Immunological synapse formation between T regulatory cells and cancer-associated fibroblasts promotes tumour development.

Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment, serving diverse functions in tumour progression. However, the mechanisms via which CAFs influence the anti-tumour immunity remain poorly understood. Here, using multiple tumour models and biopsies from cancer patients, we report that α-SMA+ CAFs can form immunological synapses with Foxp3+ regulatory T cells (Tregs) in tumours. Notably, α-SMA+ CAFs can phagocytose and process tumour antigens and exhibit a tolerogenic phenotype which instructs movement arrest, activation and proliferation in Tregs in an antigen-specific manner. Moreover, α-SMA+ CAFs display double-membrane structures resembling autophagosomes in their cytoplasm. Single-cell transcriptomic data showed an enrichment in autophagy and antigen processing/presentation pathways in α-SMA-expressing CAF clusters. Conditional knockout of Atg5 in α-SMA+ CAFs promoted inflammatory re-programming in CAFs, reduced Treg cell infiltration and attenuated tumour development. Overall, our findings reveal an immunosuppressive mechanism entailing the formation of synapses between α-SMA+ CAFs and Tregs in an autophagy-dependent manner.

Superficial acral calcified chondroid mesenchymal neoplasm harboring an FN1::FGFR2 fusion and review of the literature.

Calcified chondroid mesenchymal neoplasm is a recently recognized bone and soft tissue entity primarily found in the extremities and the temporomandibular joint. This neoplasm is typically driven by the fusion of the FN1 gene with a kinase. In this case report, we provide a detailed account of a rare superficial calcified chondroid mesenchymal neoplasm located on the left big toe, characterized by an FN1::FGFR2 fusion. The tumor exhibited a peripheral collarette and consisted of large intradermal histiocytoid to epithelioid cells with no mitotic activity. These cells displayed fine chromatin and abundant pale eosinophilic cytoplasm, forming a swirling syncytium. They were interspersed with localized areas of glassy chondromyxoid matrix containing randomly mineralized calcific material and isolated osteoclast-like giant cells. RNA sequencing confirmed the presence of an FN1 (exon 29)::FGFR2 (exon 7) gene fusion. Our report emphasizes the importance for dermatopathologists to consider this entity when evaluating superficial lesions displaying mesenchymal, chondroid, and calcified attributes.

DOG1-Positive Primary Mesenteric Leiomyosarcoma: Report of a Case and Review of the Literature.

The mesentery constitutes a common location for the metastatic spread of malignant gastrointestinal tumors. Primary mesenteric tumors, on the other hand, are very rare; lymphomas are the most common, followed by benign and malignant mesenchymal tumors. We present a case of a 43-year-old patient operated on for a primary mesenteric leiomyosarcoma with a positive immunostain for DOG1, despite having no KIT or PDGFRa mutations on molecular analysis. Moreover, we review the pertinent literature.

How to spot a basosquamous carcinoma: a study on demographics, clinical-dermatoscopic features and histopathological correlations.

Basosquamous carcinoma (BSC) is a relatively rare type of neoplasm originating from basal cell carcinoma with features of squamous differentiation. BSC has an aggressive local behaviour with a tendency for recurrence and a less frequent metastatic potential The primary objective was to describe the dermatoscopic features of the tumour. Secondary goals were to detect the morphological features of the tumour along with patients' characteristics and to evaluate possible dermatoscopic and histopathological correlations Twenty-two patients with 25 BSCs were enrolled. All tumours were surgically excised and diagnosis was based on histopathology. Clinical and dermatoscopic images were evaluated by two investigators based on pre-defined criteria, and a statistical analysis was performed The median age of the patients was 78 years old (range: 52-88) and the male/female ratio was 2.14. All patients reported history of either occupational (50%) or recreational (50%) intensive sun exposure and 72.73% had signs of actinic keratosis. The most common anatomical site of the tumours was the head/neck area (72%). Clinically, nodular (64%), ulcerated (88%) and non-pigmented (76%) lesions prevailed. Dermatoscopically, 92% had prominent vasculature and monomorphous arborizing vessels with a diffuse arrangement, representing the most frequently observed type. Ulceration (88%), SCC dermatoscopic criteria (56%), white strands/blotches (56%) and features of pigmentation (40%) were also detected We suggest that the most common prototype of BSC is an ulcerated, facial nodule in elderly males with photo-damaged skin, dermatoscopically displaying combined features of mostly nodular BCC and, to a less extent, SCC.

A rare case of extrahepatic biliary mucinous cystic neoplasm in a middle-aged woman: A case report.

Biliary mucinous cystic neoplasms are very rare tumors of the biliary tract with malignant potential. Preoperative diagnosis is challenging, as clinical, biochemical and radiological features are not specific. Surgical resection with negative margins is the gold standard treatment for these uncommon lesions. A 55-year-old woman presented at the Third Department of Surgery (Attikon University Hospital, Athens, Greece) with a history of mild right upper quadrant (RUQ) abdominal pain and jaundice. A 2-cm lesion in the distal common bile was identified by imaging. Following discussion in our multidisciplinary board meeting the patient underwent a pylorus preserving pancreatoduodenectomy, and histopathological examination revealed an ovarian-stromal type intraductal mucinous cystic neoplasm of the extra hepatic biliary. Since biliary mucinous cystic neoplasms are characterized by malignant transformation and high rates of recurrence, surgical resection with negative margins is the treatment of choice for both non-invasive and invasive biliary mucinous cystic neoplasms.

Novel Insights for Patients with Multiple Basal Cell Carcinomas and Tumors at High-Risk for Recurrence: Risk Factors, Clinical Morphology, and Dermatoscopy.

INTRODUCTION: Basal cell carcinoma (BCC) quite frequently presents as multiple tumors in individual patients. Neoplasm's risk factors for local recurrence have a critical impact on therapeutic management. OBJECTIVE: To detect risk factors for multiple BCCs (mBCC) in individual patients and to describe clinical and dermatoscopic features of low- and high-risk tumors. MATERIALS & METHODS: Our study included 225 patients with 304 surgically excised primary BCCs. All patients' medical history and demographics were recorded. Clinical and dermatoscopic images of BCCs were evaluated for predefined criteria and statistical analyses were performed. RESULTS: Grade II-III sunburns before adulthood (OR 2.146, p = 0.031) and a personal history of BCC (OR 3.403, p < 0.001) were the major predisposing factors for mBCC. Clinically obvious white color (OR 3.168, p < 0.001) and dermatoscopic detection of white shiny lines (OR 2.085, p = 0.025) represented strongly prognostic variables of high-risk BCC. Similarly, extensive clinico-dermatoscopic ulceration (up to 9.2-fold) and nodular morphology (3.6-fold) raise the possibility for high-risk BCC. On the contrary, dermatoscopic evidence of blue-black coloration had a negative prognostic value for high-risk neoplasms (light OR 0.269, p < 0.001/partial OR 0.198, p = 0.001). CONCLUSIONS: Profiling of mBCC patients and a thorough knowledge of high-risk tumors' clinico-dermatoscopic morphology could provide physicians with important information towards prevention of this neoplasm.

Palatine tonsil metastasis of cecal mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN): A unique case.

This case demonstrates the importance of understanding that patients with malignant neoplasms may exhibit metastases in unexpected sites and illustrates the necessity of a thorough clinical examination and pathologic correlation.

Dermoscopy as a Tool in Differentiating Cutaneous Squamous Cell Carcinoma From Its Variants.

BACKGROUND: Dermoscopic features of cutaneous squamous cell carcinoma (cSCC) have been widely studied, but their accuracy should be further investigated. OBJECTIVES: This study assessed the diagnostic accuracy of a set of predetermined dermoscopic structures for 3 variants of cSCC, namely Bowen disease, keratoacanthoma and invasive cSCC. METHODS: Dermoscopic images of 56 histopathologically confirmed cSCC lesions (9 Bowen disease lesions, 7 keratoacanthomas, and 40 invasive cSCCs) were examined, and the diagnostic accuracy of dermoscopic structures was assessed. Discriminative ability of statistically significant positive predictors was determined using receiver operating characteristic (ROC) curves, and defined as an area under the ROC curve >0.700. RESULTS: Dermoscopic structures with statistical significance and discriminative ability were: for Bowen disease, clustered glomerular vessels and erosions; for keratoacanthoma, a central keratin plug; and for invasive cSCC, a mixed color of the background. Clustered and glomerular vessels had, for Bowen disease, perfect diagnostic accuracy, with: sensitivity of 88.9% for both features; specificity of 97.9% and 93.6%, respectively; positive predictive value (PPV) of 88.9% and 72.7%, respectively; and negative predictive value (NPV) of 97.8% for both. Erosions had, for BD, high specificity (87.2%) and NPV (91.1%), but low sensitivity (55.6%) and PPV (45.5%). A central keratin plug had, for keratoacanthoma, high specificity (87.8%) and NPV (93.5%), but low sensitivity (57.1%) and PPV (40%). A mixed background color had, for invasive cSCC, high specificity (81.3%) and PPV (89.7%), but low sensitivity (65%) and NPV (48.2%). CONCLUSION: Dermoscopy accurately differentiates BD, through clustered glomerular vessels, from keratoacanthoma and invasive cSCC. Dermoscopic structures of keratoacanthoma and invasive cSCC overlap, and only histopathologic analysis differentiates them precisely.

Generalized Bullous Fixed Drug Eruption to Fluconazole with Positive Patch Testing and Confirmed Tolerance to Itraconazole.

Generalized bullous fixed drug eruption (GBFDE) is a specific variant of fixed drug eruption that belongs to severe cutaneous adverse reactions (SCARs) and its diagnosis is based mainly on clinical course and especially on the reoccurrence of typical bullous lesions in previous and new sites after re-administration of the offending drug. We present a well-documented case of fluconazole-induced GBFDE, with a positive patch test to fluconazole (30% weight/volume preparation) and clinical tolerance to itraconazole proven by negative oral provocation. Even in SCARs, patch testing represents a useful diagnostic tool, while oral provocation remains the gold standard in cases that an alternative but the chemically relevant drug must be administered.

Searching HPV genome for methylation sites involved in molecular progression to cervical precancer.

Background: Human Papilloma Virus has been considered as the main cause for cervical cancer. In this study we investigated epigenetic changes and especially methylation of specific sites of HPV genome. The main goal was to correlate methylation status with histological grade as well as to determine its accuracy in predicting the disease severity by establishing optimum methylation cutoffs. Methods: In total, sections from 145 cases genotyped as HPV16 were obtained from formalin- fixed, paraffin-embedded tissue of cervical biopsies, conization or hysterectomy specimens. Highly accurate pyrosequencing of bisulfite converted DNA, was used to quantify the methylation percentages of UTR promoter, enhancer and 5' UTR, E6 CpGs 494, 502, 506 and E7 CpGs 765, 780, 790. The samples were separated in different groupings based on the histological outcome. Statistical analysis was performed by SAS 9.4 for Windows and methylation cutoffs were identified by MATLAB programming language. Results: The most important methylation sites were at the enhancer and especially UTR 7535 and 7553 sites. Specifically for CIN3+ (i.e. HSIL or SCC) discrimination, a balanced sensitivity vs. specificity (68.1%, 66.2% respectively) with positive predictive value (PPV) and negative predictive value (NPV) (66.2%, 68.2% respectively) was achieved for UTR 7535 methylation of 6.1% cutoff with overall accuracy 67.1%, while for UTR 7553 a sensitivity 60.9%, specificity 69.0%, PPV=65.6%, NPV=64.5% and overall accuracy=65.0% at threshold 10.1% was observed. Conclusion: Viral HPV16 genome was found methylated in NF-1 binding sites of UTR in cases with high grade disease. Methylation percentages of E6 and E7 CpG sites were elevated at the cancer group.

Small bowel perforation with multiple intestinal metastases from lung carcinoma: A case report.

The present report describes the case of an 81-year-old woman who underwent an emergency explorative laparotomy due to small bowel perforation. Diffuse feculent peritonitis due to perforation of the jejunum was identified. In addition, six distinct tumors of the jejunum in close proximity to the perforation site, as well as two more lesions caudally at the ileum, were identified. A separate stenotic tumor was identified at the sigmoid colon, causing moderate dilatation of the whole intestine. An enterectomy, including the perforation site and the proximal six tumors, was performed, followed by limited enterectomies for the distal two tumors and side-to-side anastomoses of the small intestine. All resected tumors were identified at histology as metastatic from lung carcinoma. Postoperatively, the patient remained in a severe septic condition and succumbed the following day. Metastatic lesions from lung carcinoma in the small bowel wall are a rare finding predisposing to bowel perforation. When an acute condition coexists with multiple intestinal metastases, the mortality rate is high despite prompt surgical intervention.

BRAF Mutation Status in Primary, Recurrent, and Metastatic Malignant Melanoma and Its Relation to Histopathological Parameters.

BACKGROUND: BRAF mutations are a common finding in malignant melanoma (MM). Nevertheless, apart from their significance as a therapeutic target in advanced melanoma, their prognostic value is still debated. OBJECTIVE: To assess BRAF mutation status in primary, recurrent, or metastatic MM and its correlations with histopathological findings. METHODS: We analyzed 203 samples from 178 consecutive patients: 129 primary cutaneous MM, 49 metastatic and recurrent MM of unknown primary site, and 25 cases of recurrences or metastases of primary MM. BRAF mutations in exon 15 were identified with real-time polymerase chain reaction and/or direct sequencing or pyrosequencing. Histopathological examination was performed according to standard procedures. RESULTS: We observed a 42.1% prevalence of BRAF mutations at codon 600 among our patients, 84% of whom harbored the V600E mutation. Mutations showed a statistically significant increase in younger patients (P = 0.011), in ulcerated tumors (P = 0.020), and in tumors lacking solar elastosis in adjacent dermis (P = 0.008). Mutations were also more common in male patients, as well as in primary MMs of the torso, and in nonvisceral metastases, however without reaching statistical significance. Logistic regression analysis identified type and ulceration as the only significant predictors of BRAF mutation. The highest frequencies of mutated BRAF were identified in superficial spreading and nodular types, and the lowest in acral lentiginous and lentigo maligna types. In situ MM and primary dermal melanoma displayed intermediate frequencies. CONCLUSION: Frequency of mutated BRAF is type-related and correlated with ulceration, a known adverse prognostic factor.

Platelet to lymphocyte and neutrophil to lymphocyte ratio as predictive indices of endometrial carcinoma: Findings from a retrospective series of patients and meta-analysis.

BACKGROUND: The purpose of the present study is to present new data concerning the diagnostic efficacy of neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios in detecting endometrial carcinoma and to summarize the existing knowledge by accumulating all the available data in the existing literature. MATERIALS AND METHODS: We retrospectively identified patients with evidence of endometrial pathology (vaginal bleeding or increased endometrial thickness) that undergone dilatation and curettage. For the meta-analysis we used the Medline, Scopus, Clinicaltrials.gov, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL and Google Scholar databases to identify relevant articles in the field. RESULTS: In our retrospective series we identified 106 women with endometrioid endometrial carcinoma and 72 controls. PLR and NLR values were comparable among the two groups (p>.05). Eleven studies were included in the present systematic review with a total of 4168 patients. The meta-analysis included 1013 patients. PLR values were not significantly different among the two groups. On the other hand, NLR was significantly raised among patients with endometrial carcinoma (MD 0.73, 95% CI 0.01, 1.45). CONCLUSION: The findings of our meta-analysis support that NLR values are significantly elevated in patients with endometrial cancer compared to controls. Moreover, there seem to be evidence to support that both PLR and NLR values increase in patients with advanced stage disease, including positive lymph nodes, lymphovascular space involvement and distant metastases. Future studies are needed in this field to reach firm conclusions and these should specifically target patients with advanced stage disease.

A giant squamous cell carcinoma of the skin of the thoracic wall: a case report and review of the literature.

BACKGROUND: We report a case of a 48-year-old white woman who presented with a huge cutaneous protruding tumor of the thoracic wall below her left breast. CASE PRESENTATION: The lesion was excised with clear margins from the adjacent skin, and subcutaneous tissue was left to heal with second intention. A histological examination of the surgical specimen revealed a well-differentiated infiltrative cutaneous squamous cell carcinoma. Our patient neglected to attend our Oncological Department to receive chemotherapy. Today, 12 months after surgery, she is alive and without evidence of disease recurrence. CONCLUSIONS: Cutaneous squamous cell carcinoma can reach a huge size if left untreated. Surgery is the primary mode of treatment, followed by chemotherapy if applicable.

Carcinoid syndrome from a carcinoid tumor of the pancreas without liver metastases: A case report and literature review.

A carcinoid tumor of the pancreas (CTP) is a rare pancreatic neoplasm, and usually presents with carcinoid syndrome (CS). CS consists of the classic symptom triad of cutaneous flushing, diarrhea and valvular disease, and occurs in the majority of patients with liver metastases. In the present study, the patient presented with symptoms of CS. A diagnosis of CTP with CS was suspected due to high levels of urine 5-hydroxyindolacetic acid, and this was confirmed by a fine-needle aspiration biopsy. Computed tomography showed extended lymphadenopathy, but no liver metastases. The patient was managed conservatively with octreotide long acting repeatable. To the best of our knowledge, this is the second literature case of CS associated with CTP without liver metastases.

Duodenal gangliocytic paraganglioma, successfully treated by local surgical excision-a case report.

INTRODUCTION: Duodenal gangliocytic paragangliomas are rare neoplasms often arising in proximity to the major duodenal papilla of Vater. These neoplasms are considered to have a benign behavior with lymph node metastases being a rare phenomenon and distant metastatic disease even more so. Resection of the tumor is the only definitive therapy. PRESENTATION OF CASE: A 67year old male presented to a referring hospital with symptoms of fatigue and malaise. Evaluation with CT imaging revealed a 3.1cm intraluminal mass situated grossly at the junction of the third with the fourth portion of the duodenum. The tumor was found to be situated near the ampulla of Vater and was excised through a longitudinal duodenotomy followed by myotomy of the sphincter of Oddi. DISCUSSION: Complete resection of duodenal gangliocytic paragangliomas by surgical or endoscopic means is the only potential cure. Endoscopic removal is the first option and is both safe and adequate. Ηowever, localized excision may be utilized instead in those cases in which endoscopic removal is not possible or cannot achieve negative margins. Recurrent disease after complete resection is unlikely. CONCLUSION: Cases of duodenal gangliocytic paragangliomas are best managed with endoscopic resection. However, local surgical excision remains as a second-choice procedure. Adjuvant chemotherapy and radiotherapy are unnecessary after complete excision.

Frontal Fibrosing Alopecia and Vitiligo: Coexistence or True Association?

Frontal fibrosing alopecia (FFA) is a primary lymphocytic cicatricial alopecia characterized by a progressive band-like recession of the frontotemporal hairline and frequent loss of the eyebrows. It predominantly affects postmenopausal women. Coexistence of FFA and vitiligo is rarely reported in the literature. We retrospectively studied 20 cases diagnosed with FFA in a 14-month period in our Department. Among them, there were 2 cases, a 72-year-old woman and a 48-year-old man, who developed FFA on preexisting vitiligo of the forehead. Anatomical colocalization of the two dermatoses supports the notion that a causal link may exist and their association may not be coincidental. We suggest that interrelated immunologic events and pathologic processes may underlie both these skin conditions.

Eradication of Helicobacter pylori Infection Restores ki67, p53, and Cyclin D1 Immunoreactivity in the Human Gastric Epithelium.

INTRODUCTION: We evaluated the effect of Helicobacter pylori (HP) eradication on p53, cyclin D1 expression, and cell proliferation in gastric mucosa. MATERIALS AND METHODS: We assessed p53, cyclin D1, and ki67 immunoexpression in gastric mucosa from 31 HP chronic gastritis patients and 12 controls. Reassessment was performed 6 months after successful HP eradication. RESULTS: Successful eradication resulted in significant decrease of p53 (1.53 ± 0.16 vs 0.83 ± 0.19, P = 0.01) and ki67 (9.84 ± 0.96 vs 4.77 ± 0.27, P < 0.001) staining in the antrum. Similarly, p53 immunoreactivity significantly decreased in the corpus (1.27 ± 0.20 vs 0.46 ± 0.15, P = 0.02), while there was a trend for decreased corpus cyclin D1 and ki67 expression (0.17 ± 0.07 vs 0.0, P = 0.08 and 8.71 ± 1.24 vs 5.85 ± 0.54, P = 0.09, respectively). Importantly, after successful HP eradication, the immunoreactivity of the studied parameters was similar to that of controls. CONCLUSION: Successful HP infection eradication restores p53, cyclin D1, and ki67 immunoreactivity in the gastric mucosa to the level of controls.