Chondroblastoma of foot bones; a clinicopathological study of 29 cases confirming the diagnostic utility of H3K36M and H3G34W antibodies at an uncommon site.

OBJECTIVE: Chondroblastoma (CB) is a benign cartilaginous bone neoplasm which commonly occurs in long bones of adolescents. CB can uncommonly involve foot. Its mimics include both benign and malignant lesions. H3K36M immunohistochemical (IHC) stain is a helpful tool for establishing the diagnosis of CB in such challenging situations. In addition, H3G34W IHC stain helps to rule out giant cell tumor which is the closest differential of CB. Our objective was to describe the clinicopathological features and frequencies of H3K36M, H3G34W and SATB2 IHC stains in CB of foot. MATERIALS AND METHODS: We reviewed H&E slides and blocks of 29 cases diagnosed as "chondroblastoma" of foot at our institutions. RESULTS: Patient's age ranged from 6 to 69 (mean: 23.3 and median: 23) years. Males were almost 5 times more commonly affected than females. Talus and calcaneum were involved in 13 (44.8 %) cases each. Microscopically, tumors were composed of polygonal mononuclear cells and multinucleated giant cells and chondroid matrix. Other histological features included aneurysmal bone cyst-like (ABC-like) change (44.8 %), osteoid matrix (31 %), chicken-wire calcification (20.7 %), and necrosis (10.3 %). H3K36M was expressed in 100 % and SATB2 in 91.7 % cases. H3G34W was negative in all cases, where performed. One out of 11 patients with follow up information developed local recurrence after 48 months. CONCLUSION: CB in foot occur at an elder age and show more frequent ABC-like changes as compared to long bones. Males are affected ~5:1 as compared to 2:1 in long bones. H3K36M are H3G34W are extremely useful diagnostic markers for CB, especially elderly (aged or higher) patients and we report the largest series of foot CB cases confirmed by immunohistochemistry.

Retracted Rotator Cuff Repairs Heal With Disorganized Fibrogenesis Without Affecting Biomechanical Properties: A Comparative Animal Model Study.

PURPOSE: To determine the differences in the scar tissue formation during the healing of the repaired retracted cuff tear from that of the nonretracted tear. METHODS: Eighteen right rabbit shoulders received a 1-cm transverse cuff incision over the footprint to simulate "nonretracted cuff tears" before the transosseous repairs (group A). A 1-cm tendinous portion was excised from 18 left shoulders to create defects to simulate "retracted cuff tears" before repairing the defects (group B). At week 12 postrepair, 20 and 16 shoulders underwent histologic and biomechanical analyses, respectively. Eight shoulders were used as a control group for biomechanical analyses. RESULTS: All specimens showed good healing and continuity of the repaired tendons. At low magnification, fibrous tissue firmly held the tendon-to-bone junctions in group A; however, all specimens in group B showed medially retracted tendons with fibrous tissue continuity between the tendon stumps and footprints. At medium magnification, more irregular collagen fiber orientation was observed in group B. Polarized light microscopy showed fibrous tissue continuity with medially retracted tendons in group B. When we quantified collagen fiber orientation using ImageJ software, group B had inferior grayscale measurements when compared with group A (P = .001). At week 12, no statistical differences existed in mean loads-to-failure at the repair sites between the groups (P = .783). CONCLUSIONS: In the nonretracted cuff tears, fibrous tissue bound the tendon-to-bone junction with healing. After the healing of the retracted cuff tears, continuity of nontendinous tissue was observed adjacent to the medially retracted tendon, which comprised more disorganized immature fibrous tissue than that in the nonretracted cuff tears. CLINICAL RELEVANCE: Unlike the healing of nonretracted rotator cuff tear, repairing of the "retracted" tendon end of cuff tear still resulted in retraction of the tendon back to its original position but being held down with fibrous tissue to the footprint.

The many faces of solitary fibrous tumor; diversity of histological features, differential diagnosis and role of molecular studies and surrogate markers in avoiding misdiagnosis and predicting the behavior.

BACKGROUND: Solitary Fibrous Tumor (SFT) is a distinct soft tissue neoplasm associated with NAB2-STAT6 gene fusion. It can involve a number of anatomic sites and exhibits a wide spectrum of histological features. MAIN BODY: Apart from diversity in morphological features seen even in conventional SFT, two histologic variants (fat-forming and giant cell-rich) are also recognized. In addition, a malignant form and dedifferentiation are well recognized. Owing to diverse histological features and involvement of diverse anatomic locations, SFT can mimic other soft tissue neoplasms of different lineages including schwannoma, spindle cell lipoma, dermatofibrosarcoma protuberans, liposarcoma, gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor (MPNST), and synovial sarcoma. SFT is classified as an intermediate (rarely metastasizing) tumor according to World Health Organization Classification of Tumors of Soft tissue and Bone, 5th edition. The management and prognosis of SFT differs from its malignant mimics and correct diagnosis is therefore important. Although SFT expresses a distinct immunohistochemical (IHC) profile, the classic histomorphological and IHC profile is not seen in all cases and diagnosis can be challenging. NAB2-STAT6 gene fusion has recently emerged as a sensitive and specific molecular marker and its IHC surrogate marker signal transducer and activator of transcription 6 (STAT6) has also shown significant sensitivity and specificity. However, few recent studies have reported STAT6 expression in other soft tissue neoplasms. CONCLUSION: This review will focus on describing the diversity of histological features of SFT, differential diagnoses and discussing the features helpful in distinguishing SFT from its histological mimics.

Parosteal Lipoma Associated with a Growing Osteochondroma of the Right Ilium.

Parosteal lipoma is a rare type of lipoma, the incidence being approximately 0.3% of all lipomas. Moreover, parosteal lipoma coexisting with osteochondroma is extremely rare. A few cases with coexistence of osteochondroma and parosteal lipoma have been reported and they were thought to be reactive changes of adjacent bone by parosteal lipoma. However, temporal relationship of these tumors could not be explained. Here, we report a case of parosteal lipoma associated with osteochondroma of the right ilium developed over 6 years, with follow-up radiographs.

Histomorphometric Analysis of Pre- and Post-Denosumab-Treated Giant Cell Tumor of Bone.

Context. Denosumab is a monoclonal antibody against RANK ligand. Its administration in giant cell tumor of bone (GCTB) cases results in elimination of giant cells and new bone formation. Neoplastic stromal cells of GCTB harbor mutation of histone 3.3 and have pre-osteoblastic properties and thus express SATB2. Objectives. To (1) analyze histological changes in post-denosumab-treated GCTB, (2) analyze expression of H3.3G34W and SATB2 in pre- and post-denosumab-treated samples, and (3) to discuss why changes occur in the expression of not only H3.3G34W but also SATB2. Materials and Methods. Hematoxylin and eosin slides of 19 cases of denosumab-treated GCTB were reviewed. Immunohistochemical stains H3.3G34W and SATB2 were performed. The number of positive mononuclear cells were counted and graded. Results. Complete absence of osteoclast-like giant cells (OCLGCs) was noted in most cases along with a fibro-osseous component merging with peripheral shell of reactive bone. Irregular trabeculae of woven bone and osteoid with focal osteoblastic rimming was seen. Spindle cells were arranged predominantly in fascicular pattern. Morphometric analysis of H3.3G34W showed a mean of 68.8% positive stromal cells in pretreatment and a mean of 26.9% positive stromal cells in posttreated specimens with a statistically significant P value (.001). Mean percentage of SATB2-positive stromal cells in the pre- and posttreatment specimens was 36.46% and 20.8%, respectively. Conclusions. Our study validates that denosumab treatment results in marked reduction of OCLGCs with increased osteoblastic activity. Decreased expression of H3.3G34W in posttreatment may be a result of decreased antigenicity of neoplastic mononuclear cells. No significant change in SATB2 expression was noted.

Pathogenetic implications of early growth response 1 in Ewing sarcoma.

Ewing sarcoma (ES) is the second most common primary malignant bone tumour, mainly occurs in children and adolescents, and has an overwhelming mortality. Despite extensive studies, few effective oncogenic signals have been described. Therefore, it is crucial to exploit novel pathognomonic factors and targetable biomarkers for ES patients. Based on previous studies, we speculate that insulin-like growth factor 1 receptor (IGF1R), which is upregulated by early growth response 1 (EGR1), may play a pivotal role in strengthening the downward transmission of IGF1 cascades. Therefore, in this study, we concentrated on determining the pathogenetic contribution of EGR1 in diverse ES cells. This report is the first to study the pathogenic role of EGR1 in ES. ES cells were cultured and transfected with Stealth RNAi human EGR1 small interfering RNA (siRNA) or negative control. Cell proliferation and invasion potential were measured. mRNA and protein expression of EGR1, IGF1R, and EWS-FLI1 also were assessed. In all EGR1 siRNA-transfected cells (SK-ES-1, RD-ES, and HS863.T), cell proliferation and invasive potential decreased significantly in EGR1 siRNA-transfected ES cells. mRNA and protein expression for EGR1, IGF1R, and EWS-FLI1 were also significantly reduced. In conclusion, EGR1 upregulated IGF1R expression and enhanced the expression of the oncogenic fusion protein EWS-FLI1. The EWS-FLI1/EGR1/IGF1R cascade combined with the previously confirmed pathways can form a speculative circuit, implicating positive feedback for tumourigenesis in ES. Therefore, EGR1 inhibitors are expected to be useful for the treatment of ES by preventing oncogenic IGF1/IGF1R expression.

In Vivo Response of Growth Plate to Biodegradable Mg-Ca-Zn Alloys Depending on the Surface Modification.

Because Mg-Ca-Zn alloys are biodegradable and obviate secondary implant removal, they are especially beneficial for pediatric patients. We examined the degradation performance of Mg-Ca-Zn alloys depending on the surface modification and investigated the in vivo effects on the growth plate in a skeletally immature rabbit model. Either plasma electrolyte oxidation (PEO)-coated (n = 18) or non-coated (n = 18) Mg-Ca-Zn alloy was inserted at the distal femoral physis. We measured the degradation performance and femoral segment lengths using micro-CT. In addition, we analyzed the histomorphometric and histopathologic characteristics of the growth plate. Although there were no acute, chronic inflammatory reactions in either group, they differed significantly in the tissue reactions to their degradation performance and physeal responses. Compared to non-coated alloys, PEO-coated alloys degraded significantly slowly with diminished hydrogen gas formation. Depending on the degradation rate, large bone bridge formation and premature physeal arrest occurred primarily in the non-coated group, whereas only a small-sized bone bridge formed in the PEO-coated group. This difference ultimately led to significant shortening of the femoral segment in the non-coated group. This study suggests that optimal degradation could be achieved with PEO-coated Mg-Ca-Zn alloys, making them promising and safe biodegradable materials with no growth plate damage.

Erratum to "Melatonin Suppresses the Expression of 45S Preribosomal RNA and Upstream Binding Factor and Enhances the Antitumor Activity of Puromycin in MDA-MB-231 Breast Cancer Cells".

[This corrects the article DOI: 10.1155/2013/879746.].

Atypical maculopapular cutaneous mastocytosis showing a nevus spilus-like lesion.

A 13-year-old Korean girl presented with a 7-year history of a pruritic, light-brown patch containing multiple 0.2- to 0.5-cm brownish-to-reddish maculopapules on the left anterior chest. When her skin was rubbed, the lesion became itchy and red. Histopathologic evaluation demonstrated marked dense dermal infiltration of mast cells. We report a rare case of atypical maculopapular cutaneous mastocytosis with clinical features similar to those of nevus spilus.

Giant cell tumor of bone: updated molecular pathogenesis and tumor biology.

Giant cell tumor of bone (GCTB)-related clonal aberrations occur in a background of epigenetic histone modifications (especially the G34W mutation of H3F3A gene) that induce cytogenetic abnormalities. Clonal aberrations are closely linked to the aggressiveness of GCTB. The "neoplastic" mononuclear stromal cells in GCTB express fundamental RANKLs and various chemokines and cytokines associated with monocyte recruitment and "reactive" multinucleated giant cells (osteoclastogenesis). The reciprocal and orchestrated actions between mononuclear stromal cells and multinucleated giant cells help in the understanding of the molecular pathogenesis and tumor biology of GCTB. In the future, novel targets in the updated tumor biology and molecular pathogenesis of GCTB should be explored and scrutinized for the development of systemic therapy.

Does circumferential tumor location affect the circumferential resection margin status in mid and low rectal cancer?

BACKGROUND/OBJECTIVE: The purpose of this study was to assess the impact of circumferential tumor location on circumferential resection margin (CRM) status and the depth of tumor invasion in mid and low rectal cancer. METHODS: We retrospectively analyzed whole-mount slides of 58 patients who underwent total mesorectal excision for mid and low rectal cancer. The rate of tumor-positive CRM was compared according to the circumferential tumor location. In 31 patients, morphometric analyses of whole-mount specimens were performed to measure the depth of tumor invasion according to circumferential tumor location. RESULTS: Among 58 patients, 50% of tumors were anterior tumor and 50% were nonanterior. A tumor-positive CRM was more observed frequently in anterior tumors than in nonanterior tumors (41.1% vs. 10.3%, p = 0.007). In a multivariate analysis, anterior tumor was the only independent risk factor for a positive CRM (odds ratio 4.725, 95% confidence interval 1.102-20.261, p = 0.037). In a morphometric analysis of 31 patients, the depth of tumor invasion from the muscularis mucosa was greater (11.9 mm vs. 6.6 mm, p = 0.028) in those with anterior tumors. CONCLUSION: Anterior tumors are associated with a higher risk of tumor-positive CRM and tend to exhibit deeper invasion in mid and low rectal cancer.

A rare, low-grade appendiceal mucinous neoplasm (Pseudomyxoma peritonei) with ossification: A case report with morphoproteomic analysis of bone formation.

Heterotopic ossification occurring to low-grade appendiceal mucinous neoplasm (LAMN) (pseudomyxoma peritonei) is extremely rare. The pathogenetic mechanism of the tumor-related heterotopic bone formation remains as yet unconfirmed. Here, we describe a rare case of LAMN with ossification in a 72-year-old woman, and concentrate on the etiology of heterotopic ossification by the immunohistochemical evaluation of the novel markers such as BMP9, osteocalcin, and osteopontin. BMP9 is one of the most effective osteogenetic proteins. However, no researches associated with BMP9 in the heterotopic ossification occurring to LAMN have been performed. Consequently, we suggest the trustworthy hypothesis of tumor-associated heterotopic bone formation through this case. When osteoblastic markers such as BMP9, osteocalcin, and osteopontin are overexpressed in tumor cells, osteoblast-like transformation of such tumor cells occurs. In turn, these tumor cells increase secretion of interactive osteogenetic factors, such as BMP9, osteocalcin, and osteopontin, thus contributing to heterotopic bone formation through a microenvironmental change to mesenchymal stromal cells (osteoblastic differentiation). This phenomenon is considered a type of EMT. Patients should be followed closely because EMT-like transformed tumors have shown a tendency toward local recurrence. Our findings provide insight into the pathogenetic etiology of the heterotopic ossification in LAMN (pseudomyxoma peritonei).

Amyloid Arthropathy of the Hip Joint Associated with Multiple Myeloma: A Case Report.

Amyloidosis is a disease characterized by the deposition of non-soluble fibrous protein in multiple tissues with a number of possible causes. This protein deposition can occur in any tissue, yet is most commonly seen in kidneys, heart, and gastrointestinal tracts. However, invasion to bone tissues is not often reported. The deposition of amyloid proteins in bone tissues may result in joint pain and pathological fractures; it is important to elucidate the causes and detect early to determine prognosis and treat optimally. In the present case report, with relevant literature review, the authors report a case of total hip arthroplasty in an amyloidosis patient.

A Rare Colon Cancer with Ossification: Pathogenetic Analysis of Bone Formation.

Heterotopic ossification occurring in colon cancer is an exceedingly rare event. The pathogenetic mechanism of tumor-related heterotopic bone formation remains unclear. Herein, we describe a rare case of colon cancer with ossification in a 76-year-old woman. We also highlight the etiology of heterotopic ossification by immunohistochemical evaluation of novel markers such as bone morphogenetic protein 9 (BMP9), osteocalcin, osteopontin, and ß-catenin. BMP9 is one of the most potent osteogenetic BMPs. However, no previous research has been performed concerning BMP9 in heterotopic ossification arising in colon cancer. Subsequently, we suggest a hypothesis of tumor-associated heterotopic bone formation through this case. When osteoblastic indicators including BMP9, osteocalcin, and osteopontin are upregulated in tumor cells, osteoblast-like transformation of such tumor cells occurs. These tumor cells augment the release of interactive osteogenetic factors (BMP9, osteocalcin, and osteopontin) and stimulate uncommitted mesenchymal stromal cells into specific osteoblastic differentiation, contributing to heterotopic bone formation. This transformation of tumor cells is considered a type of epithelial-mesenchymal transition (EMT) because of overexpression of BMP9 and ß-catenin. Patients should be followed closely because EMT has a tendency toward local recurrence. Our findings provide insight into the pathogenetic etiology of heterotopic ossification in colon cancer.

Clinicopathological implications of GNAS in Ewing sarcoma.

The objective of the present study was to determine whether guanine nucleotide-binding protein α stimulating (GNAS) gene expression correlates with pathognomonic signs by analyzing the mutations, methylation status and G-protein α subunit (Gsα) expression of GNAS in Ewing sarcoma (ES). Formalin-fixed paraffin-embedded tissue samples from 77 patients with primary ES were obtained in South Korea, Argentina and Brazil, and were studied via methylation chip assay and direct sequencing of the GNAS gene and immunohistochemical analysis of Gsα. The mutation and methylation statuses of the GNAS gene were examined. Immunohistochemical results were measured with respect to proportion and staining intensity. The results revealed that GNAS genes in ES tumor samples were less methylated compared with normal controls. No mutations were detected at exons 8 or 9 of the GNAS locus complex on chromosome 20q13.3, indicating that the pathogenesis of ES was not associated with GNAS mutation. Gsα expression correlated well with the methylation status of the GNAS gene. Notably, high Gsα expression was detected more frequently in samples from living patients than from decedents, although this was not statistically significant (P=0.055). In conclusion, GNAS mutation is not associated with the pathogenesis of ES tumors. This finding may be used to differentiate ES tumors from metastatic bone lesions with morphological similarity to ES tumors. Analysis of the methylation status of the GNAS gene and immunohistochemical Gsα expression suggests that hypermethylated GNAS (low Gsα expression) in ES may be associated with unfavorable progression with a non-significant trend.

Prognostic value of ERG, PTEN, CRISP3 and SPINK1 in predicting biochemical recurrence in prostate cancer.

The established prognostic factors associated with prostatic adenocarcinoma are the Gleason score, pathological T staging and serum prostatic-specific antigen (PSA) level. However, these prognostic factors alone are not sufficient for predicting prognostic characteristics, including early stage or advanced prostate cancer, presence of metastasis or disease-related mortality. The purpose of the present study was to simultaneously evaluate the prognostic value and associations of four biomarkers, namely, transcriptional regulator ERG (ERG), phosphatase and tensin homolog (PTEN), cysteine-rich secretory protein 3 (CRISP3) and serine protease inhibitor Kazal type I (SPINK1), and to conduct risk stratification of prostate cancer for use in patient management. A total of 68 formalin-fixed, paraffin-embedded, prostate cancer samples from radical prostatectomies were obtained in the Kyung Hee University Hospital (Seoul, Korea) and were studied immunohistochemically for ERG, PTEN, CRISP3 and SPINK1 to determine the proportion and intensity of staining. SPINK1 expression was mutually exclusive of ERG expression (P=0.001). The loss of PTEN and high CRISP3 expression are unfavorable indicators for prostate cancer, as PTEN loss was associated with shorter biochemical recurrence (BCR) (P=0.039), and high CRISP3 expression was associated with increased BCR (P<0.001) and cancer-related mortalities (P=0.011). Using the combination of low PTEN and high CRISP3 expression enables attention to be focused on patients who exhibit a poor prognosis. Subgrouping of patients, into high-risk and low-risk categories, was correlated with BCR-free survival in prostate cancer upon multivariate analysis (P=0.030). Overall, low PTEN and high CRISP3 expression significantly characterize the subgroups of prostate cancer that have a poor prognosis for BCR.

Ewing sarcoma: a chronicle of molecular pathogenesis.

Sarcomas have traditionally been classified according to their chromosomal alterations regardless of whether they accompany simple or complex genetic changes. Ewing sarcoma, a classic small round cell bone tumor, is a well-known mesenchymal malignancy that results from simple sarcoma-specific genetic alterations. The genetic alterations are translocations between genes of the TET/FET family (TLS/FUS, EWSR1, and TAF15) and genes of the E26 transformation-specific (ETS) family. In this review, we intend to summarize a chronicle of molecular findings of Ewing sarcoma including recent advances and explain resultant molecular pathogenesis.

Tumoral pseudogout of the proximal interphalangeal joint of a finger: a case report and literature review.

Tumoral pseudogout is a rare clinical form of calcium pyrophosphate dihydrate crystal deposition disease. Tumoral pseudogout can mimic other diseases such as chondroid tumor, tophaceous gout, or tumoral calcinosis. Its radiological features have been presented in some case reports, but no specific radiographic features have been identified. Here, we report an unusual case of recurrent tumoral pseudogout involving the proximal interphalangeal joint of the right long finger. This case presents with progressive radiological findings of the disease with an enlarging and recurrent calcified mass and secondary bony erosion and remodeling, along with a radiological-pathological correlation. We also review previously reported imaging findings of this disease entity, differential points in comparison to other diseases, and some key points for making the correct diagnosis.