Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations.

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Calcifying Spindle Cell Soft Tissue Tumor With SOX10::PLAG1 Fusion: A Case Report of a Morphologically Distinctive and Potentially Novel Soft Tissue Tumor.

The widespread use of advanced molecular techniques has led to the identification of several tumor types with PLAG1 gene fusions some of which also affect the skin and soft tissues. Herein, we present a 38-year-old female with a subcutaneous tumor affecting her forearm, which does not seem to fit into any currently recognized entity. It was a well-circumscribed tumor measuring 6 × 4,5 × 4 cm. It had a thick capsule composed of bland spindle cells forming palisades and Verocay body-like structures within a myxocollagenous background. Scattered calcifications were dispersed throughout the lesion. No cytological atypia, mitotic activity, or necrosis were present. Targeted NGS revealed a SOX10::PLAG1 fusion and fluorescent in situ hybridization confirmed the presence of PLAG1 gene rearrangement. The neoplastic cells showed a diffuse immunohistochemical expression of S100, SOX10, and PLAG1, as well as patchy desmin and CD34 positivity. The methylation profile of this tumor did not match any other entity covered by the DKFZ sarcoma classifier and apart from the gain of chromosome 12, the copy number profile was normal. The tumor was completely excised, and the patient has been free of disease for 4 years since the excision. While more cases are needed to confirm this tumor as a distinct entity, we propose a provisional name "SOX10::PLAG1-rearranged calcifying spindle cell tumor."

Differential cyclin-E1 expression in CIC-rearranged sarcoma.

CIC-rearranged sarcoma (CRS) is a group of high-grade undifferentiated small round cell sarcomas examined as a separate entity in the current WHO classification; since it shows more aggressive clinical behavior and distinct morphological and molecular features compared to Ewing sarcoma (ES). As CCNE1 expression is associated with tumor growth in CIC::DUX4 sarcomas, we aimed to demonstrate the value of cyclin E1 expression in CRS. Cyclin E1 immunohistochemistry and break-apart FISH for EWSR1 and CIC gene rearrangements were performed on 3-mm tissue microarrays composed of 40 small round cell tumors. Five cases were classified as CRS, whereas 22 were ES and 13 were unclassified (EWSR1-/CIC-). Among all three diagnostic groups, we found cyclin E1 expression level to be higher in CRS (80 %) and unclassified groups (61.5 %) compared to ES (4.5 %, p < 0.001). In addition, high cyclin E1 expression levels were associated with higher mean age at diagnosis, presence of atypical histology and myxoid stroma, low CD99 expression, and presence of metastasis at diagnosis. The sensitivity and specificity of high cyclin E1 expression in detecting non-ES cases were 95.5 % and 66.7 %, respectively. However, the correlation between cyclin E1 expression level and survival was not statistically significant. This is the first study that shows cyclin E1 immunohistochemical expression in EWSR1-negative undifferentiated small cell sarcomas, particularly CRS.

Can endocan serve as a molecular "hepatostat" in liver regeneration?

BACKGROUND: Intriguingly, liver regeneration after injury does not induce uncontrolled growth and the underlying mechanisms of such a "hepatostat" are still not clear. Endocan, a proteoglycan, was implicated in liver regeneration. It can support the function of hepatocyte growth factor/scatter factor in tissue repair after injury. Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, may modulate the cessation of liver regeneration. eEF2K, a protein kinase that regulates protein synthesis, can regulate angiogenesis. Thus, we investigated the role of endocan, endostatin and eEF2K during normal liver regeneration. METHODS: Serum samples and regenerating remnant liver tissues were obtained on various days after partial hepatectomy in rats. mRNA expression levels of Vegf and Pcna were analyzed in addition to immunohistochemical evaluations. Liver tissue protein levels of endostatin, endocan and p-eEF2K/eEF2K were determined with Western blot. Serum levels of endostatin and endocan were assessed with ELISA. RESULTS: Pcna expression level in residual liver tissues peaked on day-1, while Vegf expression reached its highest level on days 1-3 after partial hepatectomy (70%). Endocan activity declined gradually on days 1-7. The decrease in liver endocan expression was accompanied by an increase in serum endocan levels. Partial hepatectomy induced a rapid increase in liver endostatin levels. Following its surge on day-1, endostatin expression gradually declined, which was accompanied by a peak in serum endostatin. Finally, partial hepatectomy was shown to regulate eEF2K; thus, increasing protein translation. CONCLUSIONS: We revealed possible mechanistic insights into liver regeneration by examining the associations of Pcna, Vegf, endocan, endostatin, eEF2K with hepatic regeneration after partial hepatectomy. Indeed, endocan might serve as a useful biomarker to monitor clinical prognosis in a plethora of conditions such as recovery of donor's remaining liver after living-donor liver transplant. Whether endocan might represent a strategy to optimize liver regeneration when given therapeutically needs to be investigated in future studies.

EWSR1::POU2AF3(COLCA2) Sarcoma: An Aggressive, Polyphenotypic Sarcoma With a Head and Neck Predilection.

EWSR1::POU2AF3 (COLCA2) sarcomas are a recently identified group of undifferentiated round/spindle cell neoplasms with a predilection for the head and neck region. Herein, we report our experience with 8 cases, occurring in 5 men and 3 women (age range, 37-74 years; median, 60 years). Tumors involved the head/neck (4 cases), and one each the thigh, thoracic wall, fibula, and lung. Seven patients received multimodal therapy; 1 patient was treated only with surgery. Clinical follow-up (8 patients; range, 4-122 months; median, 32 months) showed 5 patients with metastases (often multifocal, with a latency ranging from 7 to 119 months), and 3 of them also with local recurrence. The median local recurrence-free and metastasis-free survival rates were 24 months and 29 months, respectively. Of the 8 patients, 1 died of an unknown cause, 4 were alive with metastatic disease, 1 was alive with unresectable local disease, and 2 were without disease. The tumors were composed of 2 morphologic subgroups: (1) relatively bland tumors consisting of spindled to stellate cells with varying cellularity and fibromyxoid stroma (2 cases) and (2) overtly malignant tumors composed of nests of "neuroendocrine-appearing" round cells surrounded by spindled cells (6 cases). Individual cases in the second group showed glandular, osteogenic, or rhabdomyoblastic differentiation. Immunohistochemical results included CD56 (4/4 cases), GFAP (5/8), SATB2 (4/6), keratin (AE1/AE3) (5/8), and S100 protein (4/7). RNA sequencing identified EWSR1::POU2AF3 gene fusion in all cases. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization in 5 cases. Our findings confirm the head/neck predilection and aggressive clinical behavior of EWSR1::POU2AF3 sarcomas and widen the morphologic spectrum of these rare lesions to include relatively bland spindle cell tumors and tumors with divergent differentiation.

Different Attenuation Models of Diffusion-Weighted MR Imaging for the Differentiation of Benign and Malignant Musculoskeletal Tumors.

BACKGROUND: Several functional imaging techniques, including monoexponential diffusion-weighted imaging (m-DWI), intravoxel incoherent motion (IVIM), and diffusion kurtosis (DK) imaging, have been used in differentiating benign and malignant musculoskeletal tumors. Combining all three techniques in the same study population may improve differentiation. PURPOSE: To compare the diagnostic performance of m-DWI, IVIM, and DK models and their combinations in differentiating benign and malignant musculoskeletal tumors. STUDY TYPE: Prospective. POPULATION: Fifty patients with benign and malignant musculoskeletal tumors divided into nonmyxoid and nonchondroid and myxoid and/or chondroid subgroups. FIELD STRENGTH/SEQUENCE: A 1.5 T/m-DWI, IVIM, and DK single-shot spin-echo echo-planar sequences. ASSESSMENT: Minimum and volumetric values of apparent diffusion coefficient (ADC), pure molecular diffusion (Divim ), pseudodiffusion (D*), perfusion fraction (f), diffusion coefficient for kurtosis model (DK ), and Kurtosis (K) were compared between all benign and malignant tumors. Subgroup analysis was also performed for nonmyxoid and nonchondroid and myxoid and/or chondroid tumors. STATISTICAL TESTS: Independent samples t-test, Mann-Whitney U test, intraclass correlation coefficient, ROC analysis, and logistic regression analysis. A P value < 0.05 was considered statistically significant. RESULTS: ADCmin , Divim-min , D*vol , DK-min, Kvol, and Kmin values showed statistically significant differences between all benign and malignant tumors and nonmyxoid and nonchondroid tumor subgroup. Kmin showed the highest diagnostic performance in differentiating benign and malignant tumors with AUCs of 0.760 for "all tumors" and 0.825 for the nonmyxoid and nonchondroid tumor subgroup. No significant differences were detected in m-DWI-, IVIM-, and DK-derived parameters for differentiating benign and malignant myxoid and/or chondroid tumors. Only three of 63 combinations of prediction models demonstrated a higher diagnostic performance than Kmin ; however, improvements were not significantly different. DATA CONCLUSION: ADCmin , Divim-min , D*vol , DK-min , Kvol , and Kmin values can be used to differentiate benign and malignant musculoskeletal tumors. Our findings suggest that the added value of multiparametric approach in such differentiation is not significant. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Comprehensive assessment and outcomes of patients with chronic periaortitis.

OBJECTIVES: Chronic periaortitis (CP) is a less known but more frequently diagnosed fibro-inflammatory disorder, but we know little about it and data regarding follow-up and outcome are still very limited. This study aims to identify the clinicopathologic, laboratory, and radiologic features, as well as outcomes of CP patients. METHODS: Patients with CP from HUVAC database were included in the study. CP was diagnosed based on compatible imaging findings and histopathological evaluation (if available), in addition to clinical findings. Demographics, laboratory, clinical, and imaging data were retrospectively reviewed from medical records. RESULTS: A total of 51 (male/female:37/14) patients were included in the study. Median (IQR) age was 63 (53-69) years and follow-up duration was 40 (4-60) months. 32 of the patients were IgG4-related CP. The most common form of CP in our cohort was idiopathic retroperitoneal fibrosis (82%), followed by inflammatory abdominal aortic aneurysms (12%) and peri-aneurysmal retroperitoneal fibrosis (8%). 8 (15.6%) patients had thoracic periaortitis and 16 (31.6%) venous involvement. Cyclophosphamide (CYC) combined with steroids was the most preferred treatment modality (43%), followed by rituximab (RTX) (31.3%). Follow-up imaging was done after a median (IQR) of 7(3-11) months, 30% of the patients were stable and 64.1% showed regression. A total of 18 (35.2%) had been taken off therapy at the last visit. CONCLUSIONS: Idiopathic retroperitoneal fibrosis was the most frequent presentation, whereas 15.6% of patients had thoracic involvement. Venous involvement was also not uncommon. Optimal time for follow-up imaging was determined as 6-9 months. Steroids along with CYC/RTX had a favourable outcome in the treatment of these patients.

HER2-low breast cancer could be associated with an increased risk of brain metastasis.

PURPOSE: The HER2-low breast cancer is a newly recognized entity with the clinical characteristics is yet to be defined. We hypothesized that HER2-low breast cancer could lead to an increased rate of brain metastases in patients with localized breast cancer. We tested this hypothesis in a large cohort of breast cancer patients with long follow-up. METHODS: We included 2686 adult breast cancer patients followed up in Hacettepe University Cancer Center. Patients with 1 + positive HER2 expression and 2 + HER2 expression with a negative FISH were categorized as HER2-low disease. We evaluated the brain metastasis risk with binary logistic regression analyses and reported odds ratios (OR) with 95% confidence intervals (CI). RESULTS: During a median 95.4 (IQR 72.6-123.1) month follow-up, 184 patients developed brain metastasis (6.9%). The brain metastases were developed in 5.1% of the patients with HER2-negative disease, 8.5% of the patients with HER2-low disease, and 10.1% of the patients with HER2-positive disease. A multivariable binary logistic regression model demonstrated an increased risk of brain metastasis in patients with HER2-low disease (OR: 1.611, 95% CI 1.055-2.460, p = 0.027) and in HER2-positive patients (OR: 1.837, 95% CI 1.308-2.580, p < 0.001). Additionally, HR + -HER2-low disease was associated with a decreased DFS compared to HR + -HER2-negative disease (p = 0.008). CONCLUSION: In this study, we observed an increased risk of brain metastasis in localized breast cancer patients with HER2-low disease. We think that a high level of vigilance and a low threshold for brain imaging could benefit HER2-low breast cancer patients similar to the patients with HER-positive disease.

An Unusual Case of Early Dental Implant Failure in an Otherwise-Healthy Patient due to Actinomycosis.

Actinomyces species are members of normal oral flora that may give rise to a rare disease-oral actinomycosis. Presented herein is a case of early implant failure associated with actinomycosis in an otherwise healthy 43-year-old female and the treatment adopted after explantation. Clinically, 1 month after the implant placement, the peri-implant soft tissues were hyperplastic and associated with an excessive tissue reaction, bleeding, suppuration, deep probing depth, and implant mobility of #19 and #20 implants. Both implants were removed and all granulomatous tissues were thoroughly debrided. Histopathological examination revealed signs of acute ulcerative inflammatory reaction and Actinomyces colonies. The patient was prescribed short-term oral penicillins. Six months after explantation, the deficient bone was augmented using a combination of absorbable collagen membrane, autogenous block bone, and xenograft. The patient was followed for 1 year; and subsequently, 2 implants were re-inserted at the same positions. The patient was followed and no recurrences were observed. Implant failure due to actinomycosis is an extremely rare condition, and a definitive diagnosis is therefore essential for successful treatment.

Recurrent novel HMGA2-NCOR2 fusions characterize a subset of keratin-positive giant cell-rich soft tissue tumors.

Giant cell tumors of soft tissue (GCT-ST) are rare low-grade neoplasms that were at one time thought to represent the soft tissue counterparts of GCT of bone (GCT-B) but are now known to lack the H3F3 mutations characteristic of osseous GCT. We present six distinctive giant cell-rich soft tissue neoplasms that expressed keratins and carried a recurrent HMGA2-NCOR2 gene fusion. Patients were five females and one male aged 14-60 years (median, 29). All presented with superficial (subcutaneous) masses that were removed by conservative marginal (3) or wide (2) local excision. The tumors originated in the upper extremity (2), lower extremity (2), head/neck (1), and trunk (1). Five patients with follow-up (median, 21 months; range, 14-168) remained disease-free. Grossly, all tumors were well-demarcated but not encapsulated with variable lobulation. Histologically, they were composed of bland plump epithelioid or ovoid to spindled mononuclear cells admixed with evenly distributed multinucleated osteoclast-type giant cells. Foci of stromal hemorrhage and hemosiderin were seen in all cases. The mitotic activity ranged from 2 to 14/10 high power fields (median: 10). Foci of necrosis and vascular invasion were seen in one case each. The mononuclear cells were immunoreactive with the AE1/AE3 keratin cocktail and less frequently/less diffusely for K7 and K19 but lacked expression of other lineage-associated markers. RNA-based next-generation sequencing revealed an HMGA2-NCOR2 fusion in all tumors. None of the keratin-negative conventional GCT-ST showed the HMGA2-NCOR2 fusion (0/7). Metaplastic bone (4/9) and SATB2 expression (3/4) were frequent in keratin-negative conventional GCT-ST but were lacking in keratin-positive HMGA2-NCOR2 fusion-positive tumors. The distinctive immunophenotype and genotype of these tumors strongly suggest that they represent a discrete entity, differing from conventional GCT-ST and other osteoclast-rich morphologic mimics. Their natural history appears favorable, although a study of additional cases and longer follow-up are warranted.

EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers.

The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18-60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.

Diffusion-weighted imaging for the differentiation of Ewing sarcoma from osteosarcoma.

OBJECTIVE: The purpose of this study is to assess the ability of apparent diffusion coefficient (ADC) values in differentiating Ewing sarcoma and osteosarcoma. MATERIALS AND METHODS: This retrospective cross-sectional observational study included a total of 35 patients with a recent diagnosis of Ewing sarcoma (n = 13) and osteosarcoma (n = 22) who underwent conventional MRI and diffusion-weighted imaging (DWI). Three ADC measurements from the areas of the lowest diffusivity in ADC maps (ADCmin), and other areas with low diffusivity (ADCother), were made independently by two observers on pre-treatment MRI, and the means of these measurements were compared using independent samples t-test. Intraclass correlation coefficient was calculated for inter-observer agreement. RESULTS: There was a significant difference between the ADCmin (P < 0.001) and ADCother (P < 0.001) in Ewing sarcoma and osteosarcoma for both observers. For Ewing sarcoma and osteosarcoma, mean ADCmin was 0.566 ± 0.07 and 1.193 ± 0.33 × 10-3 mm2/s; 0.551 ± 0.08 and 1.182 ± 0.33 × 10-3 mm2/s; and mean ADCother was 0.813 ± 0.11 and 1.510 ± 0.35 × 10-3 mm2/s; 0811 ± 0.12 and 1.501 ± 0.33 × 10-3 mm2/s for observers 1 and 2, respectively. Inter-observer correlation coefficient for mean ADCmin was 0.994 and for mean ADCother was 0.995. CONCLUSION: Diffusion-weighted imaging and ADC values could be used in the differentiation of Ewing sarcoma and osteosarcoma in borderline cases.

Poorly differentiated chordoma showing loss of SMARCB1/INI1: Clinicopathological and radiological spectrum of nine cases, including uncommon features of a relatively under-recognized entity.

Poorly differentiated chordoma is a newly recognized entity in the recent World Health Organization (WHO) classification of tumors of soft tissue and bone. Slightly over 60 such cases have been documented. Herein, we present a clinicopathological profile, including radiological features, of nine cases, which occurred in five males and four females, with age varying from 1 to 29 years (median = 43), in the cervical spine (n = 2), skull base (n = 2), clivus (n = 2), thoracic spine (n = 1) lumbar spine (n = 1) and coccyx (n = 1) Average tumor size was 4.8 cm. None of the 6-referral cases was diagnosed as a poorly differentiated chordoma at the referring laboratory. Histopathologically, all cases displayed a cellular tumor comprising polygonal cells (n = 9) displaying moderate to marked nuclear pleomorphism with prominent nucleoli (n = 7), eosinophilic (n = 9) to vacuolated cytoplasm (n = 7), rhabdoid morphology (n = 4), interspersed mitotic figures (n = 5), focal necrosis (n = 6) and inflammatory cells (n = 9). A single tumor displayed areas resembling classic chordoma, transitioning into poorly differentiated areas. There were multinucleate giant cells and physaliphorous cells in two tumors, each, respectively. Immunohistochemically, tumor cells were positive for AE1/AE3 (7/7), EMA (7/7), cytokeratin (CK) MNF116 (1/1), OSCAR (1/1), brachyury (9/9, diffusely), S100P (4/7, mostly focally), and glypican 3(2/4). SMARCB1/INI1 was completely lost in all nine tumors. A single case tested by FISH showed homozygous deletion of the SMARCB1 gene. Therapeutically (n = 7), all patients were treated with surgical resection (invariably incomplete) (n = 5), followed by adjuvant radiation therapy (n = 4) and chemotherapy (n = 4). While a single patient partially responded to treatment and another patient is alive with no evidence of disease after 23 years, three patients died of disease, six, eight, and 11 months post-diagnosis, despite adjuvant treatments. A single patient presented with a metastatic lung nodule, while another developed widespread metastasis. Poorly differentiated chordomas display a spectrum of features, are associated with a lower index of suspicion for a diagnosis, and display aggressive outcomes. Critical analysis of radiological and histopathological features, including necessary immunostains (brachyury and SMARCB1/INI1), is necessary for their timely diagnosis. These tumors show loss of SMARCB1/INI1 immunostaining and homozygous deletion of INI1/SMARCB1 gene.

Presentation of Infantile Hemangiopericytoma/Solitary Fibrous Tumor as a Giant Extracranial Temporal Mass.

BACKGROUND: Infantile Hemangiopericytoma (HPC)/Solitary Fibrous Tumor (SFT), a vascular tumor of head and neck region, can be congenital or arise during the first year of the life. As the infantile form of hemangiopericytoma has a better course than the adult form, surgical excision is recommended. Case Report: A full-term neonate presented with a congenital right temporal soft tissue mass. MRI revealed a highly vascular mass with a hemorrhagic and possible necrotic core without intracranial extension. The lesion grew in 2 weeks from 4x4 cm to 9x7 cm. Histologically, a hypercellular spindle cell mesenchymal neoplasm had prominent staghorn vessels, alternating with hypocellular areas. Mitotic activity was low(1-3/HPF) and necrosis was absent. Conclusion: Infantile HPC/SFT of head and neck can grow rapidly during the infantile period. Complete excision without mutilating surgery should be curative.

Acquired Leukonychia of the Distal Nail Plate: A Morphologic and Proteomic Analysis.

Leukonychia, or whitening of the nail plate, is a common disease that was first described in 1919. Leukonychia is classified as acquired or congenital and may be due to abnormality of the nail bed (pseudoleukonychia) or nail plate (true leukonychia). The distal whitened area of the nail plate was clipped from a 31-year-old woman with striated leukonychia and a 32-year-old man and 34-year-old woman with punctate leukonychia. Routine hematoxylin and eosin staining of all clipped samples was performed. A piece of nail with leukonychia and a normal nail from case 2 were sent to the Mayo Clinic for mass spectrometric analysis. On hematoxylin and eosin examination, all leukonychia samples showed odd-appearing eosinophilic linear parakeratinization in the mid-segment of the nail plate. Mass spectrometric analysis of case 2 revealed serum proteins (albumin, serotransferrin IgG, gamma chain, IgG lambda chain, and haptoglobulin) and hair proteins that were not found in the keratin content of the normal nail (keratin type Ha1 and cuticular keratin Ha4). This is the first description of odd-appearing linear parakeratosis and the first proteomic analysis showing abnormal protein content in acquired leukonychia.

Primary ependymoma of the retropubic space in a male patient.

We report a case of primary intraabdominal ependymoma arising in the retropubic space of a male patient. An incidental intraabdominal mass was discovered in a 51-year-old man. Radiological studies revealed a 10 cm, solid and cystic tumor located in the Retzius fossa. Microscopically, the lesion was characterized by multiple cellular nodules composed of bland small cells forming true and pseudorosettes. No nuclear atypia, necrosis or increased mitotic activity was present. Neoplastic cells positive for AE1/3 and Cam5.2, and expressed patchy GFAP, and paranuclear dot-like to microvesicular EMA and D2-40, while S100, synaptophysin, PAX8, TLE1, WT1, inhibin, calretinin, Melan-A, and HMB45 were negative. Electron microscopy findings supported the diagnosis: 1) Frequent intracytoplasmic vacuoles with short and redundant microvilli and few cilia 2) lung intercellular junctions. The patient is alive with no evidence of disease for 4 years. Pathologists should be aware that rare extraneural ependymomas may occur in the Retzius space, even in a male patient. This entity should be kept in mind especially when the differential diagnosis is metastatic carcinoma with an unusual morphology and immune profile.

Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling.

Vascular malformations are non-neoplastic expansions of blood vessels that arise due to errors during angiogenesis. They are a heterogeneous group of sporadic or inherited vascular disorders characterized by localized lesions of arteriovenous, capillary, or lymphatic origin. Vascular malformations that occur inside bone tissue are rare. Herein, we report loss-of-function mutations in ELMO2 (which translates extracellular signals into cellular movements) that are causative for autosomal-recessive intraosseous vascular malformation (VMOS) in five different families. Individuals with VMOS suffer from life-threatening progressive expansion of the jaw, craniofacial, and other intramembranous bones caused by malformed blood vessels that lack a mature vascular smooth muscle layer. Analysis of primary fibroblasts from an affected individual showed that absence of ELMO2 correlated with a significant downregulation of binding partner DOCK1, resulting in deficient RAC1-dependent cell migration. Unexpectedly, elmo2-knockout zebrafish appeared phenotypically normal, suggesting that there might be human-specific ELMO2 requirements in bone vasculature homeostasis or genetic compensation by related genes. Comparative phylogenetic analysis indicated that elmo2 originated upon the appearance of intramembranous bones and the jaw in ancestral vertebrates, implying that elmo2 might have been involved in the evolution of these novel traits. The present findings highlight the necessity of ELMO2 for maintaining vascular integrity, specifically in intramembranous bones.

Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma of bone: Clinicopathologic features of 5 cases.

Pseudomyogenic hemangioendothelioma (PHE) is an uncommon mesenchymal tumor of intermediate malignant potential with characteristic clinicopathologic and genetic features. Although bone involvement accompanies nearly one-fourth of reported cases of soft tissue PHEs, primary intraosseous PHE is rare. Herein, we report five cases of primary intraosseous PHEs. Male to female ratio was 4:1, with an average age of 28 years (age range, 5-44 years). Radiologically, tumors presented as lytic lesions in the proximal femur (two), diaphysis of the tibia (one), distal radius (one) and vertebrae (one). Multifocal lesions were observed in four cases. Histopathologic examination revealed plump spindle cells and prominent nucleoli. New bone formation was noted in three cases. Immunohistochemically, all tumors were positive for CD31 and negative for CD34. Pan Cytokeratin (CK) (AE1/3) was positively expressed in all, except a single tumor, in which CK7 and Cam5.2 were expressed. INI1/SMARCB1 was completely retained in all tumors. A single patient underwent surgical resection. During follow-up, two cases showed no evidence of disease within two and five years, respectively. Differential diagnosis of a PHE of bone includes osteoblastoma, epithelioid angiosarcoma, metastatic carcinoma, metastatic rhabdomyosarcoma, and epithelioid sarcoma. Caution must be exercised as pan CK (AE1/3) might not be expressed; therefore, the use of other cytokeratins, such as Cam5.2 is recommended. Awareness of such an entity in bone is the key to the diagnosis.

Denosumab treatment in aneurysmal bone cyst: Evaluation of nine cases.

BACKGROUND: Aneurysmal bone cyst (ABC) is a benign bone tumor. Curettage and bone grafting is the common treatment. Here, we retrospectively evaluate nine patients treated with denosumab. PROCEDURE: Nine patients with ABC, mostly pelvic and vertebral, treated with denosumab were analyzed retrospectively. A 70 mg/m2 denosumab dose was used weekly in the first month, and then monthly. Clinical and radiological responses to treatment were evaluated. RESULTS: In all patients, clinical symptoms including pain and limping regressed completely within 3 months. Radiological evaluation revealed changes in lesion size and content. In six patients, overall volume reduction in the range of 18-82% was detected. Decreases in the size and number of cysts were detected in eight patients. In five patients, fat signal appeared on follow-up imaging. No major side effects were observed during treatment. Median follow-up time after treatment was 15 months. At 5 months, severe hypercalcemia was observed in two patients due to rebound increase in osteoclastic activity. Subsequent to denosumab treatment, three patients underwent surgery for clinical or radiological recurrence. CONCLUSIONS: Our results showed that denosumab provided a meaningful clinical and radiological improvement in ABC. It may be a treatment option, especially in spinal and pelvic tumors with potentially high surgical morbidity. However, late rebound hypercalcemia may restrict its use. Studies with more cases are required for routine use of denosumab in ABC.