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This study analyzed the expression of the PD1 receptor in tumor tissue and peripheral blood of oral squamous cell carcinoma (OSCC) patients, and correlated it with the PD1 ligands PD-L1 and PD-L2. The currently low response rates of checkpoint inhibitor treatment in OSCC could be increased by a better understanding of immune checkpoint biology. Despite evidence in the literature for upregulation of PD1 checkpoint ligands in OSCC tissue, there has been no correlation analysis of the PD1 receptor with its ligands in tissue specimens and peripheral blood of OSCC patients. An RT-qPCR analysis of PD1 mRNA expression was performed in oral cancer specimens, healthy mucosa, and corresponding blood samples. A cut-off point (COP) was determined and a chi-square (χ2) test was carried out. PD1 expression was correlated with previously reported PD-L1 and PD-L2 expression values using the Spearman test. Tissue and blood specimens of 48 OSCC patients and 26 healthy individuals were analyzed. PD1 expression in OSCC specimens was significantly increased (p = 0.006) compared with healthy oral mucosa. PD1 overexpression in tissue samples showed a significant association with the presence of malignancy (p = 0.006). PD1 expression in tissue samples showed a significant positive correlation (p < 0.001) with the ligands PD-L1 and PD-L2. In contrast, there was no correlation between PD1 and its ligands in blood samples. However, there was a significant positive correlation (p < 0.001) between the ligands PD-L1 and PD-L2, both in tissue and blood samples. Increased PD1 expression might be a manifestation of T-cell exhaustion in OSCC specimens, leading to immune tolerance. PD-L1/PD-L2-PD1 interaction may be a major mediator of local immunosuppression in OSCC, requiring advanced multimodal treatment protocols. [ABSTRACT FROM AUTHOR]

To assess long-term results after treatment of parotid pleomorphic adenomas (PPAs) with different surgical techniques, standardized according to the European Salivary Gland Society (ESGS) classification system. We analyzed ESGS categories, occurrence of facial nerve paresis (FNP), Frey's syndrome, histopathology, and recurrences. Surgical modalities were compared, differentiating techniques with and without facial nerve dissection. A strict protocol ensured a postoperative follow-up-period of more than 7 years. 205 patients were included. A complete follow-up was possible in 138 patients, 77 of whom underwent extracapsular dissection (ED) and 61 of whom had other surgical modalities (OSMs). ESGS categories correlated with the extent of surgery, significantly with the risk for FNP and Frey's syndrome, but not with recurrences. Recurrences did not differ significantly between ED and OSMs, whereas the risks for FNP (p < 0.001 each) and Frey's syndrome (p = 0.000) were significantly higher after OSMs in comparison with ED. Young women with a stroma-rich (myxoid) tumor subtype appear to have the greatest risk for recurrences. ED is the treatment of choice for PPAs, if possible, resulting in similar recurrence rates but significantly fewer comorbidities in comparison with more extensive surgery. After the treatment of PPAs, a long-term follow-up is needed, including imaging. [ABSTRACT FROM AUTHOR]

Summary Background & aims Non-celiac gluten sensitivity (NCGS) is characterized by intestinal and extra-intestinal symptoms triggered by ingestion of gluten. However, non-gluten triggers have recently been implicated, and a FODMAP (fermentable oligo-, di-, monosaccharides and polyols)-reduced diet can partially improve symptoms in NCGS. Our aim was to analyze the effect of a low FODMAP versus a gluten-free diet (GFD) on clinical symptoms, psychological well-being, intestinal inflammation and integrity, and stool microbiota. Methods Nineteen patients with NCGS and ten healthy controls consumed a gluten-containing standard diet before starting a two-week low FODMAP diet; after a five day transition period, participants ingested a GFD for another two weeks. The primary outcome measure was the improvement of clinical symptoms in NCGS patients under the different diets. Secondary outcomes were the determination of dietary effects on intestinal inflammation, psychological well-being, and differences in stool microbiota between NCGS patients and controls. Results The low FODMAP diet and especially the GFD led to a significant improvement of clinical and psychological symptoms in NCGS. A clear reduction in duodenal intraepithelial lymphocytes and mucin-producing Goblet cells was found after the GFD in these patients. Significant microbial differences between NCGS patients and controls were noticed in stool samples at every time point. Both diets caused microbial shifts in all participants, with a greater variability on genus level and metabolisms groups in NCGS patients. Conclusions Our findings suggest a multifactorial etiology of NCGS, due to a functional effect caused by FODMAPs, combined with a mild gluten-triggered immune reaction, and a microbiota dysbalance. ClinicalTrial.gov ID : NCT03268720. [ABSTRACT FROM AUTHOR]

Abstract High grade malignant tumors with a poorly-/un-differentiated morphology pose significant diagnostic challenges. Increasingly, the use of adjunct immunohistochemical and molecular tests to characterize and delineate the histopathologic phenotype of these tumors has become necessary, particularly in head and neck tumors. Recently, several entities with a poorly-/un-differentiated light microscopic morphology have been defined based on specific immunohistochemical and genetic characteristics. We herein describe two cases of high-grade myoepithelial carcinoma, one occurring in the submandibular gland and the other occurring in the left nasal cavity, both showing undifferentiated histological and anaplastic cytomorphological features. This led to very broad differential diagnostic considerations and the diagnosis was only established after extensive immunohistochemical studies. Molecular testing for HPV was negative in both cases. Gene fusion analysis using a targeted sequencing assay (Archer® FusionPlex® system) did not identify fusions involving PLAG1 , HMGA2 , EWSR1 or ALK genes in either case. The submandibular tumor showed an aggressive clinical course, with diffuse pulmonary metastases at presentation, whilst the nasal cavity tumor showed only localized disease. Awareness of a subcategory of high-grade myoepithelial carcinomas with undifferentiated light microscopical features is of significant importance in antibody selection for immunohistochemical investigation of poorly-/undifferentiated malignant tumors in the head and neck region. This histological variant of myoepithelial carcinoma adds to the growing list of differential diagnoses in this diagnostically complex and multifaceted field. Highlights • High grade malignant tumors with a poorly-/un-differentiated morphology pose significant diagnostic challenges. • Use of adjunct immunohistochemical and molecular tests to delineate the phenotype of these tumors has become necessary. • High-grade myoepithelial carcinoma can display undifferentiated histological and anaplastic cytomorphological features. • This histological variant adds to the growing list of differential diagnoses of undifferentiated head and neck tumors. [ABSTRACT FROM AUTHOR]

Serrated colorectal fibroblastic polyps (FPs) are rare benign mucosal lesions composed of serrated epithelial crypts separated and distorted by intimately associated bland spindle cell proliferations with perineurial-like phenotype. We herein describe 21 new FPs affecting 10 females and 9 males aged 45 to 80 yrs. (mean, 62 yrs). Lesions originated in the sigmoid colon/rectosigmoid junction ( n  = 16), rectum ( n  = 2), and other parts of the colon ( n  = 3). Most patients had additional synchronous or metachronous polyps: classical adenomas (12 patients), sessile serrated adenoma/SSA (1 patient), hyperplastic polyps/HPs (7 patients), both HPs and adenomas (6 patients) and colorectal cancer (2 patients). Size of the lesions varied from 1 to 6 mm (mean: 3 mm). Histologically, all lesions were composed of serrated epithelial crypts that were separated and distorted by spindle cell stromal proliferations (consistently EMA+, claudin-1+ and GLUT-1+). The epithelial component displayed features of HPs ( n  = 17) and SSA ( n  = 4). Laser-microdissection-guided molecular testing was successful for 13 epithelial and 9 stromal components (9 paired samples). The BRAF V600E mutation was detected in 54% of the epithelial but in none of the stromal components. In conclusion, colorectal FPs represent genuine serrated epithelial polyps corresponding either to HP or (less frequently) SSA and should be better classified as such with a note on the presence of the stromal component. A more concise terminology reflecting their epithelial nature is needed to fulfill the requirements for colorectal cancer risk assessment and hence adopt appropriate follow-up strategies. [ABSTRACT FROM AUTHOR]

Pleomorphic adenoma (PA) of the submandibular gland is known to have a very low recurrence rate. The aim of this study was to investigate the histopathological and capsular characteristics of submandibular gland PA, looking for any differences between submandibular PA and the reported data for PA of the parotid gland as possible explanation for its low recurrence rate. We reviewed 72 submandibular gland PAs resected at our center between 2000 and 2016. Patient age ranged from 14 to 77 years (mean, 47.2). At least follow (range, 12 to 170 months; mean, 82), none of the 72 patients developed a local recurrence. Histologically, all of the tumors were encased by a complete and intact anatomical capsule (100%). Pseudopodia were detected in 11 (15.3%) and satellite nodules in 3 (4.2%) cases. The histological subtype (according to Seifert et al.) was classic (mixed) in 39 (54.2%), stroma-rich/myxoid in 18/72 (25%) and cellular in 15 (20.8%) cases. A complete rim of healthy pericapsular tissue encasing the tumor and its capsule was observed in only 23/72 (31.9%) cases. In conclusion, submandibular PAs are characterized by consistent presence of an intact anatomical capsule, infrequent occurrence of pseudopodia, a remarkably infrequent occurrence lower frequency of secondary satellite tumor nodules and a comparatively lower proportion of the fragile risky myxoid subtype. Despite the fact that surgery of the submandibular gland can frequently lead to focal capsular exposure, the aforementioned capsular characteristics of submandibular gland PA are probably responsible for the excellent oncologic results. [ABSTRACT FROM AUTHOR]

The term “anisometric cell lipoma” (ACL) has been proposed recently by Evans for a lipoma variant characterized by striking variation in size and shape of adipocytes but little or no cytological atypia. One patient with multiple ACL had a history of retinoblastoma. The current study analyzed six patients with ACL (4 males and two females aged 34 to 87 years; median, 58); all seen in consultation. Five patients presented with solitary and one with multiple subcutaneous masses measuring 5 to 9 cm (median, 7.5 cm). Affected sites were upper arm (3), shoulder (2), neck (1), trunk (1) and chest wall (1). Surgical excision was the treatment in all cases. No recurrence was recorded at last follow-up (1–17 months). Submitted diagnoses were atypical lipomatous tumor (n = 3), lipoma with regressive changes (n = 1) and unclassified lipomatous neoplasm (n = 2). In all cases, the striking variation in size of adipocytes was mentioned as the most or sole worrisome feature justifying external consultation. Histology was similar in all cases. All fulfilled the features reported by Evans as stated above and lacked any conventional spindle cell lipoma-like areas. Multi-vacuolated (lipoblast-like) cells were seen in three cases. MDM2/CDK4 were negative by immunohistochemistry and MDM2 amplification was absent by FISH in all cases. RB1 immunoexpression was lost in 5/5 cases. Rb1 FISH analysis revealed copy number aberrations in 3 of 4 cases (heterozygous deletions in two cases and homozygous deletion in one). In conclusion, ACL shares similar clinicopathological, demographic and molecular features as spindle cell lipoma suggesting related diseases. In the light of the available literature on adipocytic neoplasms in retinoblastoma survivors (> 30 patients with multiple lipomas following retinoblastoma reported), it is probably that retinoblastoma-associated lipomas belong to the ACL category. Thus, it seems that Somatic RB1 loss probably drives sporadic ACL in a comparable way to post-retinoblastoma lipomas which were shown to be driven by LOH of the RB1 wild-type allele. [ABSTRACT FROM AUTHOR]

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive tumor affecting mostly younger patients. This is the first study to assess the expression of programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) in FH-RCC. Formalin-fixed paraffin-embedded samples from 13 FH-RCCs collected in an international multi-institutional study, were evaluated by immunohistochemistry (IHC) for PD-1/PD-L1 reactivity in tumor cells and tumor infiltrating lymphocytes (TILs). PD-1/PD-L1 expression was further evaluated by qPCR. By IHC, PD-1 was negative in tumor cells in all 13 cases. PD-L1 was positive in tumor cells in 2/13 cases, weak positive in 7/13, and negative in 4/13 cases, respectively. In TILs, PD-1 was positive in 1/13, weak positive in 3/13, and negative in 9/13 cases. In TILs, PD-L1 was weak positive by IHC in 5/13, and negative in 8/13 cases, respectively. qPCR confirmed the result for 2 of 3 IHC weak positive PD-1 samples. Of 7 IHC weak positive samples (in tumor cells), PD-L1 mRNA was detected in all 7 tumors. The majority of FH-RCCs did not express PD-1/PD-L1 by IHC, which was confirmed by molecular analysis. PD-1/PD-L1 expression in FH-RCC is restricted to a proportion of cases which may benefit from targeted therapies. [ABSTRACT FROM AUTHOR]

The authors present a distinctive perineurioma (PN) variant which morphologically strongly resembles monophasic fibrous synovial sarcoma (MSS). The patients were 3 males and 1 female. The age ranged from 15 to 61 years (mean: 44 years). Locations included the sole, lower jaw, palm and foot. The tumor size ranged from 1.3 cm to 2.5 cm in the largest dimension (mean 1.8 cm). Morphologically, all tumors had an identical, monotonous appearance. The perineurial cells were closely packed and created a confluent cellular whorls and/or sheets in a scarce stroma, with only focally discernible long, slender cytoplasmic processes typical for perineurial differentiation. The nuclei were rounded or slightly elongated to tapered, without nuclear atypia. Mitoses were rare to completely absent. Atypical mitoses, hemorrhage, necrosis or calcifications were not present. The proliferative index (Ki-67) was 1–3%. All analyzed tumors were positive for EMA, Claudin-1, GLUT-1 and negative with S100 protein, CD34, OSCAR, CK7 and TLE-1. Two cases were tested by fluorescence in situ hybridization and neither showed alterations of the SYT gene. One case studied by electron microscopy showed characteristic features of perineurial differentiation. Follow-up was available for two patients both of which showed no evidence of disease at 8 years and 6 months, respectively. Based on their bland morphology, perineurial features and presumably benign clinical outcome we propose the term “whorling cellular perineurioma” for these tumors, which may represent an extremely cellular variant of sclerosing PN. Awareness of this PN subtype and its distinction from MSS is of utmost clinical significance. [ABSTRACT FROM AUTHOR]

The chromatin remodeling switch sucrose nonfermentable (SWI/SNF) complex has been increasingly implicated in the pathogenesis and dedifferentiation of neoplasms from several organs with prognostic and potential therapeutic implications. We herein investigated the expression of the SWI/SNF complex catalytic subunits SMARCA4 (BRG1) and SMARCA2 (BRM) in 316 consecutive non-small cell lung cancer (NSCLC) specimens on tissue microarrays (171 adenocarcinomas [ADCAs], 130 squamous cell carcinomas [SCCs], 9 adenosquamous carcinomas, and 6 large cell carcinomas) excluding undifferentiated/giant cell or rhabdoid carcinomas. Complete loss of SMARCA4 was observed in 8 (5.5%) of 146 evaluable pulmonary ADCAs and 6 (5.2%) of 115 evaluable pulmonary SCCs, whereas 9 (6.4%) of 140 ADCAs and 2 (1.7%) of 117 SCCs showed SMARCA2 loss. Two of 6 large cell carcinomas were SMARCA2 deficient. Concurrent loss of both markers was observed in 4 cases (2 ADCAs and 2 SCCs). Of 15 ADCAs with loss of either or both markers, 12 (80%) were TTF1 negative. In conclusion, SMARCA4 and SMARCA2 deficiency is observed in 5.1% and 4.8% of NSCLC, respectively. SMARCB1 expression was intact in all cases. The presence of differentiated histology (glandular or squamous) is a novel aspect among SWI/SNF-deficient carcinomas which in other organs generally are associated with undifferentiated/rhabdoid morphology. The predominance of TTF1 negativity among SWI/SNF-deficient pulmonary ADCA (80%) underlines the need to include these 2 markers in the evaluation of TTF1-negative ADCA of putative pulmonary origin. Given the recently documented potential of SMARCA4 loss as a predictor of chemosensitivity to platinum-based chemotherapy in NSCLC, recognition of the clinicopathological features of SMARCA4-deficient NSCLC in routine surgical pathology practice is recommended. [ABSTRACT FROM AUTHOR]

A subset of lung carcinoma presents initially with brain metastasis. Precise subtyping is mandatory for optimized treatment of these advanced aggressive carcinomas. We herein analyzed surgical biopsies from 171 Patients (99 males and 72 females aged 48–96; mean, 72), who presented with brain metastasis of lung cancer. In addition to conventional subtyping, we applied an extended immunohistochemistry (IHC) panel and performed several molecular tests looking for potential therapeutic targets other than EGFR mutations. Non-small cell carcinoma (NSCLC) comprised 157 (91.8 %) of cases: 109 (63.7 %) adenocarcinomas, 27 (15.8 %) squamous cell (SCC), 18 (10.5 %) large cell undifferentiated, 1 (0.6 %) adenosquamous and 2 (1.2 %) unclassified carcinomas. Of the adenocarcinomas, 81.7 % were TTF1+. Notably, 45 % of those TTF1-negative cases expressed HepPar1. SMARCA4 and SMARCA2 loss was observed in 13/171 (7.6 %) and 32/163 (19.6 %) cases, respectively; mainly TTF1- (40.0 %) and HepPar1+ (38.1 %) adenocarcinomas were affected by SMARCA2/4 loss. Loss of at least one mismatch repair (MMR) protein was observed in 3/156 (1.9 %) cases (2 adenocarcinomas and 1 large cell neuroendocrine carcinoma/LCNEC). Limited available data on mutation testing showed a frequency of EGFR mutations of 4.3% and of KRAS mutations of 57%. HER2 expression (2+/3+) was found in 45/166 (27.1 %) of cases with amplification verified by CISH in 18/38 (47.4 % of immunopositive cases and 10.5 % of the whole cohort); all but one were adenocarcinomas. Other genetic abnormalities detected included EML4::ALK rearrangements in 3 (1.8 %; 2 TTF1+ adenocarcinomas and 1 LCNEC) and RET rearrangements in one SCNEC. Variable subsets of tumors revealed amplifications of several potentially therapeutically targetable genes including MYC (30.0 %), MET (10.1 %), HER2 (10 %), FGFR1 (9.6 %), FGFR3 (4.6 %), and FGFR2 (3.4 %). This study highlights a highly heterogeneous molecular background in lung cancer presenting with CNS metastases. These findings highlight the need for individualized tumor testing strategies looking for potential therapeutic targets for this aggressive disease. • The precise subtyping of lung carcinomas presenting initially with brain metastasis has not been well studied. • SMARCA2/4-deficient tumors (isolated or combined loss) are overrepresented (collectively 27.2%). • A higher proportion of SMRACA2/4 deficient cases displayed a TTF1-/HepPar1+ phenotype. • Mismatch repair deficiency is rare (1.9%), and ALK and RET rearrangements (together 2%) are rare among CNS metastasis. • Besides HER2, several other potentially targetable genes (MYC, MET , FGFR1 , FGFR2 and FGFR3) are amplified. [ABSTRACT FROM AUTHOR]

Eosinophilic angiocentric fibrosis (EAF) is a rare tumefactive fibroinflammatory disease with predilection for the upper respiratory tract, characterized by concentric (onionskin) fibrosis around small arterioles with variable intervening storiform fibrosis admixed with chronic inflammatory infiltrates rich in eosinophils. Erythema elevatum diutinum (EED), another autoimmunological disorder that mainly affects acral sites and extensor surfaces, is characterized by neutrophilic leukocytoclastic vasculitis. Rarely, older EED lesions may present as tumefactive nodular (pseudotumoral) fibrous masses closely mimicking EAF. We herein describe four patients (all males) aged 66–70 years who presented with large (median, 7 cm) tumor-like fibrous lesions in the paravertebral region not associated with a known clinical autoimmune disease. All cases were resected surgically with the suspicion of a neoplasm. They displayed a strikingly similar histological appearance with combined features of EAF and nodular fibrous EED. None had evidence of obliterative phlebitis or increased IgG4: IgG ratio. The etiology of this distinctive lesion and its predilection for the paravertebral area of males remains obscure. A distinctive tumefactive localized reaction to trauma caused by degenerative disease of adjacent vertebrae might be a possible explanation. • Four cases (all older males) of a distinctive paravertebral fibroinflammatory pseudotumor overlapping with EAF and tumoral EED are presented. • Their uniform sites and histology argue for a shared etiology. • Lack of known autoimmune disorders suggests association with degenerative vertebral disease. • This variant of pseudotumor should be distinguished from fibroblastic neoplasms, IgG4-RD and other specific etiologies. [ABSTRACT FROM AUTHOR]

Follicular dendritic cell sarcoma (FDCS) is a rare low-grade neoplasm with the phenotype of FDC cells. This rare sarcoma has been well known for being mistaken for a variety of neoplasms (mainly meningioma), particularly at extranodal sites. Diagnosis of FDCS mainly relies on characteristic histologic appearance supplemented by immunohistochemistry and electron microscopy. In this study, we reviewed 15 FDCSs retrieved from our consultation files and stained them for newly reported or novel markers (PD-L1, Rb1, MDM2, and somatostatin receptor 2A [SSTR2A]) in addition to conventional FDC markers. Patients were 7 men and 7 women (1 unspecified) with a mean age of 47 years (20-75 years). The tumor site was lymph nodes (6) or spleen (2), both (1) and extranodal sites of head and neck (4) or abdominal cavity (2). Treatment was variable combinations of surgery and aggressive chemotherapy/radiotherapy. Four of 8 patients with follow-up died of disease within 1 to 10 years. All tumors expressed at least 1 FDC marker: CD21 (8/13), CD23 (2/13), CD35 (8/12), CNA.42 (13/14), Clusterin (8/13), Fascin (15/15) and D2-40/podoplanin (7/14). Epstein-Barr virus (EBER-1/2 in situ hybridization) was performed successfully in 10 conventional variants; all were negative. Five of 14 cases (36%) stained strongly for SSTR2A with a distinctive membranous pattern. Residual lymphoid follicles surrounding some of the tumors stained similarly for SSTR2A. Seven (54%) of 13 assessable cases showed moderate to strong membranous staining for PD-L1 in greater than 5% of the neoplastic cells. The Rb1 antigen was lost in 4 (28%) of 14 cases. MDM2 stained less than 5% to 20% of the tumor cells in 5 (36%) of 14 cases; 2 of them showed amplification by fluorescence in situ hybridization (FISH). CDK4 was negative except for weak staining in 1 of 14 cases. This study adds to the existing few clinicopathologic series on FDCS and represents the first study to show MDM2 amplification in this entity. Our results regarding frequent SSTR2A expression in FDCS are novel and might be of potential diagnostic and therapeutic relevance. SSTR2A expression in FDCS represents a further confusing factor when thinking of meningioma which uniformly expresses this receptor. FDCS occurring within the retroperitoneum and/or the abdominal cavity may closely mimic dedifferentiated liposarcoma, particularly if MDM2 positive and/or amplified and should thus be carefully assessed for expression of FDC markers. [ABSTRACT FROM AUTHOR]

Background Differentiation of Ewing sarcoma family of tumors (ESFT) and Ewing-like tumors remains problematic. Certain ESFT with morphological and immunohistochemical (IHC) profiles lack the EWSR1-ETS transcript. To improve diagnostic accuracy we investigated the presence of several specific transcripts in 200 small round cell tumors (SRCT) displaying ESFT morphology and immunophenotype in which EWSR1 FISH analysis was non-informative or negative. Design 200 tumors (formalin-fixed, paraffin-embedded) were analyzed by RT-PCR. All tumors were tested for EWSR1-ETS , EWSR1 / WT1 , PAX3 / 7-FOX01 or SYT / SSX transcripts, and the negative tumors were subsequently analyzed for CIC / DUX4 , BCOR / CCNB3 and CIC / FOX04 transcripts. Results 133 (66.5%) ESFT displayed one of the above EWSR1-ETS translocations. Three cases (1.5%) revealed the SYT-SSX transcript for Synovial sarcoma, and one (0.5%) a EWSR1-WT1 transcript for Desmoplastic Small Round Cell tumor. The CIC-DUX4 translocation was found in six Ewing-like tumors (3%) with CD99 positivity. The BCOR-CCNB3 gene fusion was observed in 5 tumors (2.5%) displaying round or spindle cells with strong CCNB3 IHC expression in 3 tumors. Moreover, RT-PCR failed to detect any gene fusion transcripts in 19 tumors (9.5%) and were considered “undifferentiated small round cell sarcoma” (SRCS). Molecular biology results were non-informative in 33 SRCTs (16.5%) due to RNA degradation through inadequate fixation and/or decalcification. Conclusion Our analysis of 200 SRCTs confirms the molecular heterogeneity of neoplasms with ESFT morphology and highlight that molecular studies with RT-PCR including new emerging gene fusion transcripts are mandatory for the diagnosis when EWSR1 FISH is negative or non-informative. The incidence of CIC-DUX4 , BCOR-CCNB3 and CIC-FOX04 transcripts was relatively low. A small group of Ewing-like sarcomas or undifferentiated SRCS remains unclassified. Adopting appropriate tissue fixation and processing protocols is important to avoid degradation of fixed/embedded tissue when no frozen tumor is available. [ABSTRACT FROM AUTHOR]

Angiosarcoma may rarely arise near an inert foreign body material including vascular grafts and metal joint prostheses. Sixteen such cases have been reported since 1972 but mostly in the radiologic or surgical literature without detailed histologic or molecular analyses. We herein describe the clinicopathologic and molecular features of 2 new cases and reanalyzed 3 previously reported cases of angiosarcoma that developed in association with Dacron grafts for vascular repair (n = 3) or related to orthopedic metal prostheses for joint replacement (n = 2). All patients were men aged 50 to 84 years (median, 71 years). Mean time to development of angiosarcoma was 9 years (range, 4.6-17 years). Symptoms were recurrent bleeding/loosening of prosthesis for suspected infection (in the joint prosthesis cases) and fatigue, weight loss, and abdominal symptoms in the Dacron-associated cases. Four patients died of disease within 1 to 24 months (mean, 8 months). One patient was alive after radical surgery, radiochemotherapy, and embolization of pulmonary metastases (17 months). Histologically, all tumors were high-grade epithelioid neoplasms with a predominant solid growth pattern and variable vasoformation. All tumors expressed CD31, ERG, FLI-1, and variably pancytokeratin (diffuse in 3 cases), but none expressed D2-40, MDM2, or CDK4. Fluorescence in situ hybridization analysis revealed no MDM2 or CDK4 alterations. MYC was expressed in all cases, but only 1 case was MYC amplified by fluorescence in situ hybridization. Angiosarcomas are exceedingly rare fatal complications of long-standing metal and Dacron prostheses. Awareness of their morphology and frequent cytokeratin expression is necessary to avoid misdiagnosis as metastatic carcinoma. Limited awareness of their existence explains delayed clinical diagnosis in most of cases. Absence of MDM2 / CDK4 alterations underlines their distinction from intimal-type sarcomas. [ABSTRACT FROM AUTHOR]

We describe 9 cases of pleomorphic hyalinizing angiectatic tumor (PHAT). Recently described TGFBR3 and MGEA5 gene rearrangements in these tumors have confirmed the long-hypothesized link between PHAT and another soft tissue entity, the myxoinflammatory fibroblastic sarcoma (MIFS). Myxoinflammatory fibroblastic sarcoma and PHAT share the same translocation and in addition have a very similar clinical presentation. However, to our best knowledge, no study has ever addressed the striking morphologic similarities between MIFS and PHAT. Our findings based on histological criteria suggest that most, if not all, tumors diagnosed as PHAT might, in fact, represent examples of MIFS that, in addition to a conventional MIFS morphology, manifest aberrant angiectatic hyalinized vessels. [ABSTRACT FROM AUTHOR]

Small cell carcinoma of the ovary, hypercalcemic type is a very rare aggressive neoplasm of unknown histogenesis, affecting mainly girls and young women. Recently, inactivating mutations in SMARCA4 ( BRG1 ), a member of the switch/sucrose nonfermenting chromatin remodeling complex, has been identified as driver events in most cases. We herein describe 3 cases in 34, 34, and 37-year-old women. Symptoms were mainly abdominal pain and mass. One patient was normocalcemic, and the other 2 had no preoperative serum calcium values available. All patients received radical hysterectomy with salpingo-oophorectomy, lymphadenectomy, and variable multimodality therapy. Two developed abdominal recurrences/metastases and died of disease at 4 and 12 months. One patient was alive without disease 17 months after surgery and radiochemotherapy. Histologic examination showed undifferentiated neoplasms composed of diffuse sheets, nests and cords of noncohesive monomorphic small blue/basaloid cells (classic variant, 1 case), and large undifferentiated/rhabdoid cells with abundant cytoplasm (large cell/rhabdoid variant, 2 case) admixed with minor small cell areas. One case contained rare isolated goblet cells, but true glandular component was absent. All tumors expressed vimentin and variably pancytokeratin and WT1. Nuclear SMARCB1 was intact in all cases (1 case showed small foci with mosaic loss). All tumors showed complete loss of SMARCA4. In conclusion, SMARCA4 immunohistochemistry represents a highly valuable emerging tool in identifying small cell carcinoma of the ovary, hypercalcemic type in routine practice. Distinguishing this aggressive neoplasm from juvenile granulosa cell tumor and other undifferentiated ovarian cancers is mandatory in selecting appropriate chemotherapeutic regimens and would allow better characterization of this entity, for which targeted molecular therapy still remains to be established. [ABSTRACT FROM AUTHOR]

The role of the switch/sucrose nonfermenting chromatin remodeling complex in the initiation and progression of cancer is emerging. In the female genital tract, only ovarian small cell carcinoma, hypercalcemic type harbors recurrent inactivating SMARCA4 mutations. Otherwise, only rare case reports documented SMARCB1 involvement in endometrial cancer. We analyzed 24 grade 3 uterine endometrioid adenocarcinomas and 2 undifferentiated carcinomas for immunohistochemical expression of SMARCB1 and SMARCA4. All tumors showed high-grade nuclear features with a predominance of solid growth pattern. All cases showed intact nuclear SMARCB1 expression in all tumor cells. However, 1 case of a 78-year-old woman showed complete loss of SMARCA4 in 90% of the tumor with retained expression in 10% of the tumor. The SMARCA4-intact component was a moderate-to-poorly differentiated endometrioid adenocarcinoma. The SMARCA4-deficient dominating component showed solid growth of highly anaplastic undifferentiated large cells with prominent rhabdoid features. None of the 25 SMARCA4-intact cases showed rhabdoid cell morphology. To our knowledge, this is the first systematic study of SMARCB1 and SMARCA4 expression in endometrioid adenocarcinoma of uterus and the first description of a novel SMARCA4-deficient variant of dedifferentiated/undifferentiated endometrial carcinoma. The presence of a differentiated SMARCA4-intact endometrioid component points to a novel pathway of dedifferentiation in endometrioid adenocarcinoma as a consequence of a “second hit.” This case further underlines the close link between the “rhabdoid phenotype” and the SWI/SNF pathway. [ABSTRACT FROM AUTHOR]

Sclerosing epithelioid fibrosarcoma (SEF) is a rare fibrosarcoma variant with specific histomorphology and consistent translocation (EWSR1-CREB3L1/2). To date, 110 cases have been reported; only 15 originated within the abdomen. With only 2 cases reported parallel to our study and one case briefly mentioned in a previous series, primary renal SEF is exceptionally rare but might be underrecognized. We herein describe 2 cases affecting a 23-year-old woman and a 43-year-old man. Tumor size was 22 and 4.2 cm, respectively. Patient 1 developed skeletal and multiple pulmonary metastases. She died of disease 82 months later, despite aggressive multimodality therapy. Patient 2 has no evidence of recurrence or metastasis (8 months after surgery). Histologic examination showed similar appearance with monotonous bland medium-sized epithelioid cells with rounded slightly vesicular nuclei and clear cytoplasm imparting a carcinoma-like appearance set within a highly sclerotic hyaline fibrous stroma. The tumor cells were arranged in nests, single cell cords, trabeculae, or solid sheets with frequent entrapment of renal tubules and glomeruli. Immunohistochemistry showed strong expression of vimentin, bcl2, CD99, and MUC4, whereas cytokeratin and other markers were negative. Fluorescence in situ hybridization showed a translocation involving the EWSR1 gene locus in case 2. Molecular analysis in case 1 was not successful due to poor signal quality. To our knowledge, this is the second report documenting primary renal SEF. Awareness of this entity would help avoid misinterpretation as clear cell carcinoma, sclerosing perivascular epithelioid cell tumor, Xp.11 translocation carcinoma, and other more frequent neoplasms at this site. [ABSTRACT FROM AUTHOR]

The MDM2 gene appears to be involved in the development of nasopharyngeal carcinoma. The aim of this study was to examine MDM2 expression in a series of nasopharyngeal carcinoma biopsies to explore its potential diagnostic significance. The study cohort consisted of 26 nasopharyngeal carcinomas, including 22 EBV positive non-keratinizing squamous cell carcinomas (NKSCC), 1 EBV negative NKSCC and 3 EBV negative keratinizing SCC. For comparison, we selected 48 oropharyngeal carcinomas, including 17 HPV positive SCC (14 non-keratinizing and 3 keratinizing) and 31 HPV negative SCCs (28 keratinizing and 3 non-keratinizing). In addition, we examined MDM2 expression in a group of 26 cervical lymph node metastases, including 5 with EBV positive nasopharyngeal NKSCC and 21 from oropharyngeal carcinoma (18 non keratinizing HPV positive, 1 keratinizing HPV positive, 1 keratinizing HPV negative and 1 non-keratinizing HPV negative). Finally, 2 bone metastases from EBV positive nasopharyngeal NKSCC were also included. A tissue microarray was constructed from formalin-fixed paraffin embedded tumor tissue specimens. Sections were immunostained for MDM2 and in situ hybridization for EBER and CISH analysis for the MDM2 gene were also conducted in all cases. Overall, MDM2 positivity was detected in 28 of 102 SCCs (27.2 %). MDM2 positivity was significantly more frequent in EBV positive NKSCC (80 %) than in oropharyngeal HPV positive NKSCC (6.1 %) and keratinizing SCCs (9.4 %) (p < 0.001, Pearson chi square). Considering only the primary tumors, 86.4 % of the nasopharyngeal carcinomas were positive, versus 13.5 % of the oropharyngeal carcinomas (p < 0.001, Pearson chi square). Considering the lymph node metastases, 3 of 5 EBV positive carcinomas with nasopharyngeal primary were positive, whereas only one of the HPV positive carcinomas was positive. Finally, both the bone metastases from EBV positive nasopharyngeal carcinoma were positive for MDM2. No amplification of the MDM2 gene was identified by in situ hybridization analysis. Our data indicate that MDM2 could be a valuable diagnostic marker to support the diagnosis of nasopharyngeal EBV positive NKSCC. [ABSTRACT FROM AUTHOR]

Dedifferentiated melanoma (DedM) poses significant diagnostic challenges. We aimed to investigate the clinical, histopathological and molecular features of DedM. Methylation signature (MS) and copy number profiling (CNP) were carried out in a subgroup of cases. A retrospective series of 78 DedM tissue samples from 61 patients retrieved from EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group centres were centrally reviewed. Clinical and histopathological features were retrieved. In a subgroup of patients, genotyping through Infinium Methylation microarray and CNP analysis was carried out. Most patients (60/61) had a metastatic DedM showing most frequently an unclassified pleomorphic, spindle cell, or small round cell morphology akin to undifferentiated soft tissue sarcoma, rarely associated with heterologous elements. Overall, among 20 successfully analysed tissue samples from 16 patients, we found retained melanoma-like MS in only 7 tissue samples while a non-melanoma-like MS was observed in 13 tissue samples. In two patients from whom multiple specimens were analysed, some of the samples had a preserved cutaneous melanoma MS while other specimens exhibited an epigenetic shift towards a mesenchymal/sarcoma-like profile, matching the histological features. In these two patients, CNP was largely identical across all analysed specimens, in line with their common clonal origin, despite significant modification of their epigenome. Our study further highlights that DedM represents a real diagnostic challenge. While MS and genomic CNP may help pathologists to diagnose DedM, we provide proof-of-concept that dedifferentiation in melanoma is frequently associated with epigenetic modifications. • Dedifferentiated melanomas pose significant diagnostic challenges. • Epigenetic and copy number variation features may be useful for diagnostic purposes. • Dedifferentiated melanoma patients respond to systemic therapy. [ABSTRACT FROM AUTHOR]

Abstract: Benign peripheral nerve sheath tumors (PNSTs) showing more than one line of differentiation (hybrid PNSTs) have been increasingly recognized, mainly due to awareness of their existence and as a consequence of increased use of immunohistochemisty during the last decade. Two recent studies suggested overrepresentation of hybrid tumors among benign PNSTs in patients with neurofibromatosis type 1 (NF-1). This study was performed to assess the presence of perineurial cells in microscopic (early) neurofibromatous lesions and normal-looking peripheral nerves in specimens from 5 patients with NF-1 using markers of perineurial cell differentiation (epithelial membrane antigen, claudin-1, and glucose transporter 1). In 2 patients, multiple normal looking nerve fibers as well as hypertrophied nerves and microscopic tumor nodules showed variable intraneural perineurial cell proliferations that frequently occupied the whole nerve fascicle resulting in multiple microscopic reticular perineurioma-like nodules (microscopic hybrid neurofibromatosis/perineuriomatosis). None of the cases showed the onion skin pattern of intraneural perineurioma. However, other nerve fibers within the same specimens showed normal compact rim of perineurium without any detectable intraneural perineurial cells. Both patients had concurrent multiple larger PNSTs (plexiform neurofibromas, hybrid neurofibroma/perineurioma and lesions with features intermediate between the 2 types). One specimen harboring high-grade malignant PNST and 2 specimens with large solitary neurofibromas displayed no intraneural perineurial cells. These observations suggest that intraneural perineurial proliferations are part of the early lesions in the setting of constitutional NF-1 inactivation and support the concept of pure and hybrid perineuriomatous lesions as novel member of the spectrum of PNSTs in NF-1. [Copyright &y& Elsevier]

Approximately 15% of gastrointestinal stromal tumors (GISTs) harbor mutations in the platelet-derived growth factor receptor a (PDGFRA) gene. Chromosomal aberrations play a crucial role in tumor progression and correlate with clinical behavior. Imbalances, particularly in PDGFRA-mutated GISTs, have not yet been evaluated in larger series. We analyzed 53 PDGFRA-mutated GISTs (including 2 with corresponding metastases) for chromosomal imbalances by conventional comparative genomic hybridization and compared them with a historical collective of 122 KIT-mutated GISTs. PDGFRA exon 18 mutations (91% of cases) and exon 12 mutations (9% of cases) correlated significantly with gastric and intestinal sites, respectively. The most common aberrations were identical to those found in KIT-mutated GISTs, with -14q in 70%, -1p in 28%, and -22q in 17% of cases. Overall, there were significantly fewer chromosomal aberrations compared with KIT-mutated GISTs, with a mean of 2.8 (0.6 gains, 2.1 losses) aberrations per tumor. There was a statistically significant association of more than 5 chromosomal imbalances with intermediate/high-risk categories. Regarding specific chromosomal aberrations, -9p, -13q, and -22q correlated with intermediate/high risk, and -1p and +8q with poorer survival, although progression occurred in only 2 cases. Altogether, PDGFRAmutated GISTs display the same chromosomal aberrations as KIT-mutated GISTs, although they have a lower degree of chromosomal instability in line with their generally favorable outcome. [ABSTRACT FROM AUTHOR]

Prostate cancer is a heterogeneous, frequently multifocal disease with a broad spectrum of clinical, pathologic, and molecular characteristics. The TMPRSS2-ERG gene rearrangement is highly specific for prostate cancer. We used immunohistochemistry as a surrogate marker of the TMPRSS2-ERG fusion to study the heterogeneity of ERG expression in 280 prostate core needle biopsy series from 256 patients with early prostate cancer defined as 3 or less positive cores with no more than 50% of cancer per biopsy and a Gleason score of 7 or lower (3 + 4). Among the 163 patients with 2 or 3 cancer-positive biopsies, we found a subset of 19 patients (11.7%) with heterogeneous ERG expression. Thirteen (68.4%) of these patients showed biopsies with distinct positive and negative ERG staining in separate cores. The remaining 6 patients showed a mixture of both positive and negative staining within 1 biopsy core. This was either caused by different cancer foci (n = 3) or by one single, ERG-heterogeneous cancer focus (n = 3) in 1 core. Furthermore, we observed a heterogeneous ERG staining pattern over time in 6 (2.3%) of the 256 patients, in biopsies taken at various time points. An interobserver study of 21 cases with 2 separate cancer foci revealed that heterogeneity of ERG status in different cancer foci can be suspected based on morphologic differences (k = 0.44). We conclude that heterogeneity of ERG expression is detectable in 10% to 15% of core biopsies of early prostate cancer. Further studies are needed to explore the clinical impact of heterogeneous ERG status in this patient group. [ABSTRACT FROM AUTHOR]

Ameloblastoma is a histologically benign, locally aggressive tumor arising from the odontogenic ectoderm. It accounts for 1% of all oral tumors and for 9% to 11% of all odontogenic tumors. In up to 96.6%, the tumor can be found in the mandible, predominantly in the molar region. High recurrence rates of up to 90% have been described with conservative treatment. Recurrences most often occur after 2 to 5 years. After radical resection, significantly lower recurrence rates have been reported, sometimes as low as 3.6%. As a consequence, when recurrence rate is the main concern, there is a tendency to prefer radical resection of the ameloblastoma. Microvascular segmental reconstruction of the mandible that uses an intraoral anastomosis technique has not been described in the current literature. Therefore, the present study aimed at extending the armamentarium of bony microvascular reconstruction in cases of segmental mandibulectomy by describing an intraoral microvascular anastomosing technique. [Copyright &y& Elsevier]

Abstract: Gastrointestinal stromal tumour (GIST) is the most common mesenchymal neoplasm of the GI tract. GISTs form a biological continuum ranging from benign incidentally detected minute lesions (stromal tumourlets) of no clinical significance to large and highly malignant sarcomatous neoplasms. The disease is characterized by indistinct borders between biologically different subsets within its spectrum leading to unpredictable course of the disease in the majority of cases. Availability of effective tyrosine kinase inhibitors underlined the urgent need for a reliable risk assessment system to reliably identify those patients who are at a significant risk for disease relapse and would thus profit from currently available effective targeted molecular therapy. While several risk systems have been established for GIST over the last decade, evidence is growing that no single system is optimal for all patients. Accordingly, an individualized risk system integrating classical parameters (site, size, mitotic index), status of serosal mechanical barrier covering the tumour (presence of tumour rupture or serosal penetration) as well as several other still debatable histological (coagulative necrosis, venous invasion, mucosal infiltration), biomarkers (proliferative index, p16 expression, etc.), and molecular (specific mutation types, adverse chromosomal aberrations, etc.) prognosticators would be of superb value for selecting the most appropriate patient treatment. [Copyright &y& Elsevier]