotid gland on the ground of a benign parotid tumor, as confirmed by permanent histology. Results Sixteen patients were detected for our study. Histopathologic examination confirmed cystadenolymphoma in 11 cases (with metaplastic changes in 2 cases), 2 pleomorphic adenomas, 2 monomorphic adenomas, and 1 oncocytic cystadenoma. Diverse clinical signs (inflammation signs, facial palsy), ultrasound and MRI findings (poorly defined lesion margins), and the presence of squamous metaplastic changes on cytology often raised the suspicion of parotid malignancy or abscess. Conclusion In most cases, a high suspicion index combined with close monitoring of the patient may allow prompt and successful diagnosis and therapy. © 2014 Wiley Periodicals, Inc. Head Neck 37: 23-29, 2015 [ABSTRACT FROM AUTHOR]

Aims Sinonasal haemangiopericytoma ( SN- HPC) is a rare sinonasal mesenchymal neoplasm of perivascular myoid cell origin. Solitary fibrous tumour ( SFT) occurs only very rarely in the sinonasal tract. SFT and soft tissue HPC have been considered a single entity. Recently, recurrent gene fusions involving NAB2- STAT6 resulting in differential expression of STAT6 were characterized as central molecular events in SFT. However, no data exist for NAB2- STAT6 status or STAT6 expression in SN- HPC. Methods and results We examined six SN- HPCs and two sinonasal SFTs by immunohistochemistry and RT- PCR for NAB2- STAT6 fusions. SN- HPC affected three females and three males (mean age: 72 years). They expressed smooth muscle actin, lacked strong CD34 reactivity and were negative for nuclear STAT6 expression. RT- PCR analysis confirmed the absence of NAB2- STAT6 fusions in all cases. Conversely, both sinonasal SFTs (in males aged 39 and 52 years) displayed classical features of pleuropulmonary and soft-tissue SFTs (uniformly CD34-positive with strong nuclear expression of STAT6). RT- PCR revealed NAB2 - STAT6 fusions in both cases. Conclusions These findings confirm the molecular and phenotypical distinctness of these two entities. While SN- HPC is a site-specific sinonasal neoplasm of as yet unknown molecular pathogenesis, sinonasal SFTs show phenotypical and molecular identity to their pleural/extrapleural counterparts. [ABSTRACT FROM AUTHOR]

Chemokines are involved in both the negative and positive regulation of inflammatory processes, angiogenesis and cancer/cancer stem cell proliferation as well as the chemoattraction of tumor cells to metastatic sites. The aim of this study was to measure the mRNA expression levels of three chemokines, CCL2, CCL7 and CX3CL1, in soft tissue sarcomas (STSs) and to assess the correlations between these levels as well as their correlations with clinicopathological data and the disease-specific survival of STS patients. The mRNA levels of CCL2, CCL7 and CX3CL1 were analyzed in tumor tissues from 126 STS patients using qPCR. Low mRNA expression of CCL2 and CX3CL1 was significantly correlated with a worse prognosis (RR = 1.98; p = 0.019 and RR = 2.10; p = 0.014; multivariate Cox's regression analysis). A combined low expression of CCL2 and CX3CL1 was associated with a significantly increased risk of tumor-related death as compared to patients with high expression levels of both chemokines (RR = 3.08; p = 0.003). A gender-specific multivariate analysis revealed that female STS patients with low CX3CL1 mRNA expression had a 3.46-fold increased risk of death ( p = 0.004). Low expression of both CCL2 and CX3CL1 mRNAs resulted in an additive 5.37-fold increased risk of tumor-related death ( p = 0.003) as compared to those with high expression of both parameters in female patients. In conclusion, this is the first study to show a significant correlation between combined low expression of CCL2 and CX3CL1 and a poor prognosis for STS patients, particularly in female patients. [ABSTRACT FROM AUTHOR]