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Chondromyxoid fibroma (CMF) is a rare benign bone tumour. While CMF located entirely on the surface of a bone (i.e. juxtacortical CMF) has been well characterised, CMF has not so far been convincingly documented to arise in soft tissues without connection to an underlying bone.We report a subcutaneous CMF in a 34-year-old male, located on the distal medial aspect of the right thigh without any connection with the femur. The tumour measured 15 mm, it was well-circumscribed and displayed typical morphological features of a CMF. At the periphery, there was a small area of metaplastic bone. Immunohistochemically, the tumour cells were diffusely positive for smooth muscle actin and GRM1, and negative for S100 protein, desmin and cytokeratin AE1AE3. Whole transcriptome sequencing revealed a novel PNISR::GRM1 gene fusion.Our case indicates that CMF should be included in the differential diagnosis of soft tissue (including subcutaneous) tumours composed of spindle/ovoid cells, with a lobular architecture and chondromyxoid matrix. The diagnosis of CMF arising in soft tissues can be confirmed by identifying a GRM1 gene fusion or GRM1 expression by immunohistochemistry.

Giant cell tumor of bone (GCTB) and tenosynovial giant cell tumor (TGCT) share misleadingly similar names, soft texture and brown color macroscopically, osteoclast-like multinucleated giant cells microscopically and localisation in the musculoskeletal system. However, these two tumor types are biologically and clinically two distinct entities with different natural courses of progression and considerably different modes of surgical and medical treatment. In this article, we provide a detailed update on the similarities and the differences between both tumor types. GCTB is a locally aggressive osteolytic bone tumor, commonly seen in patients in their third decade of life. It usually occurs as a solitary lesion in the meta-epiphyseal region of long bones. It can be diagnosed using plain radiographic imaging, CT radiography or MRI to estimate the tumor extent, soft tissue and joint involvement. GCTB is usually treated with intralesional excision by curettage. Systemically, it can be treated with bisphosphonates and denosumab or radiotherapy. TGCT is a rare, slowly progressing tumor of synovial tissue, affecting the joint, tendon sheath or bursa, mostly seen in middle-aged patients. TGCT is usually not visible on radiographs and MRI is mostly used to enable assessment of potential bone involvement and distinguishing between two TGCT types. Localised TGCT is mostly treated with marginal surgical resection, while diffuse TGCT is optimally treated with total synovectomy and is more difficult to remove. Additionally, radiotherapy, intraarticular injection of radioactive isotopes, anti-TNF-α antibodies and targeted medications may be used.

Purpose Desmoid-type fibromatosis (DF) is clonal fibroblastic proliferation that arises in the deep soft tissues, tends to reoccur, and is locally invasive. Desmoid-type fibromatosis of paranasal sinuses with intracranial extension is a rare condition that is even rarer in a small child. We aim to share with the reader our literature review, decision-making, and endoscopic endonasal operation procedure that combined gained us favorable results against this benign tumor with unpredictable natural history and disease course. Case report We describe the decision-making process in the management of a 3-year-old boy with a history of sudden vision loss and vomiting. MR showed an expansive well-delineated homogeneous tumor in the sphenoid sinus with intracranial extension and optic nerves compression. The diagnosis of a sporadic form of desmoid-type fibromatosis was made using genetic testing of tumor tissue. A total gross removal was carried out with endoscopic endonasal microsurgical approach. At a 3-month follow-up, the patient is without any signs of recurrance. Conclusion The treatment of children with desmoid-type fibromatosis requires a multidisciplinary approach by clinicians experienced with the management of pediatric cancer. While the desmoid-type fibromatosis is a benign, locally invasive tumor, observation should be the first step in the management. In case of life-threatening or symptomatic cases, operations that preserve function and structure should be the first choice for this benign tumor with unpredictable natural history and disease course.

Fibroma of tendon sheath (FTS) is an uncommon benign myofibroblastic neoplasm that arises in association with tenosynovial tissue. Fusions of the USP6 gene have been recently documented in a proportion of so-called "cellular FTS" but not in "classic FTS". It remains unknown whether FTS can be defined by a USP6 fusion, regardless of cellularity, and what are USP6 fusion-negative "cellular FTS". Furthermore, FTS with low cellularity seems to be frequently confused with desmoplastic fibroblastoma. We performed a comprehensive analysis, including targeted RNA sequencing, of 58 consecutive cases originally diagnosed as FTS (n = 49), desmoplastic fibroblastoma (n = 6), or nodular fasciitis (n = 3); the latter two at the predilection sites for FTS. After review of the original slides, 28 lesions were morphologically classified as FTS (13 "classic" and 15 "cellular") and 23 as desmoplastic fibroblastoma. Among originally diagnosed FTS at the more cellular end of the spectrum, we identified seven lesions that shared many morphologic features of FTS but, in addition, showed several distinct morphologic features consistent with myofibroma, such as myoid appearance, branching thin-walled vessels, and perivascular growth. Targeted RNA sequencing showed a USP6 fusion in 17 of 18 analyzed FTS, regardless of cellularity, 0 of 5 desmoplastic fibroblastomas and 0 of 4 myofibromas. MYH9, COL1A1, and ASPN were identified as fusion partners in three cases each, and MIR22HG, CTNNB1, SPARC, CAP1, EMP1, LINC00152, NR1D1, and RAB1A in a single case each. FTS, regardless of cellularity, can be defined by a USP6 fusion with a variety of fusion partners. More cellular lesions exhibiting some morphologic features of FTS but lacking a USP6 fusion tend to be myofibromas.

AIMS PRAME (PReferentially expressed Antigen in MElanoma) is a tumour-associated antigen that is preferentially strongly expressed in most cutaneous melanomas but not or only focally in naevi. Our aim was to evaluate PRAME expression in melanocytic lesions of the conjunctiva. METHODS AND RESULTS Surgical specimens of 114 conjunctival melanocytic naevi of different types (including 67 common, 25 combined deep penetrating and 21 inflamed juvenile naevi), 30 invasive melanomas, 10 in-situ melanomas, 23 primary acquired melanoses (PAM) without atypia and 11 PAM with atypia were analysed for PRAME expression by immunohistochemistry. Nuclear positivity for PRAME in melanocytes was assessed as the percentage of positive nuclei: negative (0%), 1+ (1-25%), 2+ (26-50%), 3+ (51-75%) and 4+ (> 75%). In 113 of 114 conjunctival melanocytic naevi, PRAME was either completely negative or focally 1+ positive. Diffuse 4+ PRAME expression was identified in 17 of 30 (57%) invasive melanomas, seven of 10 (70%) in-situ melanomas, four of five (80%) PAM with severe atypia, none of three PAM with moderate atypia, none of three PAM with mild atypia, one of 23 (4%) PAM without atypia and none of 114 naevi. Diffuse 4+ PRAME expression in invasive melanomas correlated with a higher mitotic count but was not related to age and gender of the patients, Breslow thickness, location or mutational status. CONCLUSION Diffuse 4+ PRAME positivity is highly specific for malignant conjunctival melanocytic lesions. PRAME is therefore a useful ancillary marker to support the diagnosis of a suspected conjunctival melanoma.

Aneurysmal (ABC) and simple bone cysts (SBC) have been traditionally distinguished by radiological and histopathological features. However, there is some radiological and histopathological overlap between ABC and SBC. ABC is characterised by USP6 fusions while, recently, NFATC2 fusions have been found in a large proportion of SBC. Identifying these fusions may assist in confirming the diagnosis of either ABC or SBC. To elaborate the potential benefit of molecular testing, we report a prospective series of 19 consecutive bone cysts with comprehensive radiological, histopathological and molecular diagnostics. Integrating radiological, histopathological and molecular findings, 11 cysts were diagnosed as SBC and 8 as ABC. Radiologically, 6 of 11 SBC and 6 of 8 ABC were diagnosed as ABC. Fibrin-like collagen deposits were identified in 8 of 11 (73%) SBC and 3 of 8 (38%) ABC. Nodular fasciitis-like areas were identified in 6 of 8 (75%) ABC and in 7 of 11 (64%) SBC. A USP6 fusion was identified in all 8 ABC, including a novel RBM5-USP6 fusion. An NFATC2 fusion was found in 7 of 11 SBC (FUS-NFATC2 fusion in 5 and EWSR1-NFATC2 in 2 cases). There is radiological and histopathological overlap between SBC and ABC in a significant proportion of cases. A diagnosis of ABC is frequently suggested radiologically in SBC, and fibrin-like deposits, thought to be specific for SBC, may be found in some ABC. Molecular testing may significantly improve diagnostic accuracy in bone cysts.

Intraarticular nodular fasciitis arising in the joint synovium is an uncommon lesion. Most cases have been reported in the knee and rarely in other joints. A USP6 gene fusion has so far been documented in only four cases of intraarticular nodular fasciitis, three were located in the knee and one in the proximal interphalangeal joint. In all three cases located in the knee, MYH9 was detected as a USP6 fusion partner. We analysed three cases of intraarticular nodular fasciitis for the presence of USP6 fusion by targeted RNA sequencing. Two cases were located in the hip (a 25-year-old female and 48-year-old male) and one in the shoulder (a 38-year-old male). We detected a MYH9-USP6 fusion in the two hip cases and a COL1A1-USP6 fusion in the shoulder case. Our findings provide additional evidence that intraarticular nodular fasciitis is a form of nodular fasciitis arising in the joint synovium, harbouring a USP6 fusion. Although a MYH9-USP6 fusion seems to predominate in intraarticular nodular fasciitis, other fusion partners of the USP6 gene may also be involved. Detection of a USP6 fusion by targeted RNA sequencing may assist in confirming the diagnosis in selected cases.

A simple bone cyst (SBC) is a benign bone lesion of unknown etiology. It can be differentiated from an aneurysmal bone cyst (ABC) by radiologic and histopathologic features, as well as by the absence of fusions of the USP6 gene characteristic of an ABC. In an attempt to differentiate between ABC and SBC in a recurrent bone cyst, we performed targeted RNA sequencing and found an EWSR1-NFATC2 fusion and no fusion of the USP6 gene. We subsequently analyzed additional 10 cysts, consistent with SBCs after radiologic-pathologic correlation, for the presence of an NFATC2 gene fusion, by targeted RNA sequencing, reverse-transcription polymerase chain reaction (RT-PCR) and Sanger sequencing, and fluorescent in situ hybridization. Targeted RNA sequencing showed a FUS-NFATC2 fusion in 4 of 11 SBCs and an EWSR1-NFATC2 fusion in 2 of 11 SBCs. No fusion was identified in 3 SBCs and the analysis was not successful in 2 SBCs because of the low quantity or poor quality of isolated RNA. All the 6 fusions detected by targeted RNA sequencing were confirmed by RT-PCR and Sanger sequencing, and 5 of the 6 fusions by fluorescent in situ hybridization. An additional FUS-NFATC2 fusion was identified by RT-PCR, Sanger sequencing, and fluorescent in situ hybridization in 1 of the 3 cases negative for fusions by targeted RNA sequencing. At least a large subset of SBCs represents cystic neoplasms characterized by FUS-NFATC2 or EWSR1-NFATC2 fusions, which also define a group of distinct, rare "Ewing-like" sarcomas that predominantly arise in long bones. Our results provide additional evidence of the existence of benign lesions with FUS-NFATC2 or EWSR1-NFATC2 fusions. Although they can recur locally in a nondestructive manner, their clinical course and possible relation to sarcoma with EWSR1-NFATC2 or FUS-NFATC2 fusion remains to be elucidated.

Objectives To identify dysregulated microRNAs (miRNAs) and their gene targets in temporal arteries from GCA patients, and determine their association with GCA pathogenesis and related arterial wall remodelling. Methods We included 93 formalin-fixed, paraffin-embedded temporal artery biopsies (TABs) from treatment-naïve patients: 54 positive and 17 negative TABs from clinically proven GCA patients, and 22 negative TABs from non-GCA patients. miRNA expression analysis was performed with miRCURY LNA miRNome Human PCR Panels and quantitative real-time PCR. miRNA target gene prediction and pathway enrichment analysis was performed using the miRDB and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases, respectively. Results Dysregulation of 356 miRNAs was determined in TAB-positive GCA arteries, among which 78 were significantly under-expressed and 22 significantly overexpressed above 2-fold, when compared with non-GCA controls. Specifically, TAB-positive GCA arteries were characterized by a significant overexpression of ‘pro-synthetic’ (miR-21-3p/-21-5p/-146a-5p/-146b-5p/-424-5p) and under-expression of ‘pro-contractile’ (miR-23b-3p/-125a-5p/-143-3p/-143-5p/-145-3p/-145-5p/-195-5p/-365a-3p) vascular smooth muscle cell phenotype-associated regulatory miRNAs. These miRNAs targeted gene pathways involved in the arterial remodelling and regulation of the immune system, and their expression correlated with the extent of intimal hyperplasia in TABs from GCA patients. Notably, the expression of miR-21-3p/-21-5p/-146a-5p/-146b-5p/-365a-3p differentiated between TAB-negative GCA arteries and non-GCA temporal arteries, revealing these miRNAs as potential biomarkers of GCA. Conclusion Identification of dysregulated miRNAs involved in the regulation of the vascular smooth muscle cell phenotype and intimal hyperplasia in GCA arterial lesions, and detection of their expression profiles, enables a novel insight into the complexity of GCA pathogenesis and implies their potential utilization as diagnostic and prognostic biomarkers of GCA.

BackgroundDeep penetrating nevus (DPN) is not a widely recognised lesion on the conjunctiva and only a few cases consistent with combined DPN have been reported.MethodsA review of all excised and histopathologically diagnosed conjunctival melanocytic lesions between 2003 and 2018 was performed in order to identify melanocytic nevi morphologically consistent with DPN.ResultsThirty-four DPN were identified among 361 histopathologically examined conjunctival nevi (9.4%), including 33 (97%) combined with a common nevus and 1 (3%) pure DPN. The patients’ age ranged from 7 to 51 years (median, 22 years). Clinically, 21 of 29 (72%) lesions with available data were darkly pigmented, and an increase in size and/or pigmentation was noted in 13 of 18 (72%) lesions with known history. All 24 lesions in which an immunohistochemical analysis was possible were diffusely positive for BRAFV600E (in DPN and common nevus components) and showed a diffuse nuclear positivity for beta catenin and cyclin D1 in the DPN component. None of the 21 lesions with available follow-up data recurred during a follow-up period from 0.3 to 16.3 years (median, 7.5 years).ConclusionsDPN of the conjunctiva is a relatively common lesion and usually presents as a combined nevus. Genetically, DPN of the conjunctiva are characterised by a combination of BRAFV600E mutation and activation of the beta catenin pathway. Recognition of DPN of the conjunctiva is important in order not to overdiagnose it as a melanoma, and to explain its potential atypical clinical features. DPN of the conjunctiva seems to be a benign lesion.

The aggressive nature of malignant gliomas and their genetic and clinical heterogeneity present a major challenge in their diagnosis and treatment. Development of targeted therapy brought attention on detecting novel gene fusions, since they represent promising therapeutic targets (eg, TRK inhibitors in NTRK fusion‐positive tumors). Using targeted next‐generation sequencing, we prospectively analyzed 205 primary brain tumors and detected a novel PTPRZ1‐ETV1 fusion transcript in 11 of 191 (5.8%) gliomas, including nine glioblastomas, one anaplastic oligodendroglioma and one pilocytic astrocytoma. PTPRZ1‐ETV1 fusion was confirmed by RT‐PCR followed by Sanger sequencing, and in‐silico analysis predicted a potential driver role. The newly detected fusion consists of the PTPRZ1 promoter in frame with the highly conserved DNA‐binding domain of ETV1 transcription factor. The ETV1 and PTPRZ1 genes are known oncogenes, involved in processes of tumor development. ETV1 is a member of the ETS family of transcription factors, already known oncogenic drivers in Ewing sarcoma, prostate cancer and gastrointestinal stromal tumors, but not in gliomas. Its overexpression contributes to tumor growth and more aggressive tumor behavior. PTPRZ1 is already considered to be a tumor growth promoting oncogene in gliomas. In 8%–16% of gliomas, PTPRZ1 is fused to the MET oncogene, resulting in a PTPRZ1‐MET fusion, which is associated with poorer prognosis but is also a positive predictive biomarker for treatment with kinase inhibitors. In view of the oncogenic role that the two fusion partners, PTPRZ1 and ETV1, exhibit in other malignancies, PTPRZ1‐ETV1 fusion might present a novel potential therapeutic target in gliomas. Although histopathological examination of PTPRZ1‐ETV1 fusion‐positive gliomas did not reveal any specific or unique pathological features, and the follow‐up period was too short to assess prognostic value of the fusion, careful monitoring of patients and their response to therapy might provide additional insights into the prognostic and predictive value of this novel fusion.

Aneurysmal bone cyst (ABC) is a benign, expansile, multiloculated and blood-filled cystic lesion most commonly involving bones. We report herein the case of a 78-year-old woman with a dermal ABC located in the skin of the right foot. Histologically, the lesion displayed characteristic features of ABC, including blood-filled cystic spaces lined by loose connective tissue, admixed with solid areas composed of spindle cells and osteoclast-like giant cells, associated with foci of woven bone formation and matrix calcification ("blue bone" formation). Fewer than 30 cases of extraosseous ABCs have been described in soft tissues and, to the best of our knowledge, ABC primarily occurring in the skin, not associated with an underlying lesion in the bone, has not so far been reported in the literature.

Aneurysmal bone cyst (ABC) is a benign but locally aggressive, mostly pediatric neoplasm, with characteristic USP6 gene rearrangement that distinguishes it from a secondary ABC and other primary bone tumors. With the advent of next-generation sequencing (NGS) technology, several hitherto unknown USP6 fusion partners have been identified in ABC. Accordingly, we present a case of an 18-year-old male with a solid sub-periosteal primary ABC in the diaphysis of the left femur. Using an NGS-based assay, we identified SPARC-USP6 fusion, which has not previously been described in ABC. Including our case, the list of currently known USP6 fusion partners in primary ABC include: CDH11, CNBP, COL1A1, CTNNB1, EIF1, FOSL2, OMD, PAFAH1B1, RUNX2, SEC31A, SPARC, STAT3 and THRAP3.

Aneurysmal (ABC) and simple bone cysts (SBC) have been traditionally distinguished by radiological and histopathological features. However, there is some radiological and histopathological overlap between ABC and SBC. ABC is characterised by USP6 fusions while, recently, NFATC2 fusions have been found in a large proportion of SBC. Identifying these fusions may assist in confirming the diagnosis of either ABC or SBC. To elaborate the potential benefit of molecular testing, we report a prospective series of 19 consecutive bone cysts with comprehensive radiological, histopathological and molecular diagnostics. Integrating radiological, histopathological and molecular findings, 11 cysts were diagnosed as SBC and 8 as ABC. Radiologically, 6 of 11 SBC and 6 of 8 ABC were diagnosed as ABC. Fibrin-like collagen deposits were identified in 8 of 11 (73%) SBC and 3 of 8 (38%) ABC. Nodular fasciitis-like areas were identified in 6 of 8 (75%) ABC and in 7 of 11 (64%) SBC. A USP6 fusion was identified in all 8 ABC, including a novel RBM5-USP6 fusion. An NFATC2 fusion was found in 7 of 11 SBC (FUS-NFATC2 fusion in 5 and EWSR1-NFATC2 in 2 cases). There is radiological and histopathological overlap between SBC and ABC in a significant proportion of cases. A diagnosis of ABC is frequently suggested radiologically in SBC, and fibrin-like deposits, thought to be specific for SBC, may be found in some ABC. Molecular testing may significantly improve diagnostic accuracy in bone cysts.

Simple Summary Gelsolin amyloidosis is a rare autosomal dominant genetic disease, which typically affects the cornea, skin and sometimes other organ systems and is caused by mutations in a gene coding for gelsolin protein (GSN). We describe a novel mutation of GSN gene, p.Glu580Lys, associated with gelsolin amyloidosis in six members of a two-generation family, who exhibited lattice corneal dystrophy, loose facial skin and irregular heart rhythm. In one patient we reported optic nerve impairment, which is possibly a novel feature associated with gelsolin amyloidosis. Abstract Gelsolin amyloidosis typically presents with corneal lattice dystrophy and is most frequently associated with pathogenic GSN variant p.Asp214Asn. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel GSN variant p.Glu580Lys. We studied DNA samples of seven members of a two-generation family. Exome sequencing was performed in the proband, and targeted Sanger sequencing in the others. The heterozygous GSN variant p.Glu580Lys was identified in six patients. The patients exhibited corneal dystrophy (5/6), loose skin (5/6) and/or heart arrhythmia (3/6) and one presented with bilateral optic neuropathy. The impact of the mutation on the protein structure was evaluated in silico. The substitution is located in the fifth domain of gelsolin protein, homologous to the second domain harboring the most common pathogenic variant p.Asp214Asn. Structural investigation revealed that the mutation might affect protein folding. Histopathological analysis showed amyloid deposits in the skin. The p.Glu580Lys is associated with corneal dystrophy, strengthening the association of the fifth domain of gelsolin protein with the typical amyloidosis phenotype. Furthermore, optic neuropathy may be related to the disease and is essential to identify before discussing corneal transplantation.

Aneurysmal bone cyst (ABC) is a benign but locally aggressive neoplasm, with a tendency for local recurrence. In contrast to other bone tumors with secondary cystic change, ABC is characterized by USP6 gene rearrangement. There is a growing list of known USP6 fusion partners, characterization of which has been enabled with the advent of next-generation sequencing (NGS). The list of known fusion partners includes CDH11, CNBP, COL1A1, CTNNB1, EIF1, FOSL2, OMD, PAFAH1B1, RUNX2, SEC31A, SPARC, STAT3, THRAP3, and USP9X. Using NGS, we analyzed a series of 11 consecutive ABCs and identified USP6 fusions in all cases, providing further evidence that USP6 fusions are universally present in primary ABCs. We identified four novel fusion partners in five ABCs and confirmed them by RT-PCR and Sanger sequencing, ASAP1, FAT1, SAR1A, and TNC (in two cases). Because of high sensitivity and specificity, detection of a USP6 fusion by NGS may assist in differentiating between ABC and its mimics, especially in small biopsy samples when a definite diagnosis cannot be achieved on morphological grounds alone. Further studies with a large number of cases and follow-up are needed to determine whether different fusion partners are associated with specific clinical and pathologic features of ABCs.

IgA vasculitis (IgAV) represents a common systemic vasculitis in pediatric and adult population. Our current knowledge of disease pathogenesis is still very limited, without information on miRNAs in IgAV. The aim of our study was to determine the expression of five pre-selected miRNAs (miRNA-146a-5p, miRNA-148-3p, miRNA-155-5p, miRNA-223-3p, and let-7b) in the affected skin of adult IgAV patients. The study included 65 skin samples from consecutive, untreated IgAV patients (61.5% male, median age 67.6 years, range 29-91), diagnosed between October 2014 and September 2016, and 20 samples of normal skin from healthy volunteers. Total RNA was isolated from tissue sections of formalin-fixed, paraffin-embedded samples. Expression of miRNAs was measured using qRT-PCR. To present relative miRNA expression, the ΔΔCT method was used. Skin miRNA expression was correlated to clinical characteristics of adult IgAV patients. We found significantly higher levels of miRNA-155-5p, miRNA-223-3p, and let-7b in the affected skin compared to controls (18.6-fold, 6.4-fold, and 7.9-fold higher respectively). Contrary, the miRNA 148-3p expression was significantly lower (2.2-fold). The expression of the miRNA-146-5p showed near normal levels. Patients with necrotic skin lesions had significantly higher miRNA-223 tissue expression than those with non-necrotic purpura (p = 0.029). Gastrointestinal tract involvement inversely correlated with the expression of miRNA-155-5p and/or miRNA-146a-5p in affected skin. Altered expression of miRNA-148b-3p, miRNA-155-5p, miRNA-223-3p, and let-7b was found in vasculitic skin lesions in IgAV. Additionally, we found a positive association between the severity of purpura and skin miRNA-223-3p expression. Aberrantly expressed miRNAs could represent a biomarker in adult IgAV.

Giant cell arteritis (GCA) is the most common vasculitis in adults aged ≥ 50 years in Europe. Recently, colour Doppler ultrasonography (CDS) and positron emission tomography-computed tomography (PET/CT) have improved the diagnostic sensitivity. The aim of our study was to determine the incidence of GCA in a well-defined Slovenian region, supported by the temporal artery (TA) biopsy (TAB) or CDS or PET/CT. This prospective study was conducted at the University Medical Centre Ljubljana, the only secondary/tertiary centre in the region, serving a population of 323,297 residents aged ≥ 50 years. Patients with suspected GCA are referred either to the Department of Rheumatology, or in case of severe visual disturbances, to the Department of Ophthalmology. We included all GCA cases diagnosed between 1 January 2012 and 31 December 2017. We diagnosed cranial GCA (c-GCA) using the American College of Rheumatology (ACR) 1990 classification criteria and a positive TAB or TA-CDS. Large vessel GCA (lv-GCA) was diagnosed using CDS or PET/CT. During the 6-year observation, we identified 169 incipient GCA cases (66.3% female, median (IQR) age of 75.1 (68.6-80.0) years). Forty-two (24.8%) patients had lv-GCA, and the others had c-GCA. The estimated annual incidence rates of GCA were overall 8.7 (95% CI 7.5-10.1), c-GCA 6.5 (95% CI 5.5-7.8) and lv-GCA 2.2 (95%CI 1.6-2.9) per 100,000 aged ≥ 50 years. GCA is the most common vasculitis in adults aged ≥ 50 years, with an annual incidence rate of 8.7 per 100,000.

The expression of p16/CDKN2A, the second most commonly inactivated tumour suppressor gene in cancer, is lost in the majority of chordomas. However, the mechanism(s) leading to its inactivation and contribution to disease progression have only been partially addressed using small patient cohorts. We studied 384 chordoma samples from 320 patients by immunohistochemistry and found that p16 protein was lost in 53% of chordomas and was heterogeneously expressed in these tumours. To determine if CDKN2A copy number loss could explain the absence of p16 protein expression we performed fluorescence in situ hybridisation (FISH) for CDKN2A on consecutive tissue sections. CDKN2A copy number status was altered in 168 of 274 (61%) of samples and copy number loss was the most frequent alteration acquired during clinical disease progression. CDKN2A homozygous deletion was always associated with p16 protein loss but only accounted for 33% of the p16‐negative cases. The remaining immunonegative cases were associated with disomy (27%), monosomy (12%), heterozygous loss (20%) and copy number gain (7%) of CDKN2A, supporting the hypothesis that loss of protein expression might be achieved via epigenetic or post‐transcriptional regulatory mechanisms. We identified that mRNA levels were comparable in tumours with and without p16 protein expression, but other events including DNA promoter hypermethylation, copy number neutral loss of heterozygosity and expression of candidate microRNAs previously implicated in the regulation of CDKN2A expression were not identified to explain the protein loss. The data argue that p16 loss in chordoma is commonly caused by a post‐transcriptional regulatory mechanism that is yet to be defined.

AIMS IgA vasculitis (IgAV) is a common small-vessel systemic vasculitisthat is histologically characterised by granulocyte infiltration and IgA deposition in vessel walls. Information on microRNA (miRNA) involvement inIgAVis limited. The aim of this study was to analyse the association between histopathological changes and expression profiles of 14 miRNAs in the affected skin of 70 adult patients with IgAV. METHODS AND RESULTS miRNA expression analysis was performed by quantitative real-time polymerase chain reaction and evaluation of histopathological changes by light and immunofluorescence microscopy on formalin-fixed paraffin-embedded skin excision samples. In IgAV-affected skin, granulocyte infiltration was significantly associated with vessel fibrinoid necrosis. Of the analysed miRNAs, four showed two-fold increased expression (let-7d, let-7f, miR-21-5p, and miR-203-3p), five showed five-fold increased expression (let-7b, miR-17-5p, miR-155-5p, miR-423-5p, and miR-451a), and threeshowed 15-fold increased expression (let-7a, miR-21-3p, miR-223-3p), as compared with controls (all P

The aim of the paper is to give an update on molecular genetic aberrations in Spitz melanocytic proliferations with special em- phasis on their correlation with morphological features and biological behavior. The Spitz group of melanocytic proliferations is defined by a combination of distinctive morphological features and driver molecular genetic events. Morphologically, these neoplasms are characterized by large, oval, polygonal, or spindled melanocytes with abundant eosinophilic cytoplasm, vesicular nuclei with prominent nucleoli, often in association with epidermal hyperplasia. Molecular aberrations in Spitz melanocytic proliferations can be divided into two main groups, according to the driver genetic change: 1) 11p amplification/HRAS muta- tion, present in about 20% of cases, and 2) kinase fusions, present in about 50%, further subdivided into tyrosine kinase fusions (ALK, ROS1, NTRK1, NTRK3, MET, RET) or serine-threonine kinase fusions (MAP3K8, BRAF). Driver genetic aberrations can be detected along the whole biological spectrum of Spitz melanocytic proliferations, and are mutually exclusive. Although driver genetic aberrations enable proliferation of melanocytes, additional genetic events (often biallelic inactivation of CDKN2A and TERT promoter mutations) are necessary for the development of overt Spitz malignancy.Conclusions. Recent studies have demonstrated that certain driver genetic aberrations are more often associated with the benign spectrum of Spitz melanocytic proliferations and indolent biological behavior (11p amplification/HRAS mutation, tyrosine kinase fusions). In contrast, some driver aberrations are more frequent in the atypical/malignant spectrum of Spitz melanocytic proliferations with a potential for aggressive biological behavior (serine-threonine kinase fusions). In addition, certain driver aberrations are often associated with distinctive morphological features. However, none of the morphological features is entirely specific for any of these driver genetic aberrations. Immunohistochemistry for ALK, ROS1, and pan-TRK can be used for screening purposes to detect cor- responding fusion proteins.

Gelsolin amyloidosis typically presents with corneal lattice dystrophy and is most frequently associated with pathogenic GSN variant p.Asp214Asn. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel GSN variant p.Glu580Lys. We studied DNA samples of seven members of a two-generation family. Exome sequencing was performed in the proband, and targeted Sanger sequencing in the others. The heterozygous GSN variant p.Glu580Lys was identified in six patients. The patients exhibited corneal dystrophy (5/6), loose skin (5/6) and/or heart arrhythmia (3/6) and one presented with bilateral optic neuropathy. The impact of the mutation on the protein structure was evaluated in silico. The substitution is located in the fifth domain of gelsolin protein, homologous to the second domain harboring the most common pathogenic variant p.Asp214Asn. Structural investigation revealed that the mutation might affect protein folding. Histopathological analysis showed amyloid deposits in the skin. The p.Glu580Lys is associated with corneal dystrophy, strengthening the association of the fifth domain of gelsolin protein with the typical amyloidosis phenotype. Furthermore, optic neuropathy may be related to the disease and is essential to identify before discussing corneal transplantation.

Summary A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reversetranscriptase–polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.

Background:Immunopathology of giant cell arteritis (GCA) results from dysregulated interactions between arterial wall-resident non-immune cells, e.g. vascular smooth muscle cells (VSMCs), and components of the immune system [1]. In spite of several efforts at identifying microRNAs (miRNAs) implicated in the pathogenesis of GCA, the overall information on miRNA involvement in GCA and its related arterial fibro-sclerotic alterations remains scarce.Objectives:To analyze miRNA expression and identify target genes of dysregulated miRNAs in temporal arteries from GCA patients, and to determine their association with GCA-associated arterial wall remodeling.Methods:The study included formalin-fixed, paraffin-embedded temporal artery biopsies (TABs) from 71 clinically diagnosed treatment-naïve patients fulfilling the ACR 1990 classification criteria, and 22 non-GCA subjects (control group). Of GCA patients, 54 histologically positive and 17 histologically negative TABs were included. miRNA expression profiling was performed with quantitative real-time PCR (qPCR)-based miRNA PCR panels and qPCR. The miRDB database and STRING protein-protein network analysis were used for identification of miRNA gene targets and their pathway enrichment analysis, respectively.Results:Of 356 detected miRNAs, we determined significant under-expression of 78 and significant over-expression of 22 miRNAs (≥ 2-fold; p < 0.05) in TAB-positive GCA arteries compared to non-GCA controls, pointing to a strong dysregulation of miRNA expression in inflamed GCA arteries. Several dysregulated miRNAs targeted genes involved in the ubiquitin-proteasome system and the RNA silencing complex, suggesting a novel role of these pathways in GCA. qPCR validation confirmed a 1.9–14.2-fold (p < 0.001) over-expression of “pro-synthetic” (miR-21-3p/-21-5p/-146a-5p/-146b-5p/-424-5p) and 3.4–9.4-fold (p < 0.001) under-expression of “pro-contractile” (miR-23b-3p/-125a-5p/-143-3p/-143-5p/-145-3p/-145-5p/-195-5p/-365a-3p) VSMC phenotype-associated regulatory miRNAs in TAB-positive GCA arteries. These miRNAs targeted gene pathways involved in the arterial remodeling and regulation of the immune system, and their expression significantly correlated with the extent of intimal hyperplasia in TABs from GCA patients (p ≤ 0.015). Additionally, the expression of miR-21-3p/-21-5p/-146a-5p/-146b-5p/-365a-3p differentiated TAB-negative GCA arteries from non-GCA temporal arteries, making these miRNAs potential biomarkers of GCA.Conclusion:Our study demonstrated an extensive dysregulation of arterial miRNA networks in GCA, favoring the pathogenic switch in the VSMC phenotype and associated intimal hyperplasia. We identified several miRNAs, which could represent potential novel GCA biomarkers. Furthermore, our results imply that the ubiquitin-proteasome system and the RNA silencing complex are targets of dysregulated arterial miRNA networks in GCA lesions, providing new insight into the complexity of GCA pathogenesis.References:[1]Weyand CM, Goronzy JJ. Immune mechanisms in medium and large-vessel vasculitis. Nat Rev Rheumatol 2013;9:731–40.Acknowledgments:This work was supported by the Slovenian Research Agency [research core funding No. P3-0054].Disclosure of Interests:None declared

Background Giant cell arteritis (GCA) represents the most common vasculitis in adults over age of 50 years in Europe. Recently the diagnostic options greatly improved with the implementation of imaging techniques such as colour Doppler ultrasonography (CDS) and positron emission tomography-computed tomography (PET/CT). Objectives The aim of our single centre prospective study was to determine the incidence of GCA in well-defined Slovenian region, based on the temporal artery (TA) biopsy (TAB) and/or the result of CDS and/or PET/CT. Methods The study was conducted at University medical centre Ljubljana (UMC Ljubljana), that represents the only secondary/tertiary centre in a region, serving a population of 3 23 297 residents aged 50 years or more (1 76 104 females and 1 47 193 males). Patients with suspected GCA are referred either to the Department of Rheumatology, or in case of severe visual disturbances, to the Department of Ophthalmology. In the analysis we included all GCA cases diagnosed between 1 January 2012 and 31 December 2017. The diagnosis of cranial GCA (c-GCA) was established with the help of American College of Rheumatology (ACR) 1990 classification criteria, positive TAB and/or TA CDS. Cases of extracranial large vessel vasculitis (lv-GCA) were diagnosed using CDS of branches of the aortic arch and/or PET-CT. Results During the six-year observation we identified 169 new GCA cases (66.3% females), with a median (IQR) age of 75.1 (68.6–80.0) years. Forty-two (24.8%) patients had lv-GCA, and the others had c-GCA. One-hundred and thirty-nine patients (24 lv-GCA and 115 c-GCA) fulfilled ACR 1990 classification criteria. The others patients had positive arterial CDS or PET-CT (18 CDS, 9 CDS and PET-CT, 3 PET-CT). TAB was performed in 119 patients and was positive in 88.2%. Clinical characteristics of our GCA cases are presented in table 1. The estimated annual incidence rate of GCA was 8.7 per 1 00 000 adults aged ≥50 years (95% CI 7.5–10.1), in c-GCA 6.5 per 100.000 adults aged ≥50 years (95% CI 5.5–7.8) and in lv-GCA 2.2 per 100.000 aged ≥50 years (95% CI 1.6–2.9). Conclusions GCA is the most common vasculitis in adults aged 50 years or above, with an annual incidence rate of 8.7 per 100.000. c-GCA is nearly 3 times more common than lv-GCA. Disclosure of Interest None declared

PURPOSE Rejection is the leading cause of failure of limbal allogafts. Resident dendritic cell (DC) maturation plays a critical role in host allosensitization. There are two lineages: myeloid (mDC) and lymphoid (pDC), with different biological properties. The aim was to analyse the distribution of DC subtypes in limbal explant cultures on amniotic membrane (AM), cultivated on either the epithelial or stromal side and to compare the results with directly isolated cells from cadaveric whole corneoscleral tissue divided into specific areas. METHODS The expression of CD11c (mDC), CD303/CD123 (pDC) and costimulatory molecules CD80, CD86 and activation markers HLA-DR, CD83 was investigated by flow cytometry. Additionally, the corneal epithelium marker CK12 and ABCB5, a new epithelial stem cell marker, were investigated. RESULTS Cells positive for pDC and mDC markers were found in all examined areas, with a nonsignificant prevalence of pDC. In limbal explant cultures on AM, the percentage of pDC and mDC was similar, with no statistically significant difference between cultures on epithelial or stromal sides of AM. However, with ex vivo limbal explant cultivation on AM, the pDC content declined significantly (p

Malignant pleural mesothelioma is an incurable cancer strongly associated with asbestos exposure and characterised by poor response to treatment. The inhibitor-of-apoptosis protein family member survivin is involved in apoptosis and proliferation and is expressed in cancer cells only. The aims of the present study were to elucidate whether survivin expression is associated with tumour cell apoptosis and proliferation and to assess the prognostic and predictive value of survivin expression in malignant pleural mesothelioma. Archival pleural mesothelioma tissue samples from 101 patients were immunohistochemically analysed for nuclear expression of survivin, for proliferation with the use of Ki-67 as marker and for apoptosis using active caspase-3 as a marker. Staining results and clinical data were included in a survival analysis. Survivin was highly expressed in tumour cell nuclei in all samples and this correlated positively with both apoptosis and proliferation, but did not have a significant prognostic value. We found significantly higher survivin expression in patients who responded to chemotherapy compared to patients with progressive disease. Survivin expression might contribute to treatment response prediction, but survivin expression in malignant pleural mesothelioma did not have prognostic significance.

Context.—The 2015 outbreak of Zika virus in Brazil resulted in a 20-times increased prevalence of congenital microcephaly in stillborns and neonates and was instrumental in raising the suspicion of a causal association between Zika virus and microcephaly. Objective.—To provide a comprehensive description of the neuropathologic features of congenital Zika virus infection. Design.—Autopsy evaluation of the brain from a fetus of 32 weeks and 6 days of gestation, with a prenatal diagnosis of microcephaly associated with polymerase chain reaction–confirmed, fetal, Zika virus infection. Results.—Multiple severe pathology findings were present. These included lissencephaly, except for the occipital lobes, where some pachygyria was observed. Also present was reduction and thinning of white matter, ventriculomegaly of the lateral ventricles, and coalescent calcifications in the cortical-subcortical white matter border associated with glioneuronal outbursting into the subarachnoid space above and heterotopias below. There were small, scattered calcifications in the basal ganglia, with fewer in the white matter and germinal matrix, and none in the cerebellum and brainstem. The cerebellum and pontine base were atrophic because of Wallerian degeneration or maldevelopment of descending tracts and pontocerebellar connections. Conclusion.—Our findings are in agreement with neuroimaging of Zika virus–associated fetal and infant micrencephalic brains and, to some extent, with neuroimaging of other intrauterine infections causing microcephaly.

Background Eczematous (spongiotic) reaction in melanocytic lesions (Meyerson's phenomenon) has not been systematically analyzed and has not been convincingly documented in melanoma. Methods We analyzed 64 consecutive melanocytic lesions with spongiotic reaction, occurring in 57 patients (age range 14–81 years; mean, 39 years; 30 females, 27 males) including 16 common acquired nevi, 3 nevi with congenital features, 2 Spitz nevi, 29 dysplastic nevi, 6 in situ and 8 invasive melanomas. Results The intensity of the spongiotic reaction was graded as mild in 24 (38%), moderate in 22 (34%) and marked in 18 (28%) lesions. It was moderate/marked in 6 of 14 (43%) in situ or invasive melanomas. Upward migration of melanocytes in the epidermis was noted in 7 (33%) non-dysplastic and 10 (34%) dysplastic nevi but was generally limited to the lower half of the epidermis. Moderate/severe cytologic atypia was found in 14 (48%) dysplastic nevi and all melanomas but not in non-dysplastic nevi. Conclusions Prominent spongiotic reaction with eosinophils in the inflammatory infiltrate can affect all types of melanocytic lesions. Upward migration involving the uppermost layers of the epidermis, especially when extensive and present in areas with a less pronounced spongiotic reaction, and moderate/severe cytologic atypia indicate a melanoma.

The authors report 2 cases of cutaneous pseudolymphoma that occurred in 2 young adult patients who referred for relentlessly growing nodules that appeared within 4 to 5 months after the application of a mercury-based tattoo. Systemic symptoms were not present and there was no evidence of lymph node enlargement. Clinically, both lesions were limited to the red, mercury-based areas of the tattoo. Microscopic examination featured a dense cellular infiltrate composed of polytypic T cells in the upper to mid-dermis, coupled with focal interface tissue reaction. Scattered macrophages contained finely granular particles in their cytoplasm. In addition, extracellular pigment particles were also recognized. Collections of epithelioid macrophages were present in both cases and were reminiscent of epithelioid granulomas. This study confirms evidence that, among skin diseases featuring a dense lymphoid infiltrate, cutaneous pseudolymphoma secondary to tattooing is a rare but not exceptional source of diagnostic challenges.

Objective To determine the prevalence of a broad spectrum of human papillomavirus (HPV) types in conjunctival papillomas and a possible difference in clinical and histopathological presentation of HPV-positive and HPV-negative papillomas. Methods Formalin-fixed, paraffin-embedded papilloma tissue specimens obtained from 25 patients were analysed using six different PCR-based methods targeting 87 HPV types from four different papillomavirus (PV) genera: α-PV, β-PV, γ-PV and µ-PV, and in situ hybridisation for HPV-6/HPV-11. Slides were reviewed for pedunculated or sessile growth, the presence of goblet cells, keratinising or non-keratinising epithelium, elastosis, atypia and koilocytes. Results α-PV types HPV-6 and HPV-11 were detected in 19/25 (76%) conjunctival papilloma tissue specimens, 9 (47%) of which were also HPV-6/HPV-11 positive with in situ hybridisation. Six different β-PV types—HPV-9, HPV-12, HPV-20, HPV-21, HPV-22, HPV-24—were additionally detected in four cases, all of which were also HPV-6/HPV-11 positive. No γ-PVs or µ-PVs were found in any of the tested tissues samples. Extralimbal location (p=0.021), presence of goblet cells (p=0.005), non-keratinising squamous epithelium (p=0.005), and absence of elastosis (p=0.005) were associated with the presence of HPV-6/HPV-11. Conclusions We demonstrated that certain clinical and histological features are more frequently associated with HPV infection and that HPV genera other than α-PV are most probably not significant factors in conjunctival papilloma occurrence.

In 2013, the WHO revised the terminology for the family of lesions previously described as giant cell tumor of the tendon sheath and pigmented villonodular synovitis. The correct current terminology is tenosynovial giant cell tumors, further subclassified by the extent (localized or diffuse) and location (intraor extraarticular) [1]. Intraarticular lesions are usually monoarticular and usually affect the knee [2]. The localized intraarticular lesion was formerly termed as localized pigmented villonodular synovitis. The diffuse intraarticular diffuse type affects the entire joint synovium, and patients typically present with a long history of pain, swelling, restricted movement and occasional hemarthrosis [2, 3]. Localized intraarticular tenosynovial giant cell tumor is characterized by limited involvement of the synovium presenting as an intraarticular nodule or mass, which can result in mechanical symptoms, including locking, as presented in our case [2, 4]. Localized intraarticular tenosynovial giant cell tumor of the knee is usually located in the meniscocapsular junction, anterior tibial eminence, intercondylar notch region or lateral recesses. It is rarely located in the fat pad, medial femoral condyle, mediopatellar synovial plica or inside a popliteal cyst [2, 3]. Infrequently, the pedicle can be subject to torsion, resulting in tumor infarction [2]. Our patient suffered from sudden knee pain with movement limitation. A radiograph revealed a persistent secondary ossification center of the tibial tuberosity; however, this was considered irrelevant to his clinical symptoms (Fig. 1 testyourself question). An immediate MR imaging examination confirmed a nodular lesion in the anterior aspect of the femorotibial joint, which was predominantly hypointensive on PD and PD fat-suppressed images, with profoundly hypointensive signal on GRE images (Fig. 2 test-yourself question), consistent with a hemosiderin-laden lesion [4–6]. Additional MR imaging sequences were performed the following morning after resolution of the patient’s symptoms, presumed to be due to spontaneous relocation of the nodule, for further lesion characterization and included T1W, T2W and enhanced fat-suppressed T1W images (Fig. 3 testyourself question). Decreased signal intensity was again seen with a prominent peripheral rind of enhancement and mild inner enhancement [2, 4, 5, 7]. The diagnosis of intraarticular localized tenosynovial giant cell tumor was suggested, and the mass was subsequently removed arthroscopically [2, 3, 7]. Arthroscopy confirmed a pedunculated lesion arising beneath the synovial surface with histology demonstrating synoviallike mononuclear cells, scattered osteoclast-like cells, siderophages and areas of hemosiderin deposition (Fig. 4 test-yourself question). As described, localized intraarticular tenosynovial giant cell tumor can present with transient knee locking, which typically suggests a differential diagnosis that includes meniscal lesions, chondral lesions and loose bodies [2, 7]. MR imaging was indispensable in this case, showing a hemosiderin-laden nodule in Hoffa’s fat. Localized intraarticular lesions such as synovial hemangioma, synovial lipoma, ganglion, a multifocal synovial chondromatosis or primary intraarticular The case presentation can be found at doi:10.1007/s00256-015-2287-1.

Whereas the pigmented (melanotic) variant of diffuse neurofibroma (DNF) with positivity for melanocytic markers is well recognized, expression of melanocytic markers in nonpigmented DNF has not been systematically studied. We analyzed 28 unselected consecutive DNFs for expression of melanocytic markers, including melan A, microphthalmia transcription factor (MITF), and HMB-45 antigen. For comparison, we also analyzed 40 localized skin neurofibromas and 7 intraneural neurofibromas. One case of nonpigmented DNF was analyzed by electron microscopy. Of the 28 DNFs studied by immunohistochemistry, 3 were pigmented and 25 nonpigmented. The 3 pigmented DNFs and 9 of 25 (36%) nonpigmented DNFs expressed melan A, MITF, and HMB-45 antigen. These markers were expressed either focally or more diffusely, typically in a minority of the lesional cells, and usually both in the dermal and subcutaneous portion of the DNF. Melan A was expressed in the largest number of the lesional cells (up to 50%), whereas only a small fraction of the melan A-positive cells (from 5% to 10% in most cases) also expressed HMB-45 antigen. None of the 47 non-DNFs expressed these markers. Ultrastructurally, melanosomes were present in some cells in nonpigmented DNF that expressed the melanocytic markers. Twenty-three of 28 (82%) DNFs, including 10 of 12 (83%) DNFs with melanocytic differentiation, were associated with neurofibromatosis type 1. Expression of melanocytic markers, including melan A, HMB-45 antigen, and MITF in DNF is a potential pitfall in differential diagnosis with melanocytic lesions that may clinically or histopathologically resemble DNF, in particular congenital melanocytic nevus with neurotization and neurofibroma-like melanoma.

Intraarticular nodular fasciitis is a rare lesion that has only recently been recognised. We present a case of intraarticular nodular fasciitis of the hip joint in a 25-year-old woman, who presented with a 9-month-history of right groin pain and a decreased range of right hip motion. A polypoid mass, composed of five nodules attached to the synovial membrane of the distal peripheral compartment of the hip was removed arthroscopically, together with two detached nodules. Histopathological examination revealed a myofibroblastic proliferation typical of nodular fasciitis. Complete resolution of symptoms and restoration of function was achieved, without recurrence 2 years after removal of the lesion. To the best of our knowledge, this is the first case of intraarticular nodular fasciitis of the hip, presenting a new indication for arthroscopic treatment.

Eczematous (spongiotic) reaction in melanocytic lesions (Meyerson's phenomenon) has not been systematically analyzed and has not been convincingly documented in melanoma.We analyzed 64 consecutive melanocytic lesions with spongiotic reaction, occurring in 57 patients (age range 14-81 years; mean, 39 years; 30 females, 27 males) including 16 common acquired nevi, 3 nevi with congenital features, 2 Spitz nevi, 29 dysplastic nevi, 6 in situ and 8 invasive melanomas.The intensity of the spongiotic reaction was graded as mild in 24 (38%), moderate in 22 (34%) and marked in 18 (28%) lesions. It was moderate/marked in 6 of 14 (43%) in situ or invasive melanomas. Upward migration of melanocytes in the epidermis was noted in 7 (33%) non-dysplastic and 10 (34%) dysplastic nevi but was generally limited to the lower half of the epidermis. Moderate/severe cytologic atypia was found in 14 (48%) dysplastic nevi and all melanomas but not in non-dysplastic nevi.Prominent spongiotic reaction with eosinophils in the inflammatory infiltrate can affect all types of melanocytic lesions. Upward migration involving the uppermost layers of the epidermis, especially when extensive and present in areas with a less pronounced spongiotic reaction, and moderate/severe cytologic atypia indicate a melanoma.

Background: The impact of the number of sections used in cervical excision biopsies of transformation zone on sensitivity of histological detection of cervical cancer is poorly documented. Aim: To assess whether different techniques of sectioning cervical excision biopsies in 2 European laboratories influence the finding of cervical cancer by histopathological examination. Materials and Methods: The routine assessment at the Department of Histopathology and Cytology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK (Sheffield), encompassed sectioning a cone in 3-mm tissue blocks and cutting 3 levels per block. At the Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia (Ljubljana), cones were cut in a 3- to 4-mm-thick tissue block, and 10 levels were cut per block, spaced every 100 μm. The number of blocks and levels per block were assessed for each cone. Histopathological detection of cervical carcinoma between the laboratories was compared. Results: Among 820 cones in the Sheffield laboratory, we detected 35 invasive carcinomas, whereas 6 invasive carcinomas were detected among 94 cones in the Ljubljana laboratory. Although the Slovenian laboratory examined a significantly larger number of levels per cone biopsy (64 vs 24 in Sheffield), this was not associated with a larger proportion of invasive cervical carcinoma, especially foci of stage IA1 or high-grade cervical intraepithelial neoplasia diagnosed on excision biopsies: 6.4% of invasive cervical carcinomas (5 [83.3%] of stage IA1) in Ljubljana and 4.3% (30 [85.7%] of stage IA1) in Sheffield laboratory (P > 0.05); 71.2% of high-grade cervical intraepithelial neoplasia in Ljubljana and 75.5% in Sheffield (P > 0.05). Conclusions: Our assessment showed that a method with a large number of levels per cervical cone or large loop excision of the transformation zone biopsy did not increase sensitivity for the detection of cervical cancer. However, extensive sectioning substantially affects the pathologist9s workload, and this may need to be reconsidered.