Unusual presentation of fatal disseminated varicella zoster virus infection in a patient with lupus nephritis: a case report.

BACKGROUND: The risk of life-threatening complications, such as visceral disseminated varicella zoster virus (VZV) infection, is greater in immunosuppressed individuals, such as systemic lupus erythematosus (SLE) patients. CASE PRESENTATION: Here, a case is reported of a Caucasian woman diagnosed with lupus nephritis and anti-phospholipid syndrome, who was subjected to mycophenolate mofetil and high-dose steroid remission-induction therapy. Two months later she developed abdominal pain followed by a fatal rapid multi-organ failure. As no typical skin rashes were evident, death was initially attributed to catastrophic anti-phospholipid syndrome. However, autopsy and virological examinations on archival material revealed a disseminated VZV infection. CONCLUSIONS: Overall, this case highlights the importance of having a high clinical suspicion of fatal VZV infections in heavily immunosuppressed SLE patients even when typical signs and symptoms are lacking.

Papillary thyroid carcinoma with nodular fasciitis-like stroma and ß-catenin mutations should be renamed papillary thyroid carcinoma with desmoid-type fibromatosis.

Various histological variants of papillary thyroid carcinoma have been reported, some with clinical implications, some with peculiar, sometimes misleading morphologies. One of these rare and poorly characterized variants is papillary thyroid carcinoma with nodular fasciitis-like stroma, of which fewer than 30 cases have been documented, mostly as isolated reports. It is a dual tumor comprising a malignant epithelial proliferation that harbors typical features of conventional papillary thyroid carcinoma, admixed with a prominent mesenchymal proliferation resembling nodular fasciitis or fibromatosis. Thus, the terms papillary thyroid carcinoma with nodular fasciitis-like stroma and papillary thyroid carcinoma with fibromatosis-like stroma are used interchangeably; however, the former term suggests a self-limited and regressing disease, whereas the latter one suggests a recurrent and potentially aggressive one. Better genetic and ultrastructural characterization could lead to more appropriate terminology and management. We performed detailed clinicopathological and molecular analyses of two cases of PTC with prominent mesenchymal proliferation that developed in the thyroid gland of two male patients aged 34 and 48. In both cases, the epithelial component harbored a heterozygous somatic activating BRAF mutation (p.V600E). Also, in both cases, the mesenchymal component showed typical aberrant nuclear and cytoplasmic immunoreactivity for ß-catenin and harbored a heterozygous somatic activating mutation in the corresponding CTNNB1 gene (p.S45P). This mutation has never been reported in thyroid stroma; in other tissues, it is typical of desmoid-type fibromatosis rather than nodular fasciitis-like stroma. We therefore propose that in cases of papillary thyroid carcinoma with a prominent mesenchymal component, mutations in CTNNB1 should be sought; when they are present, the term 'papillary thyroid carcinoma with desmoid-type fibromatosis' should be used. As the mesenchymal component of these tumors is not expected to concentrate radioactive iodine, special considerations apply to clinical evaluation and follow-up, which should be brought to the attention of the treating specialist.

Prospective evaluation of MR-TRG (Tumor Regression Grade) in esophageal cancer after neo-adjuvant therapy: Preliminary results.

PURPOSE: To develop MRI-based criteria to assess tumor response to neoadjuvant therapies (NAT) of esophageal cancers (EC) and to evaluate its diagnostic performance in predicting the pathological Tumor Regression Grade (pTRG). METHOD: From 2018 to 2022, patients with newly diagnosed locally advanced EC underwent MRI examinations for initial staging and restaging after NAT. Magnetic Resonance TRG (MR-TRG), equivalent to the Mandard and Becker classifications, were developed and independently assessed by two radiologists, blinded to pTRG, using T2W and DW-MR Images. All patients underwent surgery and benefited from a blinded pTRG evaluation by two pathologists. The agreement between readers and between MR-TRG and pTRG were assessed with Cohen's Kappa. The correlation of MR-TRG and pTRG was determined using Spearman's correlation. RESULTS: 28 patients were included. Interrater agreement was substantial between radiologists, improved when grouping grade 1 and 2 (κ = 0.78 rose to 0,84 for Mandard and 0.68 to 0,78 for Becker score). Agreement between pTRG and MR-TRG was moderate with a percentaged agreement (p) = 87.5 %, kappa (κ) = 0.54 and p = 83.3 %, κ = 0.49 for Mandard and Becker, respectively. Agreement was improved to substantial when grouping grades 1-2 for Mandard and 1a-1b for Becker with p = 89.3 %, κ = 0.65 and p = 85.2 %, κ = 0.65 respectively. Sensitivity and specificity of MR-TRG in predicting pTRG were 88.2 % and 72.7 % for Mandard system (scores 1-2 versus 3-5), and 83.3 % and 80 % for Becker system (scores 1a-1b versus 2-3). CONCLUSION: A substantial agreement between MR-TRG and pTRG was achieved when grouping grade 1-2. Hence, MR-TRG could be used as a surrogate of complete and near-complete pTRG.

Targeting lysine-specific demethylase 1 (KDM1A/LSD1) impairs colorectal cancer tumorigenesis by affecting cancer cells stemness, motility, and differentiation.

Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A also known as LSD1), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC samples, KDM1A overexpression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted multi-omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype, supporting the role of KDM1A in CRC cells stemness maintenance. Also, KDM1A silencing resulted in up-regulation of miR-506-3p, previously reported to play a tumor-suppressive role in CRC. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A impacts CRC progression in several non-overlapping ways, and therefore it represents a promising epigenetic target to prevent tumor relapse.

Choroid Plexus Carcinoma in Adults: Literature Review and First Report of a Location into the Third Ventricle.

Choroid plexus carcinoma (CPC) is a rare intraventricular neoplasm originating from choroid plexus. CPC is the most aggressive choroid plexus tumor. Almost all the CPCs are detected in children, and the preferred location is the lateral ventricle. We reviewed the literature to evaluate the state of the art concerning the management of CPC in adults and report the first case described of the extremely rare localization into the third ventricle. A 38-year-old woman presented a medical history of Parinaud syndrome and occasional facial weakness. Brain magnetic resonance imaging revealed a mass lesion in the pineal region and posterior part of the third ventricle with obstructive hydrocephalus. She underwent subtotal resection through a supracerebellar infratentorial approach. After the histopathological diagnosis of CPC, the patient underwent a second surgery with gross total resection and adjuvant radiotherapy. CPC in adults, given its extreme rarity, does not have a standardized treatment. Gross total resection should be the first step of the treatment: however, according to the literature, gross total resection is achieved only in 40-75% of cases in CPC as opposed to 95% in choroid plexus papilloma, mainly due to the difficulty in managing a highly vascularized tumor in such a deep location. Chemotherapy has not an established role and adjuvant treatment is based on radiotherapy. In the case described hereby the gross total resection associated with surgical treatment of hydrocephalus and adjuvant radiotherapy has achieved a good clinical and radiological outcome.

Acinar cell carcinoma of the pancreas with thyroid-like follicular features: first description of a new diagnostic challenging subtype.

Acinar cell carcinomas (ACCs) of the pancreas are a heterogeneous group of neoplasms showing a wide spectrum of morphological features including acinar, solid, glandular, and trabecular architecture. In addition, uncommon cytological aspects have recently been described and include oncocytic, spindle, clear, and pleomorphic cell types. This wide histological spectrum represents a challenge in the diagnostic task for pathologists. Molecular mechanisms involved in the onset and progression of ACCs are not completely known, but, in general, they differ from those observed in ductal adenocarcinomas or neuroendocrine neoplasms of the pancreas and frequently include alterations in the APC/ß-catenin pathway. In the present paper, we describe a new variant of ACC showing thyroid-like follicular features and CTNNB1 mutation. This phenotype needs to be included in the spectrum of morphological presentation of ACC.

Expression of Prox1 in Medullary Thyroid Carcinoma Is Associated with Chromogranin A and Calcitonin Expression and with Ki67 Proliferative Index, but Not with Prognosis.

Medullary thyroid carcinoma (MTC) has been shown to express Prospero homeobox protein 1 (Prox1), a transcription factor whose expression is altered in a variety of human cancers. We conducted a retrospective study on a series of 32 patients with MTC to test the correlation of Prox1 expression in MTC with clinicopathological features and to evaluate its prognostic significance. Correlation of Prox1 immunohistochemical expression with tumor size, proliferative index (Ki67), and calcitonin and CEA serum levels prior to surgery was tested for significant correlations. The difference in Prox1 and Ki67 immunohistochemical expression according to the immunohistochemical staining intensity of CEA, chromogranin A, and calcitonin was tested using the Kruskal-Wallis H test and linear regression analysis. The prognostic value of Prox1 and Ki67 for our patient cohort was assessed by Kaplan-Meier log rank survival analysis. We demonstrated a positive correlation between Prox1 expression and Ki67 index. Prox1 also showed significant difference in expression according to chromogranin A and calcitonin immunohistochemical expression, with higher Prox1 expression in tumors with stronger chromogranin A or calcitonin staining. Prox1 expression did not correlate with PFS or OS based on Kaplan-Meier log rank survival analysis. In conclusion, Prox1 expression in MTC is positively correlated with Ki67 and with the immunohistochemical expression of chromogranin A and calcitonin. However, the present study does not support a role for Prox1 in MTC prognosis.

Autoimmune Gastritis in the Pediatric Age: An Underestimated Condition Report of Two Cases and Review.

Background: Diagnosis of pediatric autoimmune gastritis (AIG) in children is important due to poor outcome and risk of malignancy. This condition is often underestimated in the clinico-pathologic diagnostic work-up, leading to delayed time-to-diagnosis. To increase the awareness of this condition in the pediatric population, we present two cases encountered at our institution, discuss their clinical, biological, and histological presentations in relation with evidence from the literature, and propose an algorithm for diagnosis and follow-up of AIG in children. Case presentation: Two patients (12 and 17 years old) presented with iron deficiency anemia and negative family history for autoimmune disorders. In both cases, the final diagnosis of autoimmune gastritis was delayed until pathological examination of endoscopic gastric biopsies showed atrophy of oxyntic glands. Helicobacter pylori search was negative. Follow up biopsies revealed persistent disease. Literature review on this condition shows unclear etiology and poor long term outcome in some patients because of increased risk of malignancy. Conclusions: AIG should be considered in the differential diagnosis of iron deficiency anemia in the pediatric population.Standardized clinico-pathologic work-up is mandatory. Endoscopic follow-up should be performed due to the risk of malignancy.

Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B.

Notch 1/2 genes play tumor-suppressing functions in squamous cell carcinoma (SCC), a very common malignancy in skin and internal organs. In contrast with Notch, we show that the transcription factor CSL (also known as RBP-Jκ), a key effector of canonical Notch signaling endowed with intrinsic transcription-repressive functions, plays a tumor-promoting function in SCC development. Expression of this gene decreased in upper epidermal layers and human keratinocytes (HKCs) undergoing differentiation, while it increased in premalignant and malignant SCC lesions from skin, head/neck, and lung. Increased CSL levels enhanced the proliferative potential of HKCs and SCC cells, while silencing of CSL induced growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels gave rise to rapidly expanding tumors, while cells with silenced CSL formed smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKCs and SCC cells with silenced CSL revealed major modulation of apoptotic, cell-cycle, and proinflammatory genes. We also show that the histone demethylase KDM6B is a direct CSL-negative target, with inverse roles of CSL in HKC and SCC proliferative capacity, tumorigenesis, and tumor-associated inflammatory reaction. CSL/KDM6B protein expression could be used as a biomarker of SCC development and indicator of cancer treatment.

Hyalinizing trabecular tumour of the thyroid: fine-needle aspiration cytological diagnosis and correlation with histology.

Hyalinizing trabecular tumour (HTT) is a rare thyroid neoplasm of follicular cell origin characterised by a trabecular growth pattern and prominent intratrabecular and intertrabecular hyalinisation. These peculiar histological features allow the prompt recognition of this neoplasm in surgical specimens. However, cytological diagnosis of HTT remains elusive and misleading because of overlapping characteristics with other thyroid tumours, particularly papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC) and the newly described non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Nevertheless, the proper recognition of this neoplasm on preoperative cytological preparations is important to avoid unnecessary overtreatment of this indolent lesion. A thorough review of the literature has revealed that the correct diagnosis of HTT in cytological smears is achieved in only 8% of cases. In a further 6% of cases, diagnostic doubt has been indicated. Sixty percent of published cases of HTT have been misdiagnosed as suggestive, suspicious or positive for PTC. These findings underline the difficulties of a cytological-based diagnosis of such entity. In this article we review the cytomorphological features of HTT and their correlation to histological features to provide the reader with the tools to improve diagnostic performance in the identification of HTT on preoperative cytology.

Cytology of Primary Salivary Gland-Type Tumors of the Lower Respiratory Tract: Report of 15 Cases and Review of the Literature.

Primary pulmonary salivary gland-type tumors are rare neoplasms arising from the seromucinous submucosal glands of the lower respiratory tract (LRT), the most common of which are mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma. They are morphologically indistinguishable from their salivary gland counterpart and recognizing them is a challenge, especially on cytological specimens. We analyzed 15 cases of histologically proven primary salivary gland tumors of the LRT to identify cytomorphological features and define potential diagnostic clues that might assist cytopathologists in the preoperative diagnosis of these neoplasias. Three out of the four cases of adenoid cystic carcinomas showed the characteristic tridimensional cell clusters and hyaline globules, whereas the last one did not show malignant cells; only two cases of MEC presented the three characteristic cell types (i.e., squamous, intermediate, and mucin secreting) on cytology. Since these neoplasms are rare and do not have a completely specific set of cytological features, it is important for practicing cytopathologists to be aware of the possibility of encountering them, in specimens from patients with LRT masses, in order to render the correct diagnosis.

MMR vaccine in the postpartum does not expose seronegative women to untoward effects.

BACKGROUND: The aim of this study was to assess whether rubella vaccination immediately after delivery could expose seronegative women to specific untoward effects. METHODS: 163 rubella-seronegative women received Measles-Mumps-Rubella (MMR) vaccine in the immediate postpartum period; they were evaluated at one month and at three months thereafter through telephone interviews. As controls, we matched 163 rubella-seropositive women, who might experience similar symptoms for any reason in the same timeframe. RESULTS: No relevant difference was still observed in the frequency of arthralgia and myalgia at one and three months. Instead, a statistically significant difference in the frequency of cervical lymphadenopathy and cutaneous rash at one month (p = 0.028 and p = 0.005, respectively), was observed between cases and controls. However, no statistical differences were reported at three months for the same symptoms. CONCLUSIONS: Postpartum rubella vaccination with MMR is safe and advisable to avoid congenital rubella syndrome.

Columnar cell variant of papillary thyroid carcinoma: Cytomorphological characteristics of 11 cases with histological correlation and literature review.

BACKGROUND: The columnar cell variant of papillary thyroid carcinoma (PTC-CCV) is a rare entity that demonstrates a more aggressive clinical course compared with the more common subtypes of PTC. On histology, it is defined by papillae or gland-like structures lined by columnar cells displaying prominent nuclear stratification. Because to the authors' knowledge no characteristic cytomorphological features have been identified to date and typical features of PTC often are absent on cytology, the diagnosis of PTC-CCV by fine-needle aspiration (FNA) is challenging. This prompted the authors to evaluate a series of PTC-CCV cases to identify features that could facilitate its diagnosis by FNA. METHODS: A total of 11 surgical specimens of PTC-CCV with corresponding preoperative cytology were identified over a 21-year period. The cytological features of the aspirated specimens, consisting mostly of Papanicolaou and Diff-Quick smears, were evaluated retrospectively. RESULTS: All cases demonstrated the presence of papillary structures. The most important features observed in PTC-CCV FNA specimens were hypercellularity with nuclear superposition and a paucity of nuclear pseudoinclusions and grooves. CONCLUSIONS: Although PTC-CCV may demonstrate features that overlap with those of the classic variant of PTC, hypercellular smears with papillary structures covered by cells with pseudostratified nuclei that show a paucity of nuclear pseudoinclusions and grooves should alert the cytopathologist to the possibility of this diagnosis. Cancer Cytopathol 2017;125:389-97. © 2017 American Cancer Society.

Myoepithelioma of the parotid gland with extensive adipocytic metaplasia: Report of a case with intriguing aspects on fine needle aspiration and p63 immunohistochemical expression.

Myoepithelioma is a rare and usually benign salivary gland tumor derived from myoepithelial cells. Variability in cellular morphology and stromal composition leads to diagnostic pitfalls on fine-needle aspiration cytology; therefore, histology and immunohistochemistry are often required for definitive diagnosis. We describe a case of parotid gland myoepithelioma in a 76-year-old woman, which was discovered incidentally on cerebral magnetic resonance imaging. Fine-needle aspiration sampled cohesive aggregates of spindle-shaped cells embedded in a fibrillary matrix as well as abundant mature adipocytes, initially considered as part of normal salivary gland parenchyma. Histology of the resected specimen showed bundles of spindle-shaped cells embedded in loose connective tissue, admixed with numerous intralesional adipocytes. Immunohistochemical studies revealed a diffuse expression of p63 by this adipocytic population, an observation clearly indicating that myoepithelial cells can trans-differentiate and acquire the morphology of mature adipocytes. Knowledge of this phenomenon can be helpful in the work-up of salivary gland lesions. Diagn. Cytopathol. 2016;44:1090-1093. © 2016 Wiley Periodicals, Inc.