SMARCB1-deficient sinonasal adenocarcinoma: a rare variant of SWI/SNF-deficient malignancy often misclassified as high-grade non-intestinal-type sinonasal adenocarcinoma or myoepithelial carcinoma.

SMARCB1-deficient sinonasal adenocarcinoma is a rare variant of SWI/SNF-deficient malignancies with SMARCB1 loss and adenocarcinoma features. More than 200 high-grade epithelial sinonasal malignancies were retrieved. A total of 14 cases exhibited complete SMARCB1 (INI1) loss and glandular differentiation. SMARCA2 and SMARCA4 were normal, except for one case with a loss of SMARCA2. Next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) revealed an alteration in the SMARCB1 gene in 9/13 cases, while 2/13 were negative. Two tumors harbored SMARCB1 mutations in c.157C > T p.(Arg53Ter) and c.842G > A p.(Trp281Ter). One harbored ARID1B mutations in c.1469G > A p.(Trp490Ter) and MGA c.3724C > T p.(Arg1242Ter). Seven tumors had a SMARCB1 deletion. One carried an ESR1 mutation in c.644-2A > T, and another carried a POLE mutation in c.352_374del p.(Ser118GlyfsTer78). One case had a PAX3 mutation in c.44del p.(Gly15AlafsTer95). Histomorphology of SMARCB1-deficient adenocarcinoma was oncocytoid/rhabdoid and glandular, solid, or trabecular in 9/14 cases. Two had basaloid/blue cytoplasm and one showed focal signet ring cells. Yolk sac tumor-like differentiation with Schiller-Duval-like bodies was seen in 6/14 cases, with 2 cases showing exclusively reticular-microcystic yolk sac pattern. Follow-up of a maximum of 26 months (median 10 months) was available for 8/14 patients. Distant metastasis to the lung, liver, mediastinum, bone, and/or retroperitoneum was seen in 4/8 cases. Locoregional failure was seen in 75% of patients, with 6/8 local recurrences and 3 cervical lymph node metastases. At the last follow-up, 5 of 8 (62%) patients had died of their disease 2 to 20 months after diagnosis (median 8.2 months), and 3 were alive with the disease. The original diagnosis was usually high-grade non-intestinal-type adenocarcinoma or high-grade myoepithelial carcinoma. A correct diagnosis of these aggressive tumors could lead to improved targeted therapies with potentially better overall disease-specific survival.

Delphi expert consensus for whole slide imaging in thyroid cytopathology.

OBJECTIVE: Despite an increase in thyroid fine needle aspiration (FNA) and advances in whole slide imaging (WSI) adoption, digital pathology is still considered inadequate for primary diagnosis of these cases. Herein, we aim to validate the utility of WSI in thyroid FNAs employing the Delphi method strategy. METHODS: A panel of experts from seven reference cytology centres was recruited. The study consisted of two consecutive rounds: (1) an open-ended, free-response questionnaire generating a list of survey items; and (2) a consensus analysis of 80 selected shared WSIs from 80 cases by six investigators answering six morphological questions utilising a 1 to 5 Likert scale. RESULTS: High consensus was achieved for all parameters, with an overall average score of 4.27. The broad majority of items (84%) were ranked either 4 or 5 by each physician. Two badly scanned cases were responsible for more than half of the low-ranked (≤2) values (57%). Good to excellent (≥3) diagnostic confidence was reached in more than 95.2% of cases. For most cases (78%) WSI assessment was not limited by technical issues linked to the image acquisition process. CONCLUSION: This systematic Delphi study indicates broad consensus among participating physicians on the application of DP to thyroid cytopathology, supporting expert opinion that WSI is reliable and safe for primary diagnostic purposes.

Sclerosing Polycystic Adenoma of Salivary Glands: A Novel Neoplasm Characterized by PI3K-AKT Pathway Alterations-New Insights Into a Challenging Entity.

Sclerosing polycystic adenoma (SPA) is a rare salivary gland neoplasm originally thought to represent a non-neoplastic lesion. Recently we have encountered an index case of apocrine intraductal carcinoma of parotid gland of 62-year-old man with invasive salivary duct carcinoma component arising from SPA, a combination of tumor entities that has never been published so far. Here, we further explore the nature of SPA by evaluating 36 cases that were identified from the authors' consultation files. The patients were 25 females and 11 males aged 11 to 79 years (mean, 47.8 y). All tumors originated from the parotid gland. Their size ranged from 11 to 70 mm (mean, 28 mm). Histologically, all cases revealed characteristic features of SPA, such as lobulated well-circumscribed growth, focal hyalinized sclerosis, presence of large acinar cells with abundant brightly eosinophilic intracytoplasmic granules, and ductal components with variable cytomorphologic characteristics, including foamy, vacuolated, apocrine, mucous, clear/ballooned, squamous, columnar and oncocyte-like cells. In all cases, there were foci of intraluminal solid and cribriform intercalated duct-like epithelial proliferations with variable dysplasia which were positive for S100 protein and SOX10, and fully enveloped by an intact layer of myoepithelial cells. In addition, 14/36 cases (39%) had focal intraductal cribriform and micropapillary apocrine-type dysplastic epithelial structures composed of cells positive for androgen receptors and negative for S100/SOX10. The intraductal proliferations of both types showed focal mild to severe dysplasia in 17 cases (17/36; 47%). Two cases showed overt malignant morphology ranging from high-grade intraductal carcinoma to invasive carcinoma with an apocrine ductal phenotype. Next generation sequencing using ArcherDX panel targeting RNA of 36 pan-cancer-related genes and/or a TruSight Oncology 170/500 Kit targeting a selection of DNA from 523 genes and RNA from 55 genes was performed. Tumor tissue was available for molecular analysis in 11 cases, and 9 (9/11; 82%) of them harbored genetic alterations in the PI3K pathway. Targeted sequencing revealed HRAS mutations c.37G>C, p.(Gly13Arg) (2 cases) and c.182A>G, p.(Gln61Arg) (2 cases), and PIK3CA mutations c.3140A>G, p.(His1047Arg) (3 cases), c.1633G>A, p.(Glu545Lys) (1 case), and c.1624G>A, p.(Glu542Lys) (1 case). Moreover, mutations in AKT1 c.49G>A, p.(Glu17Lys) and c.51dup, p.(Tyr18ValfsTer15); c.49_50delinsAG, p.(Glu17Arg) (as a double hit) were found (2 cases). In addition, germinal and somatic mutation of PTEN c.1003C>T, p.(Arg335Ter); c.445C>T, p.(Gln149Ter), respectively, were detected. Gene fusions were absent in all cases. These prevalent molecular alterations converging on one major cancer-related pathway support the notion that SPA is a true neoplasm with a significant potential to develop intraluminal epithelial proliferation with apocrine and/or intercalated duct-like phenotype. The name SPA more correctly reflects the true neoplastic nature of this enigmatic lesion.

Odontogenic fibroma amyloid-variant: a typical case and brief considerations about mimickers.

The World Health Organization's (WHO) updated classification of head and neck tumors (2017) defined odontogenic fibroma as a rare neoplasm. In this report, we describe an unusual, typical and rare variant of a central odontogenic fibroma with diffuse amyloid-like protein stromal deposition, and discuss the differential diagnosis with other entities. Radiographically, this lesion presented as a well-defined radiolucency of the mandible, partially cystic. Histologically, the lesion showed a unique confluence of odontogenic epithelial rests in a moderately cellular connective tissue. Immunohistochemical staining highlighted a mixture of benign epithelial and Langerhans cells within connective tissue with diffuse amyloid-like stromal deposition. The importance of recognizing this variant of odontogenic fibroma is due to its benign prognosis and clinical course.

Increased VEGF levels in a case of papillary tumor of the pineal region with intracranial hemorrhage: a potential surrogate indicator of tumor angiogenesis and aggressiveness?

Pineal tumors are rare, about 1% of all intracranial tumors. At variance with pineocytomas, usually characterized by a good prognosis, papillary tumors behave more aggressively. Owing to their rarity, little is known about their biology and clinical behavior, moreover conflicting data on prognosis have been reported. Here we present an unusual case of papillary neuroepithelial tumor of the pineal region in a 40-year-old man who was admitted in a state of unconsciousness due to the presence of intracranial hemorrhage. After 21 days from admission, he underwent third ventriculostomy for hydrocephalus and biopsy of the lesion. Since bleeding manifestations are uncommonly associated with this kind of tumors, we performed some additional non routine laboratory tests in order to identify biological indicators of disease course and abnormal angiogenesis. Coagulation screening tests were performed to rule out the presence of coagulopathy and vascular endothelial growth factor (VEGF ) levels were measured in plasma as marker of tumor angiogenic potential. Histologic evaluation confirmed the diagnosis of a papillary tumor of the pineal region with the presence of tiny vessel lumens that may account for increased angiogenesis Coagulation screening was normal and VEGF levels were extremely high if compared to healthy individuals. After 20 months of follow-up the tumor mass, radiotherapy treated, appeared dramatically reduced at MRI evaluation, and, interestingly, VEGF levels, although still higher than in healthy individuals, resulted significantly decreased as compared to those measured at time of first hospital admission suggesting a role for VEGF as indicator of tumor aggressiveness. In conclusion, measurement of angiogenesis circulating soluble markers could have an additional feedback in the diagnosis, therapy and monitoring the disease in patients with very rare CNS tumors as papillary tumors of pineal region that have non univocal clinical behavior and prognosis.

Single-center outbreak of Pneumocystis jirovecii pneumonia in heart transplant recipients.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) outbreaks are described in solid organ transplant recipients. Few reports suggest interhuman transmission with important infection control implications. We described a large PJP outbreak in heart transplant (HTx) recipients. METHODS: Six cases of PJP occurred in HTx recipients within 10 months in our hospital. Demographics, clinical characteristics, treatment and outcomes were described. To identify contacts among individuals a review of all dates of out-patient visits and patient hospitalizations was performed. Cross exposure was also investigated using genotyping on PJ isolates. RESULTS: At the time of PJP-related hospitalization, patients' mean age was 49 ± standard deviation 4 years, median time from HTx was 8 (25%-75% interquartile range [Q1-Q3] 5-12) months and none of the cases were on prophylaxis. At PJP-related admission, 5 patients had CMV reactivation, of whom 4 were on antiviral preemptive treatment. Median in-hospital stay was 30 (Q1-Q3, 28-48) days; and 2 cases required intensive care unit admission. All patients survived beyond 2 years. Transmission map analysis suggested interhuman transmission in all cases (presumed incubation period, median 90 [Q1-Q3, 64-91] days). Genotyping was performed in 4 cases, demonstrating the same PJ strain in 3 cases. CONCLUSIONS: We described a large PJP cluster among HTx recipients, supporting the nosocomial acquisition of PJP through interhuman transmission. Based on this experience, extended prophylaxis for more than 6 months after HTx could be considered in specific settings. Further work is required to understand its optimal duration and timing based on individual risk factor profiles and to define standardized countermeasures to prevent and limit PJP outbreaks.

Autocrine/paracrine sphingosine-1-phosphate fuels proliferative and stemness qualities of glioblastoma stem cells.

Accumulating reports suggest that human glioblastoma contains glioma stem-like cells (GSCs) which act as key determinants driving tumor growth, angiogenesis, and contributing to therapeutic resistance. The proliferative signals involved in GSC proliferation and progression remain unclear. Using GSC lines derived from human glioblastoma specimens with different proliferative index and stemness marker expression, we assessed the hypothesis that sphingosine-1-phosphate (S1P) affects the proliferative and stemness properties of GSCs. The results of metabolic studies demonstrated that GSCs rapidly consume newly synthesized ceramide, and export S1P in the extracellular environment, both processes being enhanced in the cells exhibiting high proliferative index and stemness markers. Extracellular S1P levels reached nM concentrations in response to increased extracellular sphingosine. In addition, the presence of EGF and bFGF potentiated the constitutive capacity of GSCs to rapidly secrete newly synthesized S1P, suggesting that cooperation between S1P and these growth factors is of central importance in the maintenance and proliferation of GSCs. We also report for the first time that S1P is able to act as a proliferative and pro-stemness autocrine factor for GSCs, promoting both their cell cycle progression and stemness phenotypic profile. These results suggest for the first time that the GSC population is critically modulated by microenvironmental S1P, this bioactive lipid acting as an autocrine signal to maintain a pro-stemness environment and favoring GSC proliferation, survival and stem properties.