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In the current study, we introduced a unique method for identifying and segmenting oral squamous cell carcinoma (OSCC) nuclei, concentrating on those predicted to have significant CAF-1/p60 protein expression. Our suggested model uses the StarDist architecture, a deep-learning framework designed for biomedical image segmentation tasks. The training dataset comprises painstakingly annotated masks created from tissue sections previously stained with hematoxylin and eosin (H&E) and then restained with immunohistochemistry (IHC) for p60 protein. Our algorithm uses subtle morphological and colorimetric H&E cellular characteristics to predict CAF-1/p60 IHC expression in OSCC nuclei. The StarDist-based architecture performs exceptionally well in localizing and segmenting H&E nuclei, previously identified by IHC-based ground truth. In summary, our innovative approach harnesses deep learning and multimodal information to advance the automated analysis of OSCC nuclei exhibiting specific protein expression patterns. This methodology holds promise for expediting accurate pathological assessment and gaining deeper insights into the role of CAF-1/p60 protein within the context of oral cancer progression., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (© 2024 The Authors.)

In humans and mice, Nkx2-1 and Pax8 are crucial morphogenic transcription factors defining the early development of the thyroid and specific extrathyroidal tissues. By using 3-month-old single or double heterozygotes for Nkx2-1- and Pax8-null mutations (DHTP) mice, we studied brain abnormalities under different human-like dysthyroidisms, focusing on putative alterations of specific neurotransmitter systems, expression of markers of pre- and post-synaptic function and, given the physio-pathological role mitochondria have in controlling the bioenergetic status of neurons, of mitochondrial dynamics and oxidative balance. Compared to Wt controls, DHTP mice, bearing both systemic and brain hypothyroidism, showed altered expression of synaptic markers, generic and cholinergic (corroborated by immunohistochemistry in caudate, putamen, hippocampus, and basal forebrain) and glutamatergic ones, and reduced expression of key proteins of synaptic plasticity potency and several isoforms of glutamate receptors. The brain of DHTP mice was characterized by lower levels of H 2 O 2 and imbalanced mitochondrial dynamics. Nkx2-1 + / - mice showed dopaminergic neuron-specific alterations, morphologically, more evident in the substantia nigra of DHTP mice. Nkx2-1 + / - mice also showed enhanced mitochondrial biogenesis and oxidative capacity likely as a global response of the brain to Nkx2-1 haploinsufficiency and/or to their elevated T3 circulating levels. Reduced transcription of both tyrosine hydroxylase and dopamine transporter was observed in Pax8 + / - euthyroid mice, suggesting a dopaminergic dysfunction, albeit likely at an early stage, but consistent with the deregulated glucose homeostasis observed in such animals. Overall, new information was obtained on the impact of haploinsufficiency of Pax8 and NKx2-1 on several brain neuroanatomical, molecular, and neurochemical aspects, thus opening the way for future targeting brain dysfunctions in the management of both overt and subclinical thyroid dysfunctions., (© 2024. The Author(s).)

Background: Biphenotypic sinonasal sarcoma is a rare low-grade tumor arising from the sinonasal tract, featuring locally aggressive biological behavior, with a tendency to invade the orbit and skull base. There are no defined guidelines of treatment; thus, the management varies among different institutions. The aim of the present study is to provide a modular system of surgical approaches according to the lesion pattern of growth from a literature review. Materials and Methods: A comprehensive and detailed literature review on the PubMed and Embase online electronic databases on biphenotypic sinonasal sarcoma with orbital invasion was conducted. A personal case exhibiting peculiar features was also added. Demographic (patient's sex and age), clinical (presenting symptoms and time to treatment), neuroradiological (anatomical origin and pattern of growth), and treatment (type of treatment, surgical approach, extent of resection, peri- and postoperative complications, and adjuvant therapies) data, as well as clinical outcome, recurrence rates, and overall survival, were analyzed. Results: Thirty-one patients harboring biphenotypic sinonasal sarcoma with orbital invasion were identified. Tumors mainly affected female patients (66.7%) and a middle-aged population (median 55.2 years old). Simultaneous skull base involvement occurred in most cases (80.6%). Surgery was performed in all but one case (97%), as unique treatment (59%) or in association with radio-(23.5%) and/or chemotherapy (5.9%/2.9%), allowing for gross total tumor resection in most cases (66.7%). The endoscopic endonasal approach was the most adopted surgical corridor (51.7%). The local recurrence rate was 19.3%, and only two cases of tumor-related mortality occurred. Conclusions: Surgery is the only curative treatment, with the main goal to restore/improve/arrest progression of clinical manifestations. The endoscopic endonasal route represents the master approach for lesions confined to the midline. Microsurgical transcranial and endoscopic transorbital approaches have a complementary role for addressing the lesion's component with large intracranial extension or affecting the paramedian aspect of the anterior cranial fossa and superior-lateral orbital compartment, respectively. The approach selection should be made case by case according to the tumor pattern of growth.

Anatomical pathology is undergoing its third revolution, transitioning from analogical to digital pathology and incorporating new artificial intelligence technologies into clinical practice. Aside from classification, detection, and segmentation models, predictive models are gaining traction since they can impact diagnostic processes and laboratory activity, lowering consumable usage and turnaround time. Our research aimed to create a deep-learning model to generate synthetic Ki-67 immunohistochemistry from Haematoxylin and Eosin (H&E) stained images. We used 175 oral squamous cell carcinoma (OSCC) from the University Federico II's Pathology Unit's archives to train our model to generate 4 Tissue Micro Arrays (TMAs). We sectioned one slide from each TMA, first stained with H&E and then re-stained with anti-Ki-67 immunohistochemistry (IHC). In digitised slides, cores were disarrayed, and the matching cores of the 2 stained were aligned to construct a dataset to train a Pix2Pix algorithm to convert H&E images to IHC. Pathologists could recognise the synthetic images in only half of the cases in a specially designed likelihood test. Hence, our model produced realistic synthetic images. We next used QuPath to quantify IHC positivity, achieving remarkable levels of agreement between genuine and synthetic IHC. Furthermore, a categorical analysis employing 3 Ki-67 positivity cut-offs (5%, 10%, and 15%) revealed high positive-predictive values. Our model is a promising tool for collecting Ki-67 positivity information directly on H&E slides, reducing laboratory demand and improving patient management. It is also a valuable option for smaller laboratories to easily and quickly screen bioptic samples and prioritise them in a digital pathology workflow., Competing Interests: The author(s) declare no competing interests., (© 2023 The Authors.)

Pathological Anatomy is moving toward computerizing processes mainly due to the extensive digitization of histology slides that resulted in the availability of many Whole Slide Images (WSIs). Their use is essential, especially in cancer diagnosis and research, and raises the pressing need for increasingly influential information archiving and retrieval systems. Picture Archiving and Communication Systems (PACSs) represent an actual possibility to archive and organize this growing amount of data. The design and implementation of a robust and accurate methodology for querying them in the pathology domain using a novel approach are mandatory. In particular, the Content-Based Image Retrieval (CBIR) methodology can be involved in the PACSs using a query-by-example task. In this context, one of many crucial points of CBIR concerns the representation of images as feature vectors, and the accuracy of retrieval mainly depends on feature extraction. Thus, our study explored different representations of WSI patches by features extracted from pre-trained Convolution Neural Networks (CNNs). In order to perform a helpful comparison, we evaluated features extracted from different layers of state-of-the-art CNNs using different dimensionality reduction techniques. Furthermore, we provided a qualitative analysis of obtained results. The evaluation showed encouraging results for our proposed framework., (© 2023. The Author(s).)

PReferentially expressed Antigen in Melanoma (PRAME) is a cancer testis antigen, first isolated in tumor-reactive T-cell clones from a metastatic melanoma patient. It has been widely studied in skin pathology as an immunohistochemical marker capable of distinguishing between benign nevi and malignant melanomas. PRAME has been found to be also expressed in non-melanocytic tumors, including lung, breast, kidney and ovarian cancer. However, less is known about the diagnostic and/or prognostic role of this protein in uveal melanoma (UM); few studies have reported that PRAME expression seems to give to UM patients an additional metastatic risk beyond the other already-known prognostic parameters. In the present retrospective study, we aimed to correlate PRAME immunoreactivity to other clinico-pathologic features and follow-up data on a large series of 85 cases (45 non-metastasizing and 40 metastasizing tumors) of primary UM. A statistically significant correlation was found between PRAME expression and higher metastatic risk and lower metastasis-free survival. We propose to include PRAME in the immunohistochemical panel of UM as an easily usable marker capable of predicting higher metastatic risk and stratifying patients' outcome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Sebaceous carcinoma is a very rare, aggressive, malignant tumor arising in the adnexal epithelium of the sebaceous gland. Sebaceous carcinoma in the oral cavity is extremely rare, with only 14 cases reported in literature. We reported the fourth case of sebaceous carcinoma involving the lip CASE PRESENTATION: A 71-year-old Caucasian male smoker presented an ulcerated lesion in the lateral region of the lower lip. The patient stated that the lesion had been present for 1 year. The past medical history was unremarkable. Extraoral examination revealed a markedly ulcerated, exophytic, irregularly shaped, indurated mass of the lower right labial region, measuring 1.8 cm in size. The nodular lesion, located at the point of transition between mucosa and skin, showed a central ulceration. No other intraoral lesions were identified. The clinical differential diagnosis included squamous cell carcinoma, basal cell carcinoma with sebaceous differentiation, and salivary gland neoplasms. Operation was performed under local anesthesia. On histopathological examination, the tumor was composed by nodules or sheet of cells separated by a fibrovascular stroma. The neoplastic tissue was deeply infiltrating, involving the submucosa and even the underlying muscle. Neoplastic cells showed a range of sebaceous differentiation with finely vacuolated rather than clear cytoplasm. Neoplastic cells were positive for S-100 protein and epithelial membrane antigen, but negative for carcinoembryonic antigen. Based on these findings, a diagnosis of sebaceous carcinoma of the lower lip was rendered., Conclusion: The histogenesis, differential diagnosis, and clinicopathological conditions of this disease according to literature are reviewed. Sebaceous carcinoma should be distinguished from other tumors full of vacuolated clear cells. A periodic acid-Schiff stain and immunohistochemical stain for Ki-67, P53, cytokeratin, S-100, epithelial membrane antigen, and androgen receptor can be useful for the diagnosis., (© 2022. The Author(s).)

To date, a very small number of serum biomarkers have been identified for clinical use in squamous carcinomas of the head and neck region. Chromatin Assembly Factor-1 (CAF-1) heterotrimeric complex subunit CAF1/p60 expression levels have been reported to be of prognostic value in Oral Squamous Cell Carcinoma (OSCC), as well as in other human solid tumors. Here our aim was to detect and quantify CAF1/p60 in the peripheral blood of Head and Neck Squamous Cell Carcinoma (HNSCC) patients, and to investigate the possible associations between serum concentration of CAF-1/p60 and HNSCC tumors. A total of 63 HNSCC patients (51 OSCC, 8 OPSCC, 3 laryngeal SCC, and 1 rhinopharynx SCC) and 30 healthy controls were enrolled. The serum levels of CAF-1/p60 were measured by ELISA assay before and after surgery. Serum CAF-1/p60 concentration resulted significantly higher in cancer patients, compared with healthy controls, in pre-surgery samples (P < 0.05). Serum levels of CAF-1/p60 significantly decreased in serum samples taken after surgery (P < 0.05). Our results demonstrated that CAF-1/p60 may be detected in serum, suggesting a role for CAF-1/p60 as potential soluble biomarkers in HNSCC tumors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) includes a group of aggressive malignancies characterized by the overexpression of the epidermal growth factor receptor (EGFR) in 90% of cases. Neuropilin-1 (NRP-1) acts as an EGFR co-receptor, enhancing, upon ligand stimulation, EGFR signaling in several cellular models. However, NRP-1 remains poorly characterized in HNSCC. By utilizing in vitro cellular models of HNSCC, we report that NRP-1 is involved in the regulation of EGFR signaling. In fact, NRP-1 can lead to cisplatin-induced EGFR phosphorylation, an escape mechanism activated by cancer cells upon cytotoxic stress. Furthermore, we evaluated Neuropilin-1 staining in tissue samples of an HNSCC case series ( n = 218), unraveling a prognostic value for the Neuropilin-1 tissue expression. These data suggest a potential role for NRP-1 in HNSCC cancer progression, expanding the repertoire of signaling in which NRP-1 is involved and eliciting the need for further investigations on NRP-1 as a suitable target for HNSCC novel therapeutic approaches.

Importance: Chilblain-like lesions have been one of the most frequently described cutaneous manifestations during the COVID-19 pandemic. Their etiopathogenesis, including the role of SARS-CoV-2, remains elusive., Objective: To examine the association of chilblain-like lesions with SARS-CoV-2 infection., Design, Setting, and Participants: This prospective case series enrolled 17 adolescents who presented with chilblain-like lesions from April 1 to June 30, 2020, at a tertiary referral academic hospital in Italy., Main Outcomes and Measures: Macroscopic (clinical and dermoscopic) and microscopic (histopathologic) analysis contributed to a thorough understanding of the lesions. Nasopharyngeal swab, serologic testing, and in situ hybridization of the skin biopsy specimens were performed to test for SARS-CoV-2 infection. Laboratory tests explored signs of systemic inflammation or thrombophilia. Structural changes in peripheral microcirculation were investigated by capillaroscopy., Results: Of the 17 adolescents (9 [52.9%] male; median [interquartile range] age, 13.2 [12.5-14.3] years) enrolled during the first wave of the COVID-19 pandemic, 16 (94.1%) had bilaterally localized distal erythematous or cyanotic lesions. A triad of red dots (16 [100%]), white rosettes (11 [68.8%]), and white streaks (10 [62.5%]) characterized the dermoscopic picture. Histologic analysis revealed a remodeling of the dermal blood vessels with a lobular arrangement, wall thickening, and a mild perivascular lymphocytic infiltrate. SARS-CoV-2 infection was excluded by molecular and serologic testing. In situ hybridization did not highlight the viral genome in the lesions., Conclusions and Relevance: This study delineated the clinical, histologic, and laboratory features of chilblain-like lesions that emerged during the COVID-19 pandemic, and its findings do not support their association with SARS-CoV-2 infection. The lesions occurred in otherwise healthy adolescents, had a long but benign course to self-resolution, and were characterized by a microvascular remodeling with perivascular lymphocytic infiltrate but no other signs of vasculitis. These results suggest that chilblain-like lesions do not imply a concomitant SARS-CoV-2 infection. Ongoing studies will help clarify the etiopathogenic mechanisms.

Mycosis fungoides (MF) represents the most common type of cutaneous lymphoma. In the majority of patients, the disease has a slow evolution and a protracted course; however, a subset of patients shows poor oncologic outcomes. Unfortunately, there are no reliable prognostic markers for MF, and the currently available treatments are only effective in a minority of patients. This study aimed to evaluate the expression and clinical significance of PARP-1 and CAF-1/p60 in MF. Sixty-four MF representatives of the different stages of disease were assessed by immunohistochemistry for PARP-1 and CAF-1/p60. The association of PARP-1 and CAF-1/p60 with the MF stage and outcome was assessed by using Fisher's exact test and Kaplan-Meier survival analysis with the Log-rank test; a p value < 0.05 was considered significant. PARP-1 was overexpressed in 57.9% of MF and was significantly associated with a MF stage > II (p = 0.034) but not with the risk of death (p = 0.237). CAF-1/p60 was overexpressed in 26.8% of MF and was significantly associated with decreased overall survival (p < 0.001) but not with the MF stage (p = 1). A significant association was found between PARP-1 overexpression and CAF-1/p60 overexpression (p = 0.0025). Simultaneous overexpression of PARP-1 and CAF-1/p60 was significantly associated with decreased overall survival (p < 0.001), although less strongly than CAF-1/p60 alone (χ 2  = 14.916 vs 21.729, respectively). In MF, PARP-1 is overexpressed in advanced stages, while CAF-1/p60 is overexpressed in the cases with shorter overall survival, appearing as a significant prognostic marker. A role for PARP-1 inhibitors and anti-CAF-1/p60 targeted therapy may be reasonably hypothesized in MF.

Basal cell carcinoma (BCC) is the most common cancer in the white-skinned population accounting for about 15% of all neoplasms. Its incidence is increasing worldwide, at a rate of about 10% per year. BCC, although infrequently metastasizing, very often causes extensive tissue losses, due to the high propensity toward stromal infiltration, particularly in its dedifferentiated forms, with disfiguring and debilitating results. To date, there still is limited availability of therapeutic treatments alternative to surgery. We evaluated the immunohistochemical expression of the carbonic anhydrase IX (CAIX), one of the main markers of tissue hypoxia, in a set of 85 archived FFPE BCC tissues, including the main subtypes, with different clinical outcomes, to demonstrate a possible relationship between hypoxic phenotype and biological aggressiveness of these neoplasms. Our results showed that the expression level of the CAIX protein contributes to the stratification of BCC in the different risk classes for recurrence. We hypothesize for CAIX a potential therapeutic role as a target therapy in the treatment of more aggressive BCCs, thus providing an alternative to surgical and pharmacological therapy with Hedgehog inhibitors, a promising example of target therapy in BCCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Russo, Varricchio, Ilardi, Martino, Di Crescenzo, Pignatiello, Scalvenzi, Costa, Mascolo, Merolla and Staibano.)

Background: The association between Borrelia burgdorferi and primary cutaneous lymphoma is still unclear. This systematic review and meta-analysis aims to define the association of Borrelia burgdorferi with primary cutaneous lymphoma and its different entities., Methods: Electronic databases were searched for all studies that assessed the presence of Borrelia burgdorferi DNA in specimens of primary cutaneous lymphoma. The association between Borrelia and primary cutaneous lymphomas was assessed with an odds ratio (significant p < 0.05); cutaneous specimens with no lymphoproliferative disorders were used as controls. A secondary analysis was performed to assess the prevalence of Borrelia infection in different lymphoma entities., Results: Ten studies with 506 primary cutaneous lymphomas and 201 controls were included. The prevalence of Borrelia DNA positivity was highly heterogeneous among studies from different regions. Borrelia DNA positivity was significantly associated with primary cutaneous lymphomas (odds ratio = 10.88; p < 0.00001). The prevalence of Borrelia DNA positivity was similar among different entities (marginal zone: 7.3 %; follicular: 8.1 %; diffuse large B-cell: 7.5 %; mycosis fungoides: 8 %)., Conclusions: Borrelia burgdorferi is significantly associated with primary cutaneous lymphomas, with no differences among the several lymphoma entities (both B-cell and T-cell), but with strong geographical differences. Molecular testing for Borrelia would be justified in patients with primary cutaneous lymphoma from endemic areas., (© 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10-15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected., (Copyright © 2020 Broggi, Ieni, Russo, Varricchio, Puzzo, Russo, Reibaldi, Longo, Tuccari, Staibano and Caltabiano.)

Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite sharing the name and similar morphological features with cutaneous melanoma (CM), it is an entirely different neoplasia with a particular genetic background and clinical behavior. CDKN2A is a gene located at chromosome 9p21, encoding for P16INK4a and P14(ARF) proteins, whose role as a tumor suppressor has been clearly defined in many malignant tumors. CDKN2A frequently presents germline mutations in familial CM and epigenetic downregulation in a considerable percentage of sporadic CM. It has been hypothesized that CDKN2A alterations are early events in CM development, playing a central role in the malignant transformation of melanocytes. Alterations of the CDKN2A gene reduce the expression of P16INK4a in most CM subtypes. Immunohistochemical evaluation of P16INK4a is currently used, in association with Ki67 and HMB45, in pathology practice to discriminate between dysplastic nevi and melanoma. On the other hand, CKDN2A is rarely mutated in UM, and the immunohistochemical expression of P16INK4a has only been reported in small case series. We tested P16INK4a expression on paraffin-embedded tissue sections from 9 tissue microarrays (TMAs), built with 2 mm cores derived from 133 uveal melanoma FFPE blocks, collected from 1990 to 2018, and from selected paraffin-blocks of 3 UM liver metastases. The immunohistochemical expression of P16INK4a was assessed with a visual evaluation by light microscopy and then with a digital approach. Both approaches, with an acceptable concordance rate, revealed P16INK4a expression in a large proportion of UM cases and all liver metastases, opening new possibilities of using it in the differential diagnosis between cutaneous and uveal melanoma metastases in cases of unknown primary tumor or patients with two different primary melanomas., (Copyright © 2020 Russo, Di Crescenzo, Broggi, Merolla, Martino, Varricchio, Ilardi, Borzillo, Carandente, Pignatiello, Mascolo, Caltabiano and Staibano.)

Helicobacter pylori has been proposed as a possible etiologic factor of ocular adnexa lymphoma (OAL), although with conflicting results. To assess the involvement of H. pylori in OAL, as (1) H. pylori DNA positivity on OAL specimens, and (2) prevalence of H. pylori gastric infection in patients with OAL. A systematic review of studies assessing H. pylori in patients with OAL was conducted by searching electronic databases from their inception to May 2019. Pooled positivity for H. pylori in OAL specimens detected by polymerase chain reaction, and pooled prevalence of H. pylori gastric infection, were calculated with 95% confidence interval (CI). Eleven studies with 308 patients were included. Pooled positivity for H. pylori was 16.8% in all OALs and 22.7% in MALT OAL, with high heterogeneity among studies. Pooled prevalence of H. pylori gastric infection in patients with OAL was 34.7%, with low statistical heterogeneity. In conclusion, H. pylori seems to be involved in a subset of OAL, but the heterogeneity found needs to be investigated in further studies. The prevalence of H. pylori gastric infection in patients with OAL does not seem to differ from that of the general population.

We introduce a machine learning-based analysis to predict the immunohistochemical (IHC) labeling index for the cell proliferation marker Ki67/MIB1 on cancer tissues based on morphometrical features extracted from hematoxylin and eosin (H&E)-stained formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples. We provided a proof-of-concept prediction of the Ki67/MIB1 IHC positivity of cancer cells through the definition and quantitation of single nuclear features. In the first instance, we set our digital framework on Ki67/MIB1-stained OSCC (oral squamous cell carcinoma) tissue sample whole slide images, using QuPath as a working platform and its integrated algorithms, and we built a classifier in order to distinguish tumor and stroma classes and, within them, Ki67-positive and Ki67-negative cells; then, we sorted the morphometric features of tumor cells related to their Ki67 IHC status. Among the evaluated features, nuclear hematoxylin mean optical density (NHMOD) presented as the best one to distinguish Ki67/MIB1 positive from negative cells. We confirmed our findings in a single-cell level analysis of H&E staining on Ki67-immunostained/H&E-decolored tissue samples. Finally, we tested our digital framework on a case series of oral squamous cell carcinomas (OSCC), arranged in tissue microarrays; we selected two consecutive sections of each OSCC FFPE TMA (tissue microarray) block, respectively stained with H&E and immuno-stained for Ki67/MIB1. We automatically detected tumor cells in H&E slides and generated a "false color map" (FCM) based on NHMOD through the QuPath measurements map tool. FCM nearly coincided with the actual immunohistochemical result, allowing the prediction of Ki67/MIB1 positive cells in a direct visual fashion. Our proposed approach provides the pathologist with a fast method of identifying the proliferating compartment of the tumor through a quantitative assessment of the nuclear features on H&E slides, readily appreciable by visual inspection. Although this technique needs to be fine-tuned and tested on larger series of tumors, the digital analysis approach appears to be a promising tool to quickly forecast the tumor's proliferation fraction directly on routinely H&E-stained digital sections.

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10-8). We also detected a suggestive (P < 10-7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10-4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Sjögren syndrome (SS) is considered as a major etiologic factor for primary salivary gland lymphoma (SGL). However, the percentage of SGL that is caused by SS (and thus the real impact of SS on SGL epidemiology) is unclear. We aimed to assess the prevalence of SS in patients with SGL through a systematic review and meta-analysis., Methods: Electronic databases were searched for studies assessing the presence of SS in patients with SGL. Pooled prevalence of SS in SGL was calculated, with a subgroup analysis based on histotype (mucosa-associated lymphoid tissue [MALT] vs non-MALT)., Results: Sixteen studies with 665 SGLs were included. Pooled prevalence of SS in SGL was 18.2%, with high heterogeneity among studies. In MALT SGL, the prevalence of SS was 29.5%, with moderate heterogeneity. In non-MALT SGL, the prevalence of SS was 0%, with null heterogeneity., Conclusions: SS seems to be responsible for a significant but minor portion of SGLs. SS appears involved in MALT-type SGL but not in other histotypes., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Hepatitis C virus (HCV) has been proposed as a possible etiologic factor in ocular adnexal marginal zone lymphoma (OAML). We aimed to assess the prevalence of HCV infection in patients with OAML through a systematic review and meta-analysis., Methods: Electronic databases were searched from their inception to August 2019 for studies assessing HCV seroprevalence in patients with OAML. Pooled prevalence of HCV infection was calculated with 95 % confidence interval (CI). Statistical heterogeneity among studies was quantified via the inconsistency index (I 2 ). Funnel plot symmetry was used to assess the risk of bias across studies., Results: Nine studies with 360 patients were included. Overall pooled prevalence of HCV in OAML was 12.7 %, with low statistical heterogeneity (I 2 = 17.4 %) and with asymmetrical funnel plot. The studies clustered into two groups: 5 studies (3 from Italy and 2 multicenter with a major Italian contribution) showed a higher HCV prevalence in OAML (15.6 %), while the other 4 (from countries other than Italy) showed a lower prevalence (4.7 %); in both subgroups, statistical heterogeneity was null (I 2 = 0%) and funnel plot was symmetrical., Conclusion: HCV might be a significant etiologic factor of OAML in Italy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier GmbH. All rights reserved.)