MacroH2A1.1 as a crossroad between epigenetics, inflammation and metabolism of mesenchymal stromal cells in myelodysplastic syndromes.

Ineffective hematopoiesis is a hallmark of myelodysplastic syndromes (MDS). Hematopoietic alterations in MDS patients strictly correlate with microenvironment dysfunctions, eventually affecting also the mesenchymal stromal cell (MSC) compartment. Stromal cells are indeed epigenetically reprogrammed to cooperate with leukemic cells and propagate the disease as "tumor unit"; therefore, changes in MSC epigenetic profile might contribute to the hematopoietic perturbations typical of MDS. Here, we unveil that the histone variant macroH2A1 (mH2A1) regulates the crosstalk between epigenetics and inflammation in MDS-MSCs, potentially affecting their hematopoietic support ability. We show that the mH2A1 splicing isoform mH2A1.1 accumulates in MDS-MSCs, correlating with the expression of the Toll-like receptor 4 (TLR4), an important pro-tumor activator of MSC phenotype associated to a pro-inflammatory behavior. MH2A1.1-TLR4 axis was further investigated in HS-5 stromal cells after ectopic mH2A1.1 overexpression (mH2A1.1-OE). Proteomic data confirmed the activation of a pro-inflammatory signature associated to TLR4 and nuclear factor kappa B (NFkB) activation. Moreover, mH2A1.1-OE proteomic profile identified several upregulated proteins associated to DNA and histones hypermethylation, including S-adenosylhomocysteine hydrolase, a strong inhibitor of DNA methyltransferase and of the methyl donor S-adenosyl-methionine (SAM). HPLC analysis confirmed higher SAM/SAH ratio along with a metabolic reprogramming. Interestingly, an increased LDHA nuclear localization was detected both in mH2A1.1-OE cells and MDS-MSCs, probably depending on MSC inflammatory phenotype. Finally, coculturing healthy mH2A1.1-OE MSCs with CD34+ cells, we found a significant reduction in the number of CD34+ cells, which was reflected in a decreased number of colony forming units (CFU-Cs). These results suggest a key role of mH2A1.1 in driving the crosstalk between epigenetic signaling, inflammation, and cell metabolism networks in MDS-MSCs.

Line-field confocal optical coherence tomography of psoriasis, eczema and lichen planus: a case series with histopathological correlation.

BACKGROUND: Line-field confocal optical coherence tomography (LC-OCT) is a novel, non-invasive technique that provides in vivo, high-resolution images in both vertical and horizontal sections. OBJECTIVES: The aim of the study was to evaluate LC-OCT imaging in some inflammatory disorders and to correlate the resulting features with histopathology. METHODS: The retrospective study included patients with histopathological confirmed diagnosis of plaque psoriasis, atopic eczema and lichen planus, who were imaged with LC-OCT before the biopsy. LC-OCT was performed with the commercially available LC-OCT device. RESULTS: A total of 15 adult patients with histopathologically proven plaque psoriasis (N: 5), atopic eczema (N: 5) and lichen planus (N: 5) were included. In all cases, LC-OCT allowed the in vivo recognition of the main microscopic features of the examined inflammatory skin disease, with a strong correlation with histopathology. CONCLUSIONS: Although future studies on larger series of patients are necessary, LC-OCT, based on these preliminary findings, may represent a promising tool in inflammatory skin disorders with potential applications including enhanced diagnosis, biopsy guidance, follow-up and treatment monitoring.

Aquaporin-1 expression in fluoro-edenite-induced mesothelioma effusions: An approach by cell-block procedure.

OBJECTIVE: Aquaporin 1 (AQP-1) is a water channel protein found in cell membranes, whose expression has been considered an independent favourable prognostic factor in pleural malignant mesothelioma (MM). The aim of this study was to evaluate the expression of AQP-1 and its prognostic value in a series of pleural MM effusions, from a geographical area with high concentrations of fluoro-edenite (FE). METHODS: We selected 25 MM cases from Biancavilla (Italy), an area with high environmental concentrations of FE. Cytological samples, cell-blocks (CB), clinical and follow-up data were available for all cases. Immunohistochemistry for calretinin, CK5/6, WT1, CK7 and TTF1 was used on CB sections to confirm the cytological diagnosis of MM. Immunohistochemistry for AQP-1 was performed and high expression was defined when ≥50% of tumour cells showed linear and circumferential membranous staining. RESULTS: The cohort included 16 men and nine women (median age: 67.5 years; range: 49-88 years). The median survival was 14 months (range 1.5-60 months), with a significant value (P = 0.006). All cases have been histologically confirmed and classified as epithelioid (16 cases), biphasic (seven cases) and sarcomatoid (two cases). AQP-1 high expression has been observed in 16 cases. Comparing AQP-1 high expression to the survival of corresponding patients, a significant association with a slight increased overall survival of 12 months has been demonstrated. Nine patients with a AQP-1 score less than 50% showed a shorter median overall survival (7 months). CONCLUSIONS: AQP-1 high expression is detectable on cytological samples of FE-induced MM with a prognostic value.

Papillary squamous cell carcinoma of the palatine tonsil: a rare cancer of the head and neck.

Papillary squamous neoplasms of the upper respiratory tract are rare variants of squamous cell carcinomas. They are characterised by an exophytic, papillary growth and generally have favourable prognosis. The tumour has been described in the upper aerodigestive tract. In this context, most common sites of involvement are the larynx and hypopharynx, and rarely the oral cavity and oropharynx. The limited studies and small number of published cases of papillary squamous cell carcinoma of the palatine tonsil led us to make a complete analysis of this tumour by analysing the clinical, histological, radiological, virological and therapeutic aspects that are not always present in the literature. A case of papillary squamous cell carcinoma of the palatine tonsil is reported. The lesion (T2N0M0) was located into the left palatine tonsil that hung towards the oral cavity. Both HPV 16 DNA and E6/E7 mRNA were detected in the lesion. The clinicopathological profile of the neoplasm is presented and a comprehensive review of recent literature was made by analysing all aspects of interest of this neoplasm.

Parotid gland involvement in Heerfordt syndrome: a case report.

Sarcoidosis is a multisystemic granulomatous disease characterized by the presence of noncaseating granulomas, the exact etiology of which is yet to be determined. Most of patients show granulomas located in the lungs or in the related lymph nodes. However, lesions can affect any organ. Noncaseating granulomas are not a pathognomonic sign of sarcoidosis, being observed also in other diseases, therefore the diagnosis is often of exclusion. We report a case of sarcoidosis with parotid gland involvement in the context of a Heerfordt syndrome, discussing about its clinical presentation, pathogenesis, pathology and differential diagnosis with other granulomatous diseases.

Nasal metastasis as the first manifestation of a metachronous bilateral renal cell carcinoma.

Renal cell carcinoma is one of the most common tumours to spread by extranodal metastases to the head and neck. Metastatic renal cell carcinoma to the head and neck area has been demonstrated mostly in the paranasal sinuses, parotid gland, the mandible, larynx and hypopharinx. Renal cell carcinoma should be excluded whenever a metastatic lesion is encountered in the head and neck area, even if the metastatic lesion is the first clinical presentation. The diagnosis of metastatic RCC should be suspected in any patient with even a remote history of renal cell carcinoma. We report a case of 79 year old woman with recurrent episodes of rhinorrhea, headache, hyposmia and monolateral right epistaxis, with a history of RCC. We describe RCC nasal metastases in a metachronous bilateral neoplasm, in which a second occult lesion debuted with a homolateral nasal metastases, ten years after left nephrectomy.

The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features.

Spinal neurofibromatosis (SNF) is a related form of neurofibromatosis 1 (NF1), characterized by bilateral neurofibromas (histologically proven) of all spinal roots (and, eventually, of all the major peripheral nerve branches) with or without other manifestations of classical NF1. By rigorous application of these criteria to the 98 SNF cases published, we developed: (i) a cohort of 49 SNF patients (21 males and 28 females; aged 4-74 years]: 9 SNF families (21/49), 1 mixed SNF/NF1 family (1/49) and 27 of 49 sporadic SNF patients (including 5 unpublished patients in this report); and (ii) a group of 49 non-SNF patients including: (a) 32 patients with neurofibromas of multiple but not all spinal roots (MNFSR): 4 mixed SNF/MNFSR families (6/32); (b) 14 patients with NF1 manifestations without spinal neurofibromas, belonging to SNF (8/49) or MNFSR families (6/32); (c) 3 patients with neurofibromas in one spinal root. In addition to reduced incidence of café-au-lait spots (67% in SNF vs 56% in MNFSR), other NF1 manifestations were less frequent in either cohort. Molecular testing showed common NF1 gene abnormalities in both groups. The risk of developing SNF vs NF1 was increased for missense mutations [p = 0.0001; odds ratio (OR) = 6.16; confidence interval (CI) = 3.14-13.11], which were more frequent in SNF vs MNFSR (p = 0.0271).

Anterior, extracanalar, cervical spine osteochondroma associated with DISH: description of a very rare tumor causing bilateral vocal cord paralysis, laryngeal compression and dysphagia. Case report and review of the literature.

INTRODUCTION: Osteochondromas are common benign bone tumors, rarely involving the spine. BACKGROUND: Osteochondroma account for about 35% of bone benign tumors and 9% of all bone tumors. Spinal involvement is described in 1%-4% of cases and their origin from the anterior surface of cervical vertebral bodies is exceedingly rare. AIM: We describe the rare case of an osteochondroma arising from the anterior surface of the C4 and C5 vertebral bodies, and not involving the spinal canal, in a 68-year-old male patient suffering from Diffuse Idiopathic Skeletal Hyperostosis (DISH). MATERIALS AND METHODS: The patient presented with acute onset of respiratory distress due to laryngeal compression exerted by the lesion, dysphagia and paralysis of left vocal cord. Imaging revealed the unusual lesion compressing and dislocating the air ways. An anterior approach to cervical spine was performed to remove the tumor. RESULTS: Postoperatively, the patient sustained a progressive improvement of respiratory function and recovery of the vocal cord paralysis. DISCUSSION: We believe that this case holds some interesting peculiarities: firstly, the anterior location of a cervical osteochondroma could be considered exceptional; yet, the resulting clinical picture should be remembered for differential diagnosis. Secondly, we hypothesized a possible correlation between the tumorigenesis of osteochondroma and the co-existence of DISH. Indeed, the abnormal bone turnover in cervical segments due to DISH could explain the unusual occurrence of osteochondromas in adult age. CONCLUSIONS: The occurrence of an osteochondroma should be considered in patients suffering from DISH and harbouring large osteophytes.

Lipomatous angiomyofibroblastoma of the vulva: diagnostic and histogenetic considerations.

We report a rare case of angiomyofibroblastoma (AMFB) of the vulva, composed predominantly of a mature fatty component, representing approximately 60% of the entire tumour. The tumour, designated as "lipomatous AMFB", should be interpreted as the morphological result of an unbalanced bidirectional differentiation of the presumptive precursor stromal cell resident in the hormonally-responsive stroma of the lower genital tract, with the adipocytic component overwhelming the fibroblastic/myofibroblastic one. The close admixture of adipocytes with spindled/epithelioid cells of the conventional AMFB resulted, focally, in a pseudo-infiltrative growth pattern and pseudo-lipoblast-like appearance, raising problems in differential diagnosis, especially with well-differentiated lipoma-like liposarcoma and spindle cell liposarcoma. Awareness of the possibility that vulvo-vaginal AMFB may contain large amount of lipomatous component is crucial to avoid confusion with other bland-looking spindle cell tumours containing infiltrating fat.

Gastrointestinal stromal tumour of the stomach with osseous differentiation: a case report.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract, while osseous metaplasia of this tumour is an unexpected event. To date, no cases have been reported in the literature. Herein, we report a case of a 60-year-old man affected by a GIST with benign osseous metaplasia and mature bone formation. We also discuss the pathogenesis of intratumoural ossification and review the relevant literature. The prognostic significance of ossification in GIST remains unclear because of the limited cases reported.

A case of sclerosing angiomatoid nodular transformation of the spleen.

Sclerosing angiomatoid nodular transformation of the spleen is a rare benign vascular lesion with extensive sclerosis and unknown aetiology. Although its pathogenesis is not clear, it has been postulated that it may represent a peculiar hamartomatous transformation of red pulp in response to an exaggerated non-neoplastic stromal proliferation. However, it is unclear whether SANT is the end stage of a variety of benign splenic conditions including inflammatory pseudotumour, hamartoma or hematoma. Considering that the lesion is benign, splenectomy is curative. We report a new case of SANT, discussing differential diagnosis, immunohistochemical profile and pathogenesis.

Prognostic value of EGFR expression in de novo and progressed atypical and anaplastic meningiomas: an immunohistochemical and fluorescence in situ hybridization pilot study.

AIM: The aim of this study was to assess both the epidermal growth factor receptor (EGFR) protein expression by immunohistochemistry and the EGFR gene amplification by fluorescence in situ hybridization in meningiomas of different grade, in order to evaluate their possible role in the development of the disease. EGFR protein belongs to the family of tyrosine kinase growth factor receptors, which also includes HER2, HER3 and HER4. Elevated expression or activity of EGFR has been reported in several cancers, including brain tumours. EGFR activation can enhance the malignant potential of epithelial tissues. METHODS: We investigated whether there was a difference in the EGFR protein expression and the EGFR gene amplification between the so called de novo malignant meningiomas and recurrent meningiomas with or without malignant progression from a previously lower grade tumor. Our goal was to evaluate if EGFR expression was a useful marker to select patients affected by meningioma with a major risk of recurrences. We also assessed the prognostic value of the EGFR expression on overall survival. RESULTS: Progression from benign meningiomas to atypical or anaplastic meningiomas correlated with an increase in the expression of EGFR protein. Our study shows that EGFR immunostaining in meningiomas directly correlates to the tumor's grade. The EGFR expression did not correlate with the overall survival and the recurrence-free survival of the patients affected by meningioma (de novo, recurrent and progressed). CONCLUSION: We submit that the EGFR expression is not a useful prognostic element to identify patients with a major risk of meningioma recurrence.

Endometrial carcinoma: MR staging and causes of error.

PURPOSE: This study was undertaken to prospectively determine the diagnostic capabilities of magnetic resonance (MR) imaging in detecting myometrial and cervical invasion and lymph node involvement in endometrial carcinoma and to identify the causes of errors in staging endometrial carcinoma. MATERIALS AND METHODS: Twenty consecutive patients with a histological diagnosis of endometrial carcinoma underwent preoperative MR imaging. MR findings were compared with surgical staging, considered as the standard of reference. RESULTS: In assessing myometrial invasion, MR imaging showed 70% accuracy, 80% sensitivity, 40% specificity, 80% positive predictive value (PPV), and 40% negative predictive value (NPV). In detecting cervical invasion, MR imaging had 95% accuracy, 100% sensitivity, 94.4% specificity, 66.7% PPV, and 100% NPV. In evaluating lymph node involvement, MR imaging showed 100% accuracy, sensitivity, specificity, PPV and NPV. Errors in evaluating myometrial invasion were caused by polypoid tumour, adenomyosis and leiomyomas, whereas those in evaluating cervical invasion were caused by dilatation and curettage. CONCLUSIONS: MR imaging is a reliable technique for preoperative evaluation of endometrial carcinoma. Its main limitation is differentiating between stage IA and IB carcinomas, which is not highly important for surgical planning. Cooperation between the gynaecologist and radiologist is mandatory to avoid staging errors.

A rare location of benign osteoblastoma: case study and a review of the literature.

Osteoblastoma is a solitary, benign bone tumor that is rarely localized in the frontal sinus. It consists of hypocellular mineralized tissue that may form large masses or irregular trabeculae. A 31 year old man came to our attention with a 7 month history of diplopia, photophobia, frontal headhaches and progressive exophthalmos with proptosis of the left eye. The patient was submitted to computed tomography (CT) which allowed to appraise the extension of the lesion. The mass expanded inside the left frontal sinus and the upper ethmoidal cells invading the left orbital roof. Considering the extension of the tumor, the site and the connections with contiguous structures, a combination of endoscopic endonasal technique with intraorbital approach was performed. At histological examination typical features of benign osteoblastoma were observed. The sites of predilection for the tumor are the long bones, vertebral column, and small bones of hands and feet. Its occurrence in the skull and jaw bones is relatively rare and represents only 15% of all osteoblastomas. To our knowledge, only 5 cases of osteoblastoma of the frontal sinus have been previously reported in the English-language literature. This report describes a case of benign osteoblastoma in a rare site, namely, the frontal sinus with particular attention about the differential diagnosis and the treatment.    

An occult spinal neurenteric cyst associated with congenital hemivertebrae. A case report.

We describe a case of an occult spinal neurenteric cyst associated with congenital hemivertebrae. Different intraspinal anomalies, such as neurenteric cysts (representing 0.3 to 0.5 % of all spinal tumors) have been reported in association with congenital hemivertebrae. Indeed, although CT is the best examination to study vertebral anomalies, MRI should be performed in order to exclude a more complex dysraphic condition.

An orbital lymphoma involving the pterygopalatine and infratemporal fossae. A case report.

Lymphoma is the most common malignant orbital tumor. We describe the imaging features of diffuse orbital follicular lymphoma with extension into the pterygopalatine fossa and infratemporal fossa without bony infiltration.