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Immunotherapy of musculoskeletal tumors remains clinically challenging and requires the development of gene-engineered/adoptive exogenous immune cells or the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Recently, endogenous B-cell infiltration into tumor microenvironments appears to be an essential promising prognostic factor controlling tumor progression in musculoskeletal malignancy. Here, we explored the level of T-cell infiltration by analyzing expression profiles of CD3E, CD4, and CD8A in 1366 patients and 23 histological types. The data revealed that CD3E and CD8A expressions were predominantly inhibited in bone tumors when compared with normal bone. CD4 expression was upregulated in limited types of tumors, including chondrosarcoma and giant cell tumor of bone, whereas other tumors demonstrated relatively lower expressions. Similarly, regarding soft tissue sarcoma, the expression of T-cell-related molecules was largely inhibited. Only in patients with rhabdomyosarcoma, CD3E and CD8A expressions were significantly upregulated, showing the nature of immune-active tumor. To visualize the immunological microenvironment of rhabdomyosarcoma, we have developed a novel software aimed at analyzing numerous cell-to-cell and ligand-to-receptor interactions, that is, Environmentome. It has led to the identification of molecular interactions between CD8 + T cell and rhabdomyosarcoma via Galectin3-LAG3 binding, which is a novel immune checkpoint recently identified. In conclusion, musculoskeletal tumors may be defined as immune-quiescent tumors, whereby targeting Galectin-3 and/or immune-infiltrative agents could be crucial in these immunologically noninflamed musculoskeletal tumors, accelerating immunotherapeutic response., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

We report a case of solitary infantile myofibroma (IM) with partially CD34-positive neoplastic cells on the back of a newborn boy. Ultrasonography showed a multilocular mass with a hypoechoic center surrounded by an isoechoic rim. Histopathological analysis revealed that the lesion was composed of small, round cells that were tightly packed and uniform. The cells had oval nuclei and were pale, CD34-positive, and richly cellular. They had interlacing fascicles of spindle cells with features of myofibroblasts with α-smooth muscle actin positivity. We speculate that neoplastic cells in most IMs differentiate towards myofibroblasts. However, in rare cases, their differentiation is more primitive and they express CD34, with or without α-smooth muscle actin expression.

Background: Pediatric mastocytosis differs from adult mastocytosis in its presentation and clinical course. However, the data regarding the immunophenotypic characterization of mast cells in children are limited. Our objective was to evaluate the immunophenotype of mast cells in pediatric mastocytosis and correlate it with the clinical course., Methods: Biopsy specimens of children with cutaneous mastocytosis were retrieved from the institutions of pathology and were stained for CD25, CD2, and CD30. The percentage of mast cells and the staining intensity were correlated with the clinical data., Results: Twenty-five biopsy specimens were included in the study. Patients' average age was 15.4 at presentation and 37.5 months at biopsy performance. Clinical presentations included maculopapular cutaneous mastocytosis in 79% and mastocytoma in 21% of cases. CD25, CD2, and CD30 were positive in 60%, 44%, and 84% of the biopsy specimens, respectively. The staining score was significantly higher for CD30 as compared to those for CD25 and CD2 (P = 0.02). No correlation was found between the immunophenotype and the clinical form or course of disease., Conclusions: Our results confirm that CD30 is a sensitive marker for pediatric-onset mastocytosis. Nevertheless, its expression does not correlate with clinical subtype or clinical course. The sensitivity of CD25 is higher than that of CD2 in skin lesions., (© 2019 Wiley Periodicals, Inc.)

Tumor-induced osteomalacia (TIO) is a disease caused by fibroblast growth factor 23 (FGF23) secreted from the causative tumor. This disease is cured by complete surgical removal of the tumor. However, there are several difficult cases in which the responsible tumors cannot be found, are incompletely removed, or relapse after the surgery. Anti-FGF23 antibody is being studied as a novel therapy for FGF23-related hypophosphatemic diseases. The efficacy of anti-FGF23 antibodies were confirmed using a murine model of X-linked hypophosphatemic rickets (XLHR) , which is the most common heritable form of FGF23-related hypophosphatemic disease. In addition, results of phase I study of single injection of humanized anti-FGF23 antibody for adult patients with XLHR were recently published and the safety and effectiveness of this antibody was shown. This antibody therapy may be useful for patients with TIO with similar pathogenesis to that of XLHR.

In this review the authors focus on the differential diagnosis of small round cell tumors of soft tissue origin, giving emphasis on their specific immunohistochemical profiles. The sources of diagnostic errors and misinterpretations of the results of immunohistochemical staining are discussed in detail. It is thorough knowledge of specific characteristics of each tumor and appropriate interpretation of different staining techniques that will lead to precise classification of any given tumor, thus allowing accurate determination of prognosis and implementation of the optimal treatment.

The majority of gastrointestinal stromal tumors (GIST) express c-kit, a growth factor receptor with tyrosine kinase activity. Mutations in the c-kit proto-oncogene may lead to constitutive ligand-independent activation of c-kit and subsequent neoplastic transformation. Selective tyrosine kinase inhibitors target this property of GIST and have become the standard chemotherapy for metastatic or unresectable tumors. The mainstay of treatment, however, continues to be complete surgical resection. Tyrosine kinase inhibitors may prove expedient for adjuvant therapy, and are currently the focus of clinical trials conducted by the ACOSOG, RTOG, and ACRIN. It is important to distinguish GISTs from other mesenchymal tumors of the GI tract because of differences in natural history, as well as the efficacy of treatments targeting the GIST tyrosine kinase.

Parathyroid hormone-related peptide is one of the most important regulators of chondrocyte proliferation. Although cartilaginous neoplasms express different collagens, including Types II and X, the pathogenesis of these tumors has not been elucidated. The current study examined the hypothesis that parathyroid hormone-related peptide is expressed in cartilaginous neoplasms and its level of expression may correlate with the proliferative rate of cartilaginous neoplasms with higher levels in more malignant tumors and lower levels in benign lesions. Two hundred thirty-four biopsy and resection specimens of benign and malignant cartilage tumors from 179 patients were retrieved from surgical pathology archival material and analyzed immunohistochemically using an antibody to human parathyroid hormone-related peptide. Most cartilaginous neoplasms had some level of expression of parathyroid hormone-related peptide, and tumors with a more proliferative phenotype had higher levels of parathyroid hormone-related peptide. Although benign lesions such as enchondromas and osteochondromas had low levels of parathyroid hormone-related peptide, malignant neoplasms such as extraskeletal myxoid chondrosarcomas, dedifferentiated chondrosarcomas, and mesenchymal chondrosarcomas expressed high levels of parathyroid hormone-related peptide. Parathyroid hormone-related peptide expression correlated with grade of malignancy in chondrosarcoma. Although there were highly significant differences between Grade I chondrosarcoma versus Grade II and Grade III lesions, the difference between Grade II and Grade III chondrosarcomas approached significance. Parathyroid hormone-related peptide may represent a new tumor marker with potential diagnostic use in classifying cartilaginous neoplasms.

Synovial sarcoma (SS), clear cell sarcoma (CCS), and desmoplastic small round cell tumor (DSRCT) are soft-tissue malignancies occurring primarily in adolescents and young adults. These tumors contain specific chromosomal translocations that fuse the 5' region of one gene with the 3' region of another, resulting in the formation of characteristic fusion proteins. These translocations are unique to tumor cells and may be required for persistence, thereby serving as targets for immunotherapy. It was hypothesized that the fusion breakpoint sequences associated with SS, CCS, and DSRCT can serve as tumor-specific neoantigens. To test this, peptides corresponding to the fusion breakpoints were designed and assessed for ability to bind to various class I HLA molecules. Two peptides derived from the SS breakpoint specifically bind the HLA-B7 antigen, and a 10-amino acid minimal epitope was identified for this interaction. Specific binding of a SS peptide and a CCS peptide to HLA-B27 molecule was also observed. Finally, a peptide designed from the DSRCT breakpoint specifically binds the HLA-A3 molecule, and a 9-amino acid optimal epitope was identified for this interaction. The physiological/immunological relevance of these peptide/MHC interactions was demonstrated by the induction of SS-specific CTLs from normal donor lymphocytes using in vitro stimulation with autologous, peptide-pulsed dendritic cells and by the ability of these CTLs to lyse human SS tumor cells endogenously expressing the full-length fusion protein. These results suggest that sequences in the fusion region of sarcoma-associated chimeras can bind class I HLA molecules and serve as neoantigens. These may be useful for the development of novel immunotherapies for sarcoma patients with appropriate HLA molecules and tumors bearing these translocations.

A recombinant antibody-lymphotoxin-alpha fusion protein induced an adaptive immune response protecting mice from melanoma. Importantly, this fusion protein elicited the formation of a lymphoid-like tissue in the tumor microenvironment containing L-selectin+ T cells and MHC class II+ antigen-presenting cells, as well as B and T cell aggregates. Furthermore, PNAd+/TCA4+ high endothelial venules were observed within the tumor, suggesting entry channels for naive T cell infiltrates. Over the course of therapy, a marked clonal expansion of certain TCR specificities occurred among tumor-infiltrating lymphocytes that displayed reactivity against melanoma cells and the TRP-2(180-188) peptide. Consequently, naive T cells may have been recruited to as well as primed and expanded in the lymphoid-like tissue induced by the lymphotoxin-alpha fusion protein at the tumor site.

Neoplasms of the small intestine are very rare. Gastrointestinal stromal tumors (GISTs) are one of the new undifferentiated stromal tumors of the gastrointestinal tract diagnosed by immunohistochemistry. We present a case of a malignant GIST arising from the small intestine and report the radiologic characteristics of the tumor and pathological correlation. CT showed a very large, enhancing mass with extensive central necrosis located on the mesenteric side of the jejunum. A perforation into the jejunal lumen was observed by upper GI series. MRI showed a very large tumor which was hypointense on T2-weighted images. Ultrasound revealed a mixed solid and cystic mass. Grossly, the tumor was solid peripherally with extensive central necrosis. Microscopically, it consisted of spindle and epithelioid cells. Immunohistochemically, the cells stained positive for CD34, which is diagnostic of GIST.

The term "gastrointestinal stromal tumor" (GIST) has been applied to mesenchymal tumors that represent neither typical leiomyomas nor schwannomas. In this study we analyzed immunohistochemically 67 histologically benign [< 2 mitoses/10 high-power field (HPF)], six borderline (3-5 mitoses/10 HPF), and 23 malignant GIST (> 5 mitoses/10 HPF) and compared them with 10 typical leiomyomas and 5 schwannomas of the gastrointestinal tract. The benign GISTs with spindle cell pattern (67 cases) were typically negative for muscle cell markers (only 3% positive for desmin and 25% for alpha-smooth muscle actin) and S100 protein, but 70% of the cases were positive for CD34, the myeloid progenitor cell antigen also present in endothelial cells and some fibroblasts. However, none of the cases was positive for CD31 (PECAM-1), a more endothelial cell-specific antigen. The absence of CD31 in GIST separates it from Kaposi's sarcoma, a tumor known to be positive for both CD34 and CD31. Fourteen cases of benign GIST of epithelioid cell type showed an immunophenotypic profile similar to the spindle cell tumors. The small intestinal tumors were more commonly actin positive and less commonly CD34 positive than were the gastric tumors. The malignant spindle and epithelioid GIST showed features essentially similar to those in corresponding benign tumors. In contrast, all typical leiomyomas were positive for muscle cell markers and were negative for CD34 and S100 protein. Gastrointestinal schwannomas were S100-protein positive, and negative for muscle markers and CD34. Our results show that gastrointestinal mesenchymal tumors can be immunophenotypically divided in categories that correlate with light microscopically defined diagnostic entities, namely typical leiomyomas, schwannomas, and GIST, most cases of the latter representing tumors of primitive mesenchymal cells that are CD34 positive.

Critical evaluation of the anti-complement immunofluorescence (ACIF) test for Epstein-Barr virus-associated nuclear antigen (EBNA) in known EBV-associated cell lines was carried out. The ACIF procedure, in which the cell smears were thoroughly air-dried and fixed with carbon tetrachloride (for 15 min at room termperature), provided reproducible staining results with minimum variations. The fixed smears coulb be stored for at least 5 weeks at minus 80 degrees C without loss of reactivity. On the basis of the above evaluation, a total of 59 human cell lines, which had unknown or uncertain association with EBV, were examined for the presence or absence of EBNA by the ACIF procedure. All of the cell lines tested could be judged positive or negative for EBNA. All of 21 lines growing as monolayer or in a mixed state of monolayer and suspension, were negative. Of 38 lines grown in suspension, 36 lymphoblastoid lines were positive but the remaining 2 lines (seemingly not lymphoblastoid) were negative.

By means of a semiquantitative antigenic analysis in the reaction of precipitation in agar with the use of a monospecific serum, obtained by the authors, dynamical changes have been studied in the content of the tissue-specific antigen in cells of subcutaneous connective tissue in rats: in the original and tripsinzed tissues, in 3, 6, 16-day and 1--2--3 month and malignized cultures, as well. It was found that at the 3, 11--13 day and then in 2--3 months of explantation there was a decrease in the content of the tissue-specific antigen, that is positively correlated with the degree of cell differentiation.

The expression of the CD10 antigen, formerly designated as common acute lymphoblastic leukemia antigen and recently identified as neutral endopeptidase, was examined immunohistochemically in 26 benign and in 55 malignant mesenchymal tumors. CD10 expression was found in 4 of 4 leiomyomas, 7 of 10 leiomyosarcomas, 1 of 6 rhabdomyosarcomas, 2 of 2 Triton tumors, 1 of 2 aggressive fibromatoses, 1 of 3 fibrosarcomas, 1 of 4 synovial sarcomas, 1 of 1 giant cell tumors of tendon sheath, 4 of 4 malignant fibrous histiocytomas, 3 of 3 Ewing's sarcomas, and 2 of 3 osteosarcomas. Furthermore, CD10 was expressed consistently in the myoepithelial compartment of 12 fibroadenomas and, in 7 of these cases, in a minor stromal cell population, probably of (myo-) fibroblastic origin. Tumors of adipose tissue (4 lipomas, 5 liposarcomas), tumors of autonomic ganglia (2 ganglioneuromas, 1 ganglioneuroblastoma, 2 neuroblastomas), tumors of peripheral nerves with purely schwannian differentiation (7 malignant schwannomas), and tumors of disputed origin were consistently CD10-negative, however, as were single cases of fibroma and chondrosarcoma. These findings indicate that the expression of CD10 is a frequent but not obligatory feature in some mesenchymal tumors. Therefore CD10 is of value in the differential diagnosis of mesenchymal tumors.