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TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remain poorly explored. Here we combined extensive immunolabeling of human tissues with in silico analysis of pan-cancer transcriptomic data sets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (CATIM4+MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (TLSTIM4+MΦ). In silico analysis of a pan-cancer data set revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8+ T cells, and a 12-chemokine signature defining tertiary lymphoid structure. In addition, TLSTIM4+MΦ were enriched in cancers displaying microsatellite instability and high CD8+ T-cell infiltration, confirming their association with immune-reactive tumors. Both CATIM4+MΦ and TLSTIM4+MΦ express FOLR2, a marker of tissue-resident MΦ. However, CATIM4+MΦ had a higher expression of the immunosuppressive molecules TREM2, IL10, and TGFβ as compared with TLSTIM4+MΦ. By analyzing a scRNA sequence data set of tumor-associated myeloid cells, we identified two TIM4+FOLR2+ clusters coherent with CATIM4+MΦ and TLSTIM4+MΦ. We defined specific gene signatures for each subset and found that the CATIM4+ MΦ signature was associated with worse patient survival. In contrast, TLSTIM4+MΦ gene signature positively correlates with a better prognosis. Together, these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotypes and tissue localization and that may have opposing roles in tumor immunity.

Supplementary Table from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Supplementary Figure from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Supplementary Data from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Pleomorphic adenoma (PA) is the most common benign parotid tumor, with a well-known propensity to recur. Many factors have been advocated as prognostic, but there is no consensus on how they affect local control. We studied how PA recurrence-free survival (RFS) may be affected by the most relevant risk factors in a time-to-event analysis, comparing them with those observed in a population of non-PA (NPA). Patients undergoing parotidectomy for benign lesions between 2002 and 2018 in a single academic tertiary referral center were included. A description of patients, tumors, and treatment characteristics was performed, highlighting differences between PA and NPA. Analysis of PA RFS and relative risk factors was also conducted. Eight hundred fifty patients underwent parotidectomy for benign lesions, 455 (53.5%) for PA and 57 (6.7%) for NPA. Significant differences between PA and NPA were age at surgery, surgical procedure, and resection margins. Recurrence occurred in 3.1% of PA, with a median disease-free interval of 54 months. 2-, 5-, and 10-year RFS were 99.2, 98.5, and 93.9%, respectively. Age

AIM: The scar of cesarean section (CS) is the most common site of abdominal wall endometriosis (AWE), whose tumor degeneration has been reported in an increasing number of cases; the most frequent histological type is clear cell carcinoma (CCC). METHODS: We conducted a systematic research of the literature, collecting data regarding the evidence on tumor degeneration from AWE after CS. Moreover, we reported a case of clear cell borderline tumor (CCBT) originating from AWE. RESULTS: We included data of 37 patients with diagnosis of CCC. The average time between the last CS and the diagnosis of CCC was around 15 years. Overall, 26.0% and 73.9% patients received exclusive local abdominal resection of the lesion and additional surgery, respectively. Lymph nodes involvement was detected in 26.0 % patients and adjuvant chemotherapy was administered in 52.0 % cases. During follow-up period, 15.2% patients died of disease, 32.6% had no evidence of disease, and 17.4% recurred. We diagnosed a CCBT arose in a patients with AWE and a personal history of several surgical procedures for endometriosis, a CS and a subsequent transverse laparotomy. We performed an open bilateral ovariectomy and a large excision of the endometriotic abdominal lesion. CONCLUSION: Tumor degeneration from AWE seems to be a real occurrence with an increasing number of events. Considering the lack of risk factors and diagnostic instruments for tumor degeneration, the removal of AWE localization could be advisable, even though there was long average time between the trigger surgery and the tumor finding.

Background Histotype and tumor grading of endometrial cancer are the most important factors that have to be assessed by preoperative endometrial sampling, and their concordance with the final surgical and definitive histological findings is of paramount importance. We aim to compare histotype and tumor grading concordance of various endometrial sampling techniques (ESTs) and to investigate the role of endometrial volume biopsy. Methods We performed a retrospective analysis of patients with apparent early stage endometrial cancer collecting demographic, clinical data, type of EST, pathological characteristics of endometrial biopsies and final specimens. We classified ESTs as dilation and curettage (D&C), diagnostic hysteroscopy with D&C, outpatient hysteroscopy and operative hysteroscopy with or without D&C. Diagnostic and operative hysteroscopy were performed with Bettocchi’s 5 mm hysteroscope. We evaluated concordance for histotype, and tumor grading, and we performed subgroup analysis based on the technique and final tumor grading. Concordance was classified from good, moderate, sufficient, fair, poor and none using Cohen k-statistic. Finally, we investigated the existence of independent risk factors for discordant tumor grading using multivariate binary logistic regression. Results We collected 148 patients and of these 131 (88.5%) were diagnosed with endometrioid histotype and 65 (44%), 46 (31%) and 37 (25%) respectively with well, moderate and poor differentiated tumors. Atypical hyperplasia (AH) was detected preoperatively in 28 patients (19%). Histotype concordance was fair (k=0.35) and tumor grading concordance was moderate (k=0.45); particularly, concordance was fair in well-differentiated cases (k=0.38); concordance was moderate in moderate- and poor-differentiated cases (k=0.52) and good (k=0.71). Operative hysteroscopy showed moderate concordance for histotype (k=0.41), while grading concordance was fair for G1 (k=0.41), moderate for G2 (k=0.58) and good for G3 (k=0.72), regardless the use of D&C. Preoperative volume biopsy did not impact the concordance of tumor grading, while the adoption of operative hysteroscopy (with or without D&C) decreased the risk of grading discordance in G3 tumors (HR 0.17; 95% CI: 0.03–0.94; P=0.04). Conversely, time elapsed from diagnosis to treatment in well-differentiated tumors increased the risk of discordant results (HR 1.06; 95% CI: 1.02–1.52; P=0.04). Conclusions Operative hysteroscopy demonstrated the best tumor grading concordance, especially in poor-differentiated tumors. The volume of biopsy did not affect the tumor grading concordance.

TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remain poorly explored. Here we combined extensive immunolabeling of human tissues with in silico analysis of pan-cancer transcriptomic data sets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (CATIM4+MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (TLSTIM4+MΦ). In silico analysis of a pan-cancer data set revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8+ T cells, and a 12-chemokine signature defining tertiary lymphoid structure. In addition, TLSTIM4+MΦ were enriched in cancers displaying microsatellite instability and high CD8+ T-cell infiltration, confirming their association with immune-reactive tumors. Both CATIM4+MΦ and TLSTIM4+MΦ express FOLR2, a marker of tissue-resident MΦ. However, CATIM4+MΦ had a higher expression of the immunosuppressive molecules TREM2, IL10, and TGFβ as compared with TLSTIM4+MΦ. By analyzing a scRNA sequence data set of tumor-associated myeloid cells, we identified two TIM4+FOLR2+ clusters coherent with CATIM4+MΦ and TLSTIM4+MΦ. We defined specific gene signatures for each subset and found that the CATIM4+ MΦ signature was associated with worse patient survival. In contrast, TLSTIM4+MΦ gene signature positively correlates with a better prognosis. Together, these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotypes and tissue localization and that may have opposing roles in tumor immunity.

Adenoid cystic carcinoma (AdCC) is a rare disease, with indolent behavior and poor long-term survival. Many studies have evaluated the role of clinical and pathological factors at presentation on the risk of recurrence. In this study we investigated whether baseline demographic, clinical, and pathological characteristics at the time of primary curative treatment could influence the prognosis of patients once local and/or distant recurrence occurred.All patients affected by primary salivary gland AdCC and treated with curative surgery from January 1997 to June 2016 were reviewed, evaluating those who later developed loco-regional recurrence and/or distant metastasis. Time from the first relapse to death (recurrent/metastatic overall survival, RMOS) was considered the outcome of interest.Out of 87 surgically treated AdCC patients, 36 relapsing lesions were included. Median ages at first presentation and recurrence were 55 and 60-year-old, respectively; 58% were females. Median disease-free-interval (DFI) was 22.0 months. Five-year RMOS was 47%. At univariate analysis, age ≥ 60-year-old (HR:2.67, p = 0.030), primary tumor lympho-vascular invasion (LVI) (HR:5.38, p = 0.003), adjuvant radiotherapy (RT) in the primary setting (HR:0.37, p = 0.043), and DFI 30 months (HR:3.94, p = 0.008) significantly affected RMOS. Multivariable analysis confirmed the presence of LVI and shorter DFI as independent risk factors.Knowledge of baseline clinicopathological features is helpful in the prognostic stratification of patients with recurrent AdCC, with LVI as the most relevant baseline factor. Adjuvant RT demonstrated its protective role on survival even once recurrence occurred, further supporting its adoption in the primary setting.

Choriocarcinoma is a highly malignant and rare tumor characterized by secretion of the beta-subunit-of-humanchoriogonadotropin (β-HCG). We report a case of primary nasal choriocarcinoma with good response to chemotherapy. A 36-years-old woman gravida 0 and with history of 4 spontaneous abortion, in December 2018 referred to Otorhinolaryngology Department for repeated episodes of epistaxis. Cervical Magnetic Resonance Imaging (MRI) revealed a tumor mass involving right nasal cavity, right ethmoid, sphenoidal and maxillary sinuses. For a differential diagnosis between metastatic gestational choriocarcinoma and primary choriocarcinoma in January 2019 she underwent 18Fluorine-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG-PET/CT) scan that demonstrated intense uptake only in the nasal-ethmoid tumor mass showed by MRI. This was suggestive of primary nasal-ethmoid choriocarcinoma she received 3 courses of BEP - regimen and after β-HCG was reduced to 500 mIU/mL and 18F-FDG-PET/CT scan showed a decreased uptake in tumor mass but the appearance of a new uptake in cervical lymph node which was analysed and reported as metastatic localization of choriocarcinoma. Therefore she was treated with 2 cycles of TIP-regimen. Subsequents 18F-FDG-PET/CT and MRI showed a complete tumor remission. This case proved the fundamental role of PET/CT to make diagnosis of primitive choriocarcinoma and to exclude the hypothesis of distant metastasis.

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

Background High-grade serous ovarian carcinoma (HGSOC) is generally associated with a very dismal prognosis. Nevertheless, patients with similar clinicopathological characteristics can have markedly different clinical outcomes. Our aim was the identification of novel molecular determinants influencing survival. Methods Gene expression profiles of extreme HGSOC survivors (training set) were obtained by microarray. Differentially expressed genes (DEGs) and enriched signalling pathways were determined. A prognostic signature was generated and validated on curatedOvarianData database through a meta-analysis approach. The best prognostic biomarker from the signature was confirmed by RT-qPCR and by immunohistochemistry on an independent validation set. Cox regression model was chosen for survival analysis. Results Eighty DEGs and the extracellular matrix-receptor (ECM-receptor) interaction pathway were associated to extreme survival. A 10-gene prognostic signature able to correctly classify patients with 98% of accuracy was identified. By an ‘in-silico’ meta-analysis, overexpression of FXYD domain-containing ion transport regulator 5 (FXYD5), also known as dysadherin, was confirmed in HGSOC short-term survivors compared to long-term ones. Its prognostic and predictive power was then successfully validated, both at mRNA and protein level, first on training than on validation sample set. Conclusion We demonstrated the possible involvement of FXYD5 and ECM-receptor interaction signal pathway in HCSOC survival and prognosis.

Simple Summary Vulvar squamous cell carcinoma (VSCC) is the most frequent malignant vulvar tumor, with a peak incidence in the 7–8th decades of life. However, VSCCs can also occur in young women. This unfortunate event is even rarer and more worrisome in pregnant women, being hard to manage for gynecologists, oncologists, and radiotherapists. Very few cases have been reported and we felt the need for an updated review on this topic. Thus, we performed a systematic literature review of VSCCs diagnosed during pregnancy, discussing the clinic-pathologic features, the implications in pregnancy outcomes, and the effects of such a diagnosis in the management of mothers and their babies. Abstract According to our systematic literature review (PRISMA guidelines), only 37 vulvar squamous cell carcinomas (VSCCs) were diagnosed during pregnancy (age range: 17–41 years). The tumor size range was 0.3–15 cm. The treatment was performed after (14/37, 38%), before (10/37, 27%), or before-and-after delivery (11/37, 30%). We found that 21/37 (57%) cases were stage I, 2 II (5%), 11 III (30%), and 3 IVB (8%). HPV-related features (condylomas/warts; HPV infection; high-grade squamous intraepithelial lesion) were reported in 11/37 (30%) cases. We also found that 9/37 (24%) patients had inflammatory conditions (lichen sclerosus/planus, psoriasis, chronic dermatitis). The time-to-recurrence/progression (12/37, 32%) ranged from 0 to 36 (mean 9) months. Eight women died of disease (22%) 2.5–48 months after diagnosis, 2 (5%) were alive with disease, and 23 (62%) were disease-free at the end of follow-up. Pregnant patients must be followed-up. Even if they are small, newly arising vulvar lesions should be biopsied, especially in women with risk factors (HPV, dermatosis, etc.). The treatment of VSCCs diagnosed in late third trimester might be delayed until postpartum. Elective cesarean section may prevent vulvar wound dehiscence. In the few reported cases, pregnancy/fetal outcomes seemed to not be affected by invasive treatments during pregnancy. However, clinicians must be careful; larger cohorts should define the best treatment. Definite guidelines are lacking, so a multidisciplinary approach and discussion with patients are mandatory.

Olfactory neuroblastoma (ONB) is a rare sinonasal neoplasm with a peculiar behavior, for which limited prognostic factors are available. Herein, we investigate the transcriptional pathways altered in ONB and correlate them with pathological features and clinical outcomes. We analyze 32 ONB patients treated with curative intent at two independent institutions from 2001 to 2019 for whom there is available pathologic and clinical data. We perform gene expression profiling on primary ONB samples and carry out functional enrichment analysis to investigate the key pathways associated with disease-free survival (DFS). The median age is 53.5 years, all patients undergo surgery and a pure endoscopic approach is adopted in the majority of cases (81.2%). Most patients have advanced disease (stages III–IV, 81.2%) and 84.4% undergo adjuvant (chemo)radiotherapy. The median follow-up is 35 months, 11 (26.8%) patients relapse. Clinical characteristics (gender, stage and Hyams’ grade) are not associated with the outcomes. In contrast, TGF-beta binding, EMT, IFN-alpha response, angiogenesis, IL2-STAT5 and IL6-JAK-STAT3 signaling pathways are enriched in patients experiencing recurrence, and significantly associated with shorter DFS. Clustering of transcriptional profiles according to pathological features indicates two distinct molecular groups, defined by either cytokeratin-positive or -negative immunostaining. Definition of the characterizing ONB transcriptomic pathways may pave the way towards tailored treatment approaches.

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

PURPOSE Under common therapeutic regimens, the prognosis of human papillomavirus (HPV)–positive squamous oropharyngeal carcinomas (OPCs) is more favorable than HPV-negative OPCs. However, the prognosis of some tumors is dismal, and validated prognostic factors are missing in clinical practice. The present work aimed to validate the prognostic significance of our published three-cluster model and to compare its prognostic value with those of the 8th edition of the tumor-node-metastasis staging system (TNM8) and published signatures and clustering models. METHODS Patients with HPV DNA-positive OPCs with locoregionally advanced nonmetastatic disease treated with curative intent (BD2Decide observational study, NCT02832102 ) were considered as validation cohort. Patients were treated in seven European centers, with expertise in the multidisciplinary management of patients with head and neck cancer. The median follow-up was 46.2 months (95% CI, 41.2 to 50), and data collection was concluded in September 2019. The primary end point of this study was overall survival (OS). Three-clustering models and seven prognostic signatures were compared with our three-cluster model. RESULTS The study population consisted of 235 patients. The three-cluster model confirmed its prognostic value. Two-year OS in each cluster was 100% in the low-risk cluster, 96.6% in the intermediate-risk cluster, and 86.3% in the high-risk cluster ( P = .00074). For the high-risk cluster, we observed an area under the curve = 0.832 for 2-year OS, significantly outperforming TNM 8th edition (area under the curve = 0.596), and functional and biological differences were identified for each cluster. CONCLUSION The rigorous clinical selection of the cases included in this study confirmed the robustness of our three-cluster model in HPV-positive OPCs. The prognostic value was found to be independent and superior compared with TNM8. The next step includes the translation of the three-cluster model in clinical practice. This could open the way to future exploration of already available therapies in HPV-positive OPCs tailoring de-escalation or intensification according to the three-cluster model.

Encroachment on the orbital cavity represents a challenge in the management of sinonasal cancer. Criteria guiding orbital preservation lack univocal consensus. Stage of orbital involvement is best assessed through magnetic resonance imaging (MRI).Patients affected by orbit-encroaching sinonasal cancer with available preoperative MRI, receiving surgery-based treatment at the University of Brescia between May 2005 and October 2018 were included. All cases were reviewed by expert radiologists and pathologists. Diagnostic performance of MRI was calculated using pathological information as reference. Survival analysis was performed.The study included 123 patients. The orbit was abutted in 53 (43.1%) patients, whereas orbital invasion reached the periorbit in 18 (14.6%), extraconal fat and/or medial lacrimal sac in 29 (23.6%), extrinsic ocular muscles in 7 (5.7%), intraconal compartment in 4 (3.3%), and orbital apex in 12 (9.8%). Seventy-six (61.8%) patients received orbit-sparing surgery, 47 (38.2%) underwent orbital ablation (OA). Accuracy of MRI in detecting involvement by cancer was ≥80.0% for the orbital wall, extraconal fat, and muscles, and80.0% for the periorbit and intraconal compartment. Previous surgery, neoadjuvant chemotherapy, and perineural invasion decreased MRI accuracy. Age, histology, tumor grade, pT category, N status, perineural invasion, orbital invasion stage, and need for OA were found to affect prognosis. Five-year orbital dysfunction-free survival was 92.8%.Conservative management of sinonasal cancers encroaching the orbit is feasible. MRI is essential to preoperatively stage orbital invasion, yet with some limitation. Given the dismal prognosis despite aggressive surgery, neoadjuvant non-surgical therapies should be considered in patients requiring OA.

Background and objectives: Cervical leiomyomas are a rare benign disease. Although they are mainly treated surgically, currently, there is not a standardized treatment for cervical leiomyomas. This study aims to summarize current literature evidence about treatment options for cervical leiomyomas. Materials and methods: A systematic research of the literature was conducted in Scopus, PubMed/MEDLINE, ScienceDirect, and the Cochrane Library, including observational prospective and retrospective studies, case series and case reports. We collected data regarding studies related to treatment options for cervical leiomyomas, evaluating the following aspects: study design, population, treatment type, rate of surgical complications, and fertility outcome. Results: According to literature research, 38 articles were included. Among 214 patients, the weighted average age was 39.4 years-old; 23 patients were pregnant. Most of the leiomyomas (78%) were extracervical; in 22% of cases (29 patients) were intracervical; 188 patients (88%) received surgical treatment, 6 (3%) received exclusive conservative management and 21 (10%) underwent interventional radiology treatment. One hundred twenty-seven patients (67.5%) underwent myomectomy, while 54 (28.7%) and 7 (3.7%) hysterectomy and trachelectomy, respectively. Cervical myomectomy was performed by open surgery in 21 out of 127 cases (16.5%), while in 92 (72.4%) and 6 (4.7%) patients the surgical approach was performed by traditional and robot-assisted laparoscopy, respectively. The total rate of surgical complications was 5.6%. Conclusion: Surgery is the primary therapeutic option for cervical leiomyomas with a low rate of surgical complications. Interventional radiology techniques have reported promising but still limited results.

Solitary fibrous tumor (SFT) is an uncommon fibroblastic tumor occurring preferentially in the pleura, with a variable clinical course. SFT can arise also in numerous extrathoracic sites and very rarely in the female genital tract, with only scarce reports of uterine SFT. We reported a new uterine SFT arising in a 45-year-old woman, and we performed a systematic review of SFT cases of the uterine corpus interrogating the electronic databases PubMed, Web of Science, and Scopus. We identified only 13 patients diagnosed with SFT of the uterine corpus, including our one. Complete clinical workout at disease presentation showed no evidence of extrauterine spread in all cases, except for 1 patient who presented with metastatic disease. Tumor recurrences/metastases occurred in a minority of the patients and were poorly related to clinicopathological risk factors and patients stratification based on different scoring systems. Since the long-term clinical behavior of uterine SFT is limited and poorly predictable, extended follow-up is recommended also for all cases arising in the uterine corpus.

Oncocytic mucoepidermoid carcinoma (OMEC) is a rare but diagnostically challenging variant of mucoepidermoid carcinoma (MEC). OMEC is notable for differential diagnostic considerations that are raised as a result of overlap with other benign and low-grade oncocytic salivary gland tumors. Diffuse and strong immunoreactivity of p63 protein may be useful in distinguishing OMEC from its mimics. However, focal p63 staining can be present in benign oncytomas. Presence of mucin-containing cells, mucinous cystic formation, and foci of extravasated mucin are considered a hallmark of MEC. True mucocytes may be, however, very few and hardly discernable in OMECs. Recent evidence has shown that most MECs harbor gene fusions involving MAML2. A retrospective review of archived pathology files and the authors' own files was conducted to search for "low-grade/uncertain oncocytic tumor," "oncocytoma," and "oncocytic carcinoma" in the period from 1996 to 2019. The tumors with IHC positivity for p63 and/or p40, and S100 negativity, irrespective of mucicarmine staining, were tested by next-generation sequencing using fusion-detecting panels to detect MAML2 gene rearrangements. Two index cases from consultation practice (A.S. and A.A.) of purely oncocytic low-grade neoplasms without discernible mucinous cells showed a CRTC1-MAML2 fusion using next-generation sequencing, and were reclassified as OMEC. In total, 22 cases of oncocytic tumors, retrieved from the authors' files, and from the Salivary Gland Tumor Registry, harbored the MAML2 gene rearrangements. Presence of mucocytes, the patterns of p63 and SOX10 immunopositivity, and mucicarmine staining were inconsistent findings. Distinguishing OMEC devoid of true mucinous cells from oncocytoma can be very challenging, but it is critical for proper clinical management. Diffuse and strong positivity for p63 and visualization of hidden mucocytes by mucicarmine staining may be misleading and does not always suffice for correct diagnosis. Our experience suggests that ancillary studies for the detection of MAML2 rearrangement may provide useful evidence in difficult cases.

Adenoid cystic carcinoma (ACC) is a rare tumor, usually arising in the salivary gland, accounting for 1% of all head and neck cancers. ACC may have a long-term poor prognosis, as about 40% of radically treated patients will recur locoregionally and up to 60% will develop distant metastasis. Factors influencing risk of recurrence have been well studied, but few data exist about prognostic factors in Recurrent/Metastatic (RM) setting. Moreover, treatment of RM ACC is often a challenge for clinicians, in the context of a rare disease, which may have an indolent clinical behavior or less frequently a quicker growth and with a paucity of available clinical trials. This review critically analyzes pathological and molecular prognostic factors in RM ACC and make an overview on actual therapeutic choices and future direction of therapy. Recognized prognostic factors in RM ACC are the presence and site of distant metastasis (lung vs other), the presence of nodal metastasis and of extranodal extension, skull base recurrence, disease free interval, lymphovascular invasion, solid histotypes and grading of disease, and the presence of mutation of NOTCH1 family, PI3K, and TP53. Due to disappointing results with chemotherapy, new approaches are under study, also on the basis of biomolecular research. Ongoing clinical trials are evaluating treatment targeting MYB and NOTCH1 alterations, immunotherapy or combination of targeted treatments and immune checkpoint inhibitors.

Objective Malignant ovarian tumours are diagnosed at an advanced stage in the majority of cases. However, only a small percentage present as extra-abdominal, non-lymph-node solid metastases, as in the breast, and they are usually cases of relapse. The discovery of mono- or bilateral breast lesions with peritoneal carcinosis and/or abdomino-pelvic lesions can be cumbersome in the differential diagnosis of primary tumours. This article aims to summarize current evidence on the detection of breast metastases at diagnosis of ovarian cancer. Study design A systematic review of the literature in Scopus, PubMed/MEDLINE, ScienceDirect and the Cochrane Library, including case reports and case series, was undertaken. Data regarding study features; population characteristics; clinical, radiological and histological assessment of the disease; treatment and follow-up were collected. In addition, a case report of a patient managed at the authors’ centre is provided. Results According to the search strategy, 16 articles (18 patients) were included in this review. Serous ovarian, fallopian tube or primary peritoneal cancer was detected in 61% of cases, while another type or a non-specified type of epithelial ovarian cancer was detected in 27.7% of cases; there was one case with granulosa cell tumour of the ovary and one case with mucinous ovarian tumour of low malignant potential. Breast metastases were mainly monolateral (66.6%), with other extra-abdominal sites of disease in the majority of the cases. A minority of patients (16.6%) received treatment for primary breast cancer with a subsequent diagnosis of ovarian cancer. Concomitant breast and abdominal surgery can be an option. PAX8, WT1 and CA125 immunohistochemical staining can aid in differential diagnosis. Conclusion Breast metastases of malignant ovarian tumours must be promptly recognized to ensure proper treatment. Specific immunohistochemical analysis can be a decisive assessment in uncertain cases.

Sinonasal adenocarcinomas (SNAC) are rare and heterogeneous. Management of SNAC follows a rather standardized and internationally accepted paradigm. Several refinements have been introduced during the last decade. A narrative review of most updated literature on SNACs has been conducted. SNACs are classified as intestinal-type and non-intestinal-type, which are further categorized according to grade. Preoperative work-up should include magnetic resonance imaging (or contrast-enhanced computed tomography as a secondary or complementary choice) and biopsy under general anesthesia, or under local anesthesia in case of a history of exposure to wood and/or leather dust. Positron emission tomography, neck ultrasound, and fine-needle aspiration cytology are indicated in selected cases. Surgery represents the most common upfront modality of treatment and is usually accomplished via a transnasal endoscopic approach. Adjuvant radiation therapy is indicated for high-grade, locally advanced tumors and/or in case of margins involvement. Neoadjuvant chemotherapy with cisplatin, 5-fluorouracil and leucovorin may offer high response rates and long-term control in a subgroup of patients affected by intestinal-type adenocarcinoma, and in particular in those whose tumors harbor a functional p53 protein. Most of the bio- and immune-therapeutic potentials on SNACs still remain theoretical, and no clinical data are currently available. Management of SNAC consists of histological diagnosis, radiological staging, radical surgery, and adjuvant radiation therapy. Neoadjuvant chemotherapy can be indicated in selected cases. The role of biotherapy and immune therapy still needs to be elucidated.

Carcinoma showing thymic-like differentiation (CASTLE) is a rare tumor most commonly occurring in the thyroid and soft tissues of the neck. We report the first case of CASTLE occurring in the sublingual gland. The patient, a 35-year-old healthy man, presented with a submucosal lesion located in the anterior right floor of the oral cavity and an ipsilateral neck mass. The lesion had been previously investigated by neck computed tomography and ultrasound-guided fine needle aspiration cytology and diagnosed as metastatic squamous cell carcinoma. After oral cavity magnetic resonance imaging, positron emission tomography, and a non-diriment, fine needle aspiration cytology of the sublingual mass, the patient was treated as affected by a sublingual gland malignancy with removal of primary tumor and neck dissection. Morphological and immunohistochemical findings were diagnostic for primary sublingual gland CASTLE. The patient received adjuvant radiotherapy and is free of disease 2 years after treatment. We describe the pathological features of the lesion and discuss the possible differential diagnoses.

Background The existence of cancer stem cells (CSCs) within a tumor bulk has been demonstrated for many solid tumors including epithelial ovarian carcinoma (EOC). CSCs have been associated to tumor invasion, metastasis and development of chemoresistant recurrences. In this context, we aim to characterize EOC CSCs from the molecular point of view in order to identify potential biomarkers associated with chemoresistance. Methods We isolated a population of cells with stem-like characteristics (OVA-BS4 spheroids) from a primary human EOC cell line under selective conditions. OVA-BS4 spheroids were characterized for drug response by cytotoxicity assays and their molecular profile was investigated by microarray and RT-qPCR. Finally, we performed a gene expression study in a cohort of 74 high-grade serous EOC (HGSOC) patients by RT-qPCR. Results Spheroids exhibited properties of self-renewal and a pronounced expression of well-known stem cell genes. Moreover, they demonstrated greater resistance towards several anticancer drugs compared to parent cell line, consistent with their higher ABCG2 gene expression. From microarray studies MAL (T-cell differentiation protein) emerged as the most up-regulated gene in spheroids, compared to parent cell line. In HGSOC patients, MAL was significantly overexpressed in platinum-resistant compared to platinum-sensitive patients and resulted as an independent prognostic marker of survival. Conclusions This investigation provides an important contribution to the identification of molecular markers of ovarian CSCs and chemoresistance. Successful translation of molecular findings would lead to a better comprehension of the mechanisms triggering chemoresistant recurrences, to the individuation of novel therapeutic targets and to the personalization of treatment regimens. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3334-1) contains supplementary material, which is available to authorized users.

Background Spleen tyrosine kinase (SYK) is frequently upregulated in recurrent ovarian carcinomas, for which effective therapy is urgently needed. SYK phosphorylates several substrates, but their translational implications remain unclear. Here, we show that SYK interacts with EGFR and ERBB2, and directly enhances their phosphorylation. Methods We used immunohistochemistry and immunoblotting to assess SYK and EGFR phosphorylation in ovarian serous carcinomas. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. To study its role in EGFR signaling, SYK activity was modulated using a small molecule inhibitor, a syngeneic knockout, and an active kinase inducible system. We applied RNA-seq and phosphoproteomic mass spectrometry to investigate the SYK-regulated EGF-induced transcriptome and downstream substrates. Findings Induced expression of constitutively active SYK130E reduced cellular response to EGFR/ERBB2 inhibitor, lapatinib. Expression of EGFRWT, but not SYK non-phosphorylatable EGFR3F mutant, resulted in paclitaxel resistance, a phenotype characteristic to SYK active ovarian cancers. In tumor xenografts, SYK inhibitor reduces phosphorylation of EGFR substrates. Compared to SYKWT cells, SYKKO cells have an attenuated EGFR/ERBB2-transcriptional activity and responsiveness to EGF-induced transcription. In ovarian cancer tissues, pSYK (Y525/526) levels showed a positive correlation with pEGFR (Y1187). Intense immunoreactivity of pSYK (Y525/526) correlated with poor overall survival in ovarian cancer patients. Interpretation These findings indicate that SYK activity positively modulates the EGFR pathway, providing a biological foundation for co-targeting SYK and EGFR. Fund Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, NIH/NCI, Ovarian Cancer Research Foundation Alliance, HERA Women's Cancer Foundation and Roseman Foundation. Funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript and eventually in the decision to submit the manuscript.

to assess the prognostic role in recurrence and survival of perineural invasion (PNI) in vulvar squamous cell cancer (VSCC).Patients underwent primary surgery for VSCC from January 2009 to December 2016 served as the study cohort. We collected demographic, clinical, pathological characteristics and follow-up data, and we compared them among PNI-negative versus -positivepatients. We calculated disease-free survival (DFS) and overall survival (OS) using Kaplan-Meier and univariate log-rank test. We conducted a multivariate analysis with cox-proportional hazard models for DFS and OS, including age, tumor size, depth of invasion, free tumor margin8 mm, high-grade histology, lymph vascular space invasion, PNI, extracapsular lymph nodal disease, lymph nodal ratio0.2 and FIGO Stage 2009 (Early I-II versus Advanced III-IV).We found 74 patients with a PNI prevalence of 31.1%. The 5-year DFS was favourable for PNI-negative patients (72% versus 18%; p = 0.00). The 5-year OS was 75% versus 35% in favor of PNI-negative patients (p = 0.00). The subgroup analysis conducted among stage confirmed a decreased DFS and OS in PNI-positive patients. Multivariate analysis showed that PNI (HR 2.74; CI95% 1.10-7.13; p = 0.03) and extracapsular lymph nodal disease (HR 13.54; CI95% 2.87-64.07; p = 0.01) are independent prognostic factors for earlier recurrence. OS was significantly reduced in case of PNI (HR 4.93; CI95% 1.33-18.35; p = 0.01) and extracapsular lymph nodal disease (HR 10.63; CI95% 1.65-68.57; p = 0.01).PNI is an independent prognostic factor for aggressive behavior and unfavorable course in VSCC and should be considered in adjuvant treatment planning.