Search

We report the largest series to date (N = 6) of EWSR1-SMAD3 rearranged fibroblastic tumor. Initially described in 2018, the tumor features a marked female predominance (F:M, 5:1, mean age 44-years, median age 45.5 years; range 27-57), with most cases (5/6, 83%) arising in acral locations (4 on foot/toe, 1 on hand). One case presented on the lower extremity. The lesions presented as nodules and were composed of short, variably cellular, intersecting fascicles of uniform spindled cells in a collagenous to myxoid stroma. In four cases, the tumor abutted the epidermis without a grenz zone. In one case, there was an abrupt transition to a central, acellular hyalinized area. Two other cases had admixed smaller collagenous areas, reminiscent of collagen rosettes. One had a concentric arrangement of tumor cells around blood vessels. Mitotic activity was low (<1/10 HPFs). All were positive for ERG by immunohistochemistry and negative for CD34 (6/6). An EWSR1-SMAD3 fusion was identified in three cases tested by next-generation sequencing (3/3). Rearrangement of EWSR1 by fluorescence in situ hybridization was showed in 1/1 case. Our series reaffirms prior findings and expands the known histopathologic spectrum of this emerging entity., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Uterine inflammatory myofibroblastic tumors (IMTs) have been reported in association with pregnancy and, in some instances, secondarily involve the placenta. The clinicopathological spectrum of these tumors in the setting of pregnancy is not well defined. We investigated the clinical, morphologic, immunohistochemical, molecular cytogenetic, and genetic features of 6 uterine IMTs occurring in pregnant women. Each tumor was discovered at parturition, and none was identified by prenatal ultrasound. Patient age ranged from 25 to 41 years (mean 31.5). Tumor size ranged from 1.5 to 9 cm (mean 4.7). Four of 6 had usual IMT features, with at least focal deciduoid change in 3. Necrosis was identified in 3 tumors; and multinucleated cells, in 3 tumors. Sex hormone receptor expression was consistent with estrogen receptor negative or focally weakly positive and progesterone receptor diffusely moderately or moderately to strongly positive in all 6 tumors. ALK immunohistochemistry was strongly positive in 5 tumors, and all of these had an ALK rearrangement detected by break-apart fluorescence in situ hybridization. Subsequent RNA sequencing of these 5 tumors identified a TIMP3-ALK fusion in 4 and a THBS1-ALK in 1. In the ALK-negative tumor, RNA sequencing detected a novel TIMP3-RET fusion that was confirmed by RET break-apart fluorescence in situ hybridization. Follow-up was available for 2 of 6 patients 5 and 19 months after diagnosis. Neither patient developed recurrence. ALK immunohistochemistry will distinguish most uterine IMTs, but if ALK expression and gene studies are negative, in the appropriate morphologic context, evaluation of other tyrosine kinase genes known to be more commonly altered in extrauterine IMTs such as ROS1, NTRK3, PDGFRβ, and RET may be necessary for diagnostic confirmation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Over the last 10 years, a number of advances have been made in our understanding of fibroblastic and myofibroblastic tumors. The rapidly evolving field of molecular diagnostics has resulted in the recognition of new entities and better understanding of tumor pathogenesis, while careful clinicopathologic correlative analyses have led to improvements in modeling tumor behavior. This review will discuss new and emerging entities in fibroblastic neoplasia and provide updates on the pathogenesis, diagnosis, and prognostication of these diverse and challenging tumors.

Based on histological findings, calcifying fibrous tumor (CFT) may be a late (burned out) stage of inflammatory myofibroblastic tumor (IMT). This concept, however, has not been proven by molecular means. Five CFTs were analyzed for IMT-related rearrangements in ALK, ROS1 and RET using fluorescence in situ hybridization (FISH). Additionally, genome-wide methylation patterns were investigated and compared with IMT (n = 7), leiomyoma (n = 7), angioleiomyoma (n = 9), myopericytoma (n = 7) and reactive soft tissue lesions (n = 10) using unsupervised hierarchical cluster analysis and t distributed stochastic neighbor embedding. CFT patients, 4 females and 1 male, had a median age of 20 years ranging from 7 to 43 years. Two patients were younger than 18 years old. The tumors originated in the abdomen (n = 4) and axilla (n = 1). Histologically, all lesions were (multi) nodular and hypocellular consisting of bland looking (myo)fibroblasts embedded in a collagenous matrix with calcifications. FISH analysis brought up negative results for ALK, RET and ROS1 rearrangements. However, genome-wide methylation analysis revealed overlapping methylation patterns of CFT and IMT forming a distinct homogeneous methylation cluster with exception of one case clustering with myopericytoma/angioleiomyoma. In conclusion, DNA methylation profiling supports the concept that CFT and IMT represent both ends of a spectrum of one entity with CFT being the burn out stage of IMT., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Calcifying fibrous tumor of the pleura (CFTP) is a rare mesenchymal tumor of unknown pathogenesis. The diagnosis often requires exclusion of other common entities. Our aim was to determine if genomic changes were associated with CFTP that could contribute to mechanisms underlying tumorigenesis. Three cases of CFTP with their corresponding uninvolved control lung tissue were identified. Two patients were male, and 1 was female (age range, 21-32 years). Tumors were multifocal in 2 cases and solitary in 1. Immunohistochemistry for STAT6, BCL-2, CD34, cytokeratin AE1/AE3, calretinin, desmin, S100, ALK, and β-catenin was used. All immunohistochemistries were negative in CFTPs. DNA was isolated from all 3 pairs of CFTPs and matching normal lungs for whole-exome sequencing. Damaging, tumor-specific, coding variants were identified in 3 genes including multiple heterozygotic, de novo mutations in the Zinc Finger Protein 717 (ZNF717), fascioscapulohumeral muscular dystrophy-1 (FRG1) and cell division cycle 27 (CDC27) genes. Whole-exome sequencing revealed statistically significant, focal, tumor-specific copy number losses among all CFTPs including a large (302 kb) loss at 6p22.2 comprising 32 genes of the histone cluster 1 family and the hemochromatosis (HFE) gene. This is the first study to evaluate the molecular pathogenesis of CFTP and to identify novel deleterious mutations in ZN717, FRG1, and CDC27 genes as well as significant copy number losses on 8 chromosomes with a large loss common to all samples on chromosome 6. These mutations deleteriously altered coding domains in a manner predicted to be damaging to protein function and may contribute to CFTP tumorigenesis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Benign/low-grade fibroblastic tumors encompass a broad spectrum of tumors with different morphologies and molecular genetic abnormalities. However, despite significant progress in recent genomic characterization, there are still tumors in this histologic spectrum that are difficult to classify, lacking known molecular characteristics. Triggered by a challenging congenital spindle cell neoplasm arising in the heel of a 1-year-old boy, we applied RNA sequencing for genetic discovery and identified a novel EWSR1-SMAD3 gene fusion. On the basis of the index case superficial acral location and fibroblastic appearance with a nonspecific immunophenotype, we searched our files for similar cases and screened them by fluorescence in situ hybridization for these abnormalities. Thus an identical EWSR1-SMAD3 fusion was identified in 2 additional spindle cell tumors with similar clinicopathologic features. Both cases occurred in the feet of adult women (58 and 61 y old) and were characterized by distinctive nodular growth with zonation pattern of peripheral hypercellular areas arranged in short fascicles, transitioning to hypocellular central areas of hyalinization and infarction. Focal stippled calcification in the collagenous area was present in 1 case. All 3 tumors had similar immunoprofiles, being negative for SMA, CD34, CD31, and S100, but showing consistent ERG positivity of uncertain significance. Follow-up information was available in 2 patients who developed local recurrences after incomplete initial excisions, at 5 and 14 months, respectively. None developed metastatic disease. In summary, we report a group of locally recurrent superficial acral tumors, characterized by bland spindle cell fascicular growth, occasional zonation pattern, ERG positivity, and recurrent EWSR1-SMAD3 gene fusions.

Here, we report an inflammatory myofibroblastic tumor (IMT) of the urinary bladder with a novel HNRNPA1-ALK fusion. To the best of our knowledge, this is the first case of a tumor with HNRNPA1-ALK fusion. A 42-year-old Japanese man underwent total cystectomy because of an invasive urinary bladder tumor. Grossly, the tumor had invaded the peribladder fat tissue. Histologically, it comprised spindle neoplastic cells with intermingled inflammatory cells. Immunohistochemically, it was positive for ALK, SMA, desmin, cytokeratin, and vimentin, consistent with the immunohistochemical characteristics of IMTs. Fluorescence in situ hybridization demonstrated an ALK split, and the presence of HNRNPA1-ALK was revealed by RNA sequencing. We identified a novel transcript fusion of exon 2 of HNRNPA1 and exon 18 of ALK, resulting in ALK protein overexpression. These findings provide useful information on the biology and tumorigenesis of IMTs, thus facilitating the development of molecular-targeted therapeutics., (Copyright © 2017 Elsevier Inc. All rights reserved.)

HT1080 - a human fibrosarcoma-derived cell line - forms aggressive angiogenic tumours in immuno-compromised mice. In spite of its extensive use as a model of tumour angiogenesis, the molecular event(s) initiating the angiogenic program in these cells are not known. Since hypoxia stimulates tumour angiogenesis, we examined the hypoxia-induced events evoked in these cells. In contrast to cells grown under normoxic conditions, hypoxia-primed (1% O(2)) HT1080 cells formed robust tubules on growth factor-reduced matrigel and formed significantly larger tumours in xenograft models in a chetomin-sensitive manner, indicating the role of HIF-1α-mediated transcription in these processes. Immuno-histochemical analyses of tumours formed by GFP-expressing HT1080 cells clearly showed that the tumour cells themselves expressed various angiogenic markers including Neuropilin-1 (NRP-1) and formed functional vessels containing red blood cells, thereby unambiguously demonstrating the vasculogenic mimicry of HT1080 cells in vivo. Experiments performed with the HT1080 cells stably transfected with plasmid constructs expressing shNRP-1 or full-length NRP-1 clearly established that the HIF1α-mediated up-regulation of NRP-1 played a deterministic role in the process. Hypoxia-exposure resulted in an up-regulation of c-Myc and OCT3/4 and a down-regulation of KLF4 mRNAs, suggesting their involvement in the tumour formation and angiogenesis. However, silencing of NRP-1 alone, though not affecting proliferation in culture, was sufficient to abrogate the tumour formation completely; clearly establishing that the hypoxia-mediated HIF-1α-dependent up-regulation of NRP-1 is a critical molecular event involved in the vasculogenic mimicry and tumor formation by HT1080 cells in vivo.

Calcifying fibrous tumor (CFT) is a rare benign mesenchymal tumor composed of hyalinized fibrous tissue with interspersed bland fibroblastic spindled cells, scattered psammomatous, and/or dystrophic calcifications and variably prominent mononuclear inflammatory infiltrate. CFTs show a predilection for the abdominal cavity and soft tissue. To date, 6 gastric and 3 intestinal CFTs have been reported. We analyzed 7 gastric CFTs including 6 new cases. Patients were 4 men and 3 women with a mean age of 53 years (range, 40 to 77). Mean tumor size was 2.2 cm. Most tumors originated in the gastric body (6/7). Six were incidental findings at autopsy or during surgery for other diseases. One ulcerated tumor caused iron deficiency anemia and ulcer symptoms. Six tumors involved the muscularis propria with variable submucosal and subserosal extension and 1 arose within thickened muscularis mucosae adjacent to a mucosal invagination. Histology was typical with uniformly hypocellular vaguely storiform collagen, lymphoplasmacytic infiltrates, lymphoid aggregates and psammomatous, and dystrophic calcifications. Peritumoral lymphoid aggregates were seen in 3 cases. Adjacent muscle coat contained lymphoid aggregates with fiber degeneration (2), minute CFT-like foci (1), and calcifications (1). In none of the cases were there remnants of burnt-out GIST, inflammatory fibroid polyp, inflammatory myofibroblastic tumor, leiomyoma, schwannoma, or other specific lesion. All tumors were negative for CD117, S100, smooth muscle actin, desmin, ALK1, h-caldesmon, and PDGFRA. Two stained focally with CD34. Scattered IgG4-positive plasma cells were seen in 4 of 6 cases stained with this marker. All 5 tumors with available tissue for molecular analysis were wild-type for KIT and PDGFRA. Three patients had follow-up (range, 12 to 24 mo); none developed recurrence. Gastric CFTs are distinct from sclerosing GIST and other mesenchymal gut lesions and may represent a localized inflammatory fibrosclerosis in response to immune-mediated or other-type tissue injury affecting the muscularis propria. They differ from soft tissue CFTs by smaller size, older age at presentation and lack of recurrence, and from peritoneal CFTs by equal gender distribution, older age, and absent multifocal occurrence.

We report on a case of a solitary fibrous tumor that developed in the thigh of an 82-year-old woman. The tumor was composed of areas of high-grade sarcoma and typical solitary fibrous tumor. Its karyotype was: 70,XXX,+X[4],+1[2],add(1)(p36)[4],add(1)[2],+2[4],-3[4],+6[4],add(6)(p11)x2[4],+7[4],+9[3],-11[4],-12[4],-13[4],add(13)(p11)x2[4],-14[4],+15[4],-16[3],-17[4],-19[4],+20,[4],+21[4],+22[2],+mar1x2[4][cp4].

A case of solitary fibrous tumor of the pleura with the karyotype 46,XY,t(8;12)(p11.2;q24.3) is reported. Although rearrangement of 12q15 approximately 24 is a recurring abnormality in solitary fibrous tumors, rearrangement of chromosome 8 was previously unreported in these tumors.

Lipomatous hemangiopericytoma is a rare mesenchymal tumor showing areas of lipid-containing cells admixed with a spindle-cell component. Like other hemangiopericytomas, it shows a similar vascular pattern to solitary fibrous tumor and, partly for this reason, it and other hemangiopericytomas have been subsumed into solitary fibrous tumor. The present study provides a comprehensive documentation of a single case of pulmonary lipomatous hemangiopericytoma of the lung, the first to be described at this site, and compares it with solitary fibrous tumor, in terms of clinical, histological, immunohistochemical, ultrastructural, and cytogenetic findings. Apart from the lipid-laden-cell component, pulmonary lipomatous hemangiopericytoma and solitary fibrous tumor were similar histologically. Bcl-2 was positive in both. CD34 was minimally expressed in pulmonary lipomatous hemangiopericytoma, which possessed some non-descriptive intercellular junctions, a feature shared by solitary fibrous tumor, which was CD34 positive. However, one of the latter was rich in gap junctions, a feature consistent with strong connexin (Cx) 43 staining and the existence, hitherto unappreciated, of a CD34/Cx43-positive tumor cell network. In pulmonary lipomatous hemangiopericytoma, chromosomal deletions of 43-44, X, -Y were found. In solitary fibrous tumor, 46, XY, del(13)(q?) abnormalities and abnormalities involving chromosome 10 were frequently observed. These similarities and differences are discussed in the context of the currently favored diagnostic fusion of hemangiopericytoma and solitary fibrous tumor.

A 3-month-old African American female infant had a rapidly growing lipoblastoma with a prominent fibrous component in the soft tissue of the left lateral knee, which recurred at 10 months. Cytogenetic analysis revealed deletion of 8(q11.2q13) with a 19(q12q13.3) insertion at that site, confirming that this is closely related to the conventional lipoblastoma. The presence of multivacuolated lipoblasts and the staining characteristics (no staining for CD99, CD34, or smooth muscle actin) distinguish this from the recently described lipofibromatosis.

We report the case of an 18-month-old girl who came to medical attention with a left cervical mass. Surgical excision was performed 16 months later. Histology revealed a fibrous hamartoma of infancy. Follow-up has been uneventful, and no recurrence of the mass has been observed. Cytogenetic analysis showed a complex translocation involving chromosomes 6, 8, and 12, namely, t(6;12;8)(q25;q24.3;q13). This case represents the second cytogenetic analysis reported to date in fibrous hamartoma of infancy and reveals a different translocation than the reciprocal translocation t(2;3)(q31;q21) previously reported.

Pleural malignant solitary fibrous tumors (SFTs) are uncommon, and little is known about their histogenesis and molecular features. We report a case of pleural SFT with sarcomatous overgrowth that showed expression for PDGFRbeta and a missense mutation on exon 18 of the PDGFRbeta gene. The involvement of the PDGFRbeta gene in SFT is compatible with a pericytic derivation, also supporting a possible role of this tyrosine kinase in malignant transformation and in the adoption of novel molecular therapies.

Using comparative genomic hybridization (CGH), array CGH, fluorescence in situ hybridization, and loss of heterozygosity analysis, we examined a recurrent solitary fibrous tumor of the orbit for chromosomal imbalances. In the primary tumor, loss of chromosomal material was observed at 9p, 9q, and 16q. In the first recurrent tumor, cells with these abnormalities were detected, but in some parts of the tumor, cells with losses at 13q (homozygous deletion at 13qter) and 20p were dominant. In the second recurrence, only cells with losses at 13q and 20p were seen. Although morphologically similar, the second recurrent tumor invaded the anterior cranial fossa and demonstrated considerably faster growth than the first recurrent tumor. Thus, the clone of tumor cells that dominated the second recurrent tumor was shown by cytogenetic analysis to be different from that present in the primary tumor, and was associated with a more aggressive nature of the tumor.

This report describes the occurrence of solitary fibrous tumors of the pleura in a mother and her daughter. No other occurrence of this rare tumor in members of the same family has ever been reported.

We report a case of a benign solitary fibrous tumor that occurred in the right shoulder of a 9-year-old girl. This case is remarkable due to the unusual location of its occurrence and the young age of the patient. In addition, cytogenetic analysis revealed a karyotype unreported in this neoplasm: 46,XX,der(4)t(4;9)(q31.1;q34), del(9)(p22p24),der(9)t(4;9)(q31.1;q34)ins(9;?)(q34;?) (17 cells)/46,XX (3 cells).

Calcifying fibrous tumor (CFT) is usually solitary, involving the soft tissue, pleura, or peritoneum. The cause and pathogenesis are unclear. Cases with multifocal lesions are rare, and a familial occurrence has not been reported. Herein, a family in which 2 sisters developed multifocal peritoneal CFT is described. The sisters each had abdominal pain, and each was found at laparotomy to have multiple nodular lesions on the mesenteric, omental, and small bowel serosal surfaces. Many lesions were composed of collagenous, paucicellular, fibrous tissue with psammomatous or dystrophic calcification, consistent with CFT. Some lesions were composed of more cellular spindle-celled tissue resembling inflammatory myofibroblastic tumors. Both patients were alive and well 19 and 17 years after diagnosis, respectively. One other sibling and 2 children of one of the sisters were speculated to have the same disorder, based on clinical findings. This report suggests that there may be genetic susceptibility to CFT, although chance and common environmental etiologic factors cannot be excluded.

The majority of solitary fibrous tumors (SFTs) of the pleura are benign, but 10-30% locally recur or metastasize. Pathogenic factors relevant to the determinism of their biological properties are largely unknown. Cytogenetic data on SFTs of the pleura are sparse. We report herein a case of a malignant SFT of the pleura where successful karyotyping was obtained from the primary and recurrent tumors. The initial karyotype showed two abnormal clones: 48, XY; +8; +8; del(9)(q22; q32) [19] and 46, XY, t(1;16)(q25;p12) [7]. Culture of the recurrent tumor yielded one clone identical to the dominant clone of the initial karyotype. Demonstration of a recurrent abnormal karyotype largely supports its relevance to the malignant clone and suggests a role of supernumerary chromosome(s) 8 in the determinism of malignant behavior in SFT.

Solitary fibrous tumors (SFTs) are rare neoplasms with a probable mesenchymal origin that were first reported in the pleura but can occur in different sites. We report a case of SFT arising in the inguinal region of a 55-year-old woman. The patient presented with a mass in the left groin; she underwent wide excision of the lesion which was well-circumscribed and without evidence of adjacent soft tissue involvement. The histological, immunohistochemical and electron microscopic criteria for SFT were found. She had an uneventful recovery and she is alive without evidence of disease five years after operation. To our knowledge, this neoplasm has never been reported in this location.

Solitary fibrous tumor (SFT) is a mesenchymal neoplasm found predominantly in the subpleural region but also in many other body sites. We report a malignant solitary fibrous tumor of the peritoneum with a 47,XY,t(4;9)(q13;p23),+5 karyotype. The chromosome 4q13 breakpoint in the presented and previously published case of pleural solitary fibrous tumor with a 46,XY,t(4;15)(q13;q26) karyotype was further characterized by fluorescence in situ hybridization analysis and localized within the 5-cM interval that was flanked by regions specific to YAC clones 761A7 and 886C11. Chromosome translocations involving chromosome 4q13 may characterize a separate cytogenetic subgroup of SFT.

Aims: Cytogenetic data on solitary fibrous tumours (SFT) are very limited. We studied a benign pleural SFT for its ultrastructural and immunohistochemical details, and made cytogenetic analyses for comparison with other genetic and ultrastructural studies of SFT., Results: Immunohistochemistry showed strong positivities for CD34 and vimentin, but no reactions with anti-cytokeratins and epithelial membrane antigens. Electron microscopy revealed primitive desmosomes in our SFT. The results thus evinced fibroblast-like cells with intermediate epithelial-mesenchymal character. Comparative genomic hybridization of the tumour revealed losses of 1p33-->pter, 17pter q21, entire copies of chromosomes 19 and 22, and gains of 1p21-p22, 2q23-q32.3, 3pl2-q13.2, 4p14-q28, 6p12-q21, 9p21-->pter and 13q21-q31. Furthermore, there was loss of 20q, as was previously reported elsewhere in a case of benign and a case of malignant SFT., Conclusions: The results furnish further evidence of the involvement of -20q in SFT. In addition, they show that SFT may have complex genomic imbalances and primitive features, despite having a benign appearance.

Background: Malignant transformation requires the accumulation of multiple genetic alterations such as chromosomal abnormalities, oncogene activation, loss of tumor suppressor genes, or abnormalities in genes that control DNA repair and genomic instability. Sarcomas are a heterogeneous group of malignant mesenchymal tumors of difficult histologic classification and strong genetic predisposition. This article provides a comprehensive review of the cytogenetic abnormalities observed in bone and soft-tissue tumors, emphasizing known downstream molecular changes that may play a role in oncogenesis., Methods: The database of the National Library of Medicine was searched for literature relating to genetic and molecular mechanisms in sarcomas in general and in each of the main tumor entities., Results: Recent techniques in chromosome analysis and molecular cytogenetics have improved our ability to characterize genetic changes in mesenchymal tumors. Some changes are so characteristic as to be virtually pathognomonic of particular histologic types, while others are complex, difficult to characterize, and of unknown relevance to pathogenesis. The implications to the cell of some of these abnormalities are now being recognized., Conclusions: The study of sarcomas will benefit from the information derived from genetic studies and translational research. The human genome project and new methodologies, such as computer-based DNA microarray, may help in the histogenetic classification of sarcomas and in the identification of molecular targets for therapy.

Solitary fibrous tumors are well-described neoplasms found predominantly in the subpleural region but also in many other body sites. They generally behave in a benign fashion, although a few cases that exhibit a malignant course have been reported. Genetic information on solitary fibrous tumors is sparse. This case illustrates a previously unreported finding of a tumor-specific t(9;22)(q31;p13) in a solitary fibrous tumor of the orbit of a 58-year-old man.

Soft-tissue tumors have proved to be a fruitful area for the identification of reproducible cytogenetic aberrations, especially among pediatric round-cell sarcomas and lipomatous tumors. Thus far, however, data regarding sarcomas of monomorphic spindle cell type have been limited and somewhat disappointing, with the notable exception of synovial sarcoma. As part of an ongoing international collaborative study, 130 karyotyped spindle-cell sarcomas were reviewed and classified histologically, without knowledge of the clinical and karyotypic data, with the aim of identifying objective correlations between morphology, karyotype, and clinical parameters. Clonal chromosomal abnormalities were identified in 82 cases studied (63%), but only in the group of synovial sarcomas was there clear correlation between the cytogenetic findings, in the form of a consistent t(X;18)(p11;q11), and morphology. Among leiomyosarcomas (41 cases) and malignant peripheral nerve sheath tumors (MPNSTs; 27 cases) as well as in individual examples of rarer entities, there was a general tendency for karyotypic complexity associated with frequent loss or rearrangement of chromosome arms 1p, 10p, 11q, 12q, 17p, and 22q. Rearrangements of 17q (the region of the NF1 gene) were seen in 9/27 (33%) of MPNSTs. Among nine cases of solitary fibrous tumor (in which previous cytogenetic data are very limited) no consistent aberrations were identified. We conclude that, with the exception of synovial sarcoma, most spindle-cell sarcomas share with pleomorphic sarcomas the tendency for karyotypic complexity. There was no indication (in most of these lesions) that detectable cytogenetic aberrations could either facilitate their diagnosis or help to determine prognosis. There is a clear need to further study and understand the significance of multiple chromosomal abnormalities in this group of mesenchymal neoplasms with the particular goal of determining their role in the process of tumor development.

Solitary fibrous tumor (SFT) presenting in the pleura and other soft tissue sites and hemangiopericytoma (HPC) presenting at various soft tissue sites are mesenchymal tumors that share many histologic and immunohistochemical features. This raises the questions of whether these tumors are related and whether they belong within the spectrum of a single biologic entity. The behavior of both SFTs and HPCs is difficult to predict histologically. The genetic background of both SFTs and HPCs is poorly known, but it could be helpful in the evaluation of malignancy and could give clues to their possible relationship. In this study, we analyzed 15 SFTs and 11 HPCs by comparative genomic hybridization (CGH), a powerful molecular cytogenetic tool that can be applied to DNA extracted from formaldehyde-fixed and paraffin-embedded tissue. All of these tumors were immunohistochemically similar and showed reactivity for CD34-antigen but not for keratins, desmin, or muscle actins. Only 1 SFT smaller than 10 cm showed DNA copy number changes (a single loss in chromosome 13), but 7 of 8 SFTs larger than 10 cm (including all 4 tumors with more than 4 mitoses per 10 high power fields) showed changes, mostly chromosomal gains in 5q 7, 8, 12, and 18. Four cases showed losses, two of them in chromosome 13 and two others in 20q. These findings suggest that CGH might be useful in the evaluation of malignant transformation in SFT. The most common change, gain of the entire chromosome 8, seen in two cases as the only change, suggests trisomy 8 and parallels a similar finding previously described in other fibrous tumors, such as subsets of desmoid fibromatosis and infantile fibrosarcoma. In contrast, HPCs, including large and mitotically active tumors, showed no DNA copy number changes on CGH. This suggests that HPC is genetically different from SFT.

An immunohistochemical method utilizing microwave oven treated avidin-biotin complex (ABC) technique was used in this study to detect P53 protein expression in 87 parafin-embedded fibrous neoplasm tissues. The results showed that the total positive staining rate was 20.7%. The positive staining rate in fibroma (FA), dermatofibrosarcoma protuberans (DFSP) fibrosarcoma (FS) and malignant fibrous histiocytoma (MFH) were 0%, 4.0%, 37.5% and 62.5% respectively. The positive staining rate of P53 protein was increased with the increase in malignancy of the neoplasma. The expression of P53 protein was not correlated with the subtypes of DFSP and MFH, but correlated with cell differentiation. Therefore, detection of P53 protein expression may have significant value in the evaluation of malignancy, metastatic potential and the prognosis of fibrous neoplasma.

Myxoid liposarcomas have a unique and specific t(12;16)q13;p11) chromosomal translocation. The breakpoint has recently been identified and shown to involve the TLS/FUS gene on chromosome 16 and the CHOP gene on chromosome 12. This translocation causes fusion of these genes resulting in the expression of a novel chimeric TLS/FUS-CHOP message. Using the polymerase chain reaction with primer sets derived from sequences of TLS/FUS and CHOP cDNAs, we could amplify three types of the fusion transcripts from seven of seven samples of myxoid and round cell liposarcomas. In six of the seven positive samples, two kinds of chimeric messenger RNAs were found that have been reported previously. However, the last sample had a novel chimeric message that had an extra sequence of 33 bp derived from the TLS/FUS gene. Thus, it was shown that these fusion transcripts had a varying extent of the sequence of TLS/FUS gene incorporated at the site of the fusion. However, the TLS/FUS-CHOP fusion transcripts were not detected in two pleomorphic liposarcomas or in three myxoid variants of malignant fibrous histiocytomas. Our findings indicate that in liposarcomas TLS/FUS-CHOP fusion transcripts have variations at the junction of chimeric messages, which was the case for Ewing's sarcoma. Detection of the chimeric message by reverse transcription polymerase chain reaction was also suggested to be a useful approach for the diagnosis of myxoid and round cell liposarcomas that have (12;16) translocation, and for distinguishing them from pleomorphic liposarcoma and myxoid variant of malignant fibrous histiocytomas.

Characteristic chromosome abnormalities and karyotype profiles are emerging for the soft tissue tumors. The notable findings are summarized in the Table 1. Within the broad range of solid tumors, it is certainly the soft tissue tumors in which the most spectacular success has occurred with regard to neoplasia-associated chromosome abnormalities. Cytogenetic studies of soft tissue tumors have been encouraged by the early and growing supporting interest of pathologists and clinicians concerned with soft tissue tumors. However, when one considers the variety of types and subtypes of benign and malignant soft tissue tumors, the number that has been so far characterized by a specific chromosome change is still very small. But, as we attempt to demonstrate in this report, these data should be viewed as paradigms for the importance of cytogenetic investigations in solid tumors. Cytogenetic studies of solid tumors are of more than clinical interest. Cytogenetic studies allow molecular investigations of the chromosomal breakpoints. They allow the search to proceed for genes involved in the chromosomal changes, providing a better knowledge of the malignant transformation process. In addition, the fruits of the combined efforts in cytogenetic and molecular technologies, from which has come "molecular cytogenetics," will let us recognize more conveniently, more quickly and, hopefully, less expensively the well-characterized diagnostic chromosome markers in tumor cells. Thus, we may be able to reach the goal of incorporating cytogenetics into standard diagnostic procedures for solid tumors, as has been achieved with hematological malignancies. Molecular cytogenetics including fluorescent in situ hybridization (FISH) technology promises to bring soft tissue tumor cytogenetics into regular diagnostic armamentaria and concurrently speed research into the basis of soft tissue tumors.

Mutations in the p53 tumor suppressor gene occur in > 50% of human malignancies, but are exceedingly rare in benign tumors. The malignant potential of fibrous tumors of children may be unpredictable at microscopic examination. We therefore sought to determine whether malignant fibrous tumors could be distinguished from their benign counterparts by the presence of mutations in p53. We screened 27 fibrous tumor samples from 20 young patients. Tumors were classified as benign, borderline, or malignant by conventional microscopic criteria. RNA extracted from each specimen was used as the template for reverse transcription followed by polymerase chain reaction (PCR) amplification, with six pairs of primers covering the whole coding region of the p53 gene. All PCR products were screened for the presence of mutations using single-strand conformation polymorphism analysis. In addition, PCR products encompassing exons 5-9, the sites of the most frequent mutations in human tumors, were sequenced directly. Both methods detected a single point mutation in a highly malignant tumor (malignant fibrous histiocytoma). The mutation was a silent one at codon 36 (CCG-CCA, Pro-Pro). We conclude that p53 mutations are infrequent in childhood fibrous tumors, consistent with previous observations of low malignant potential (< 10%) and better prognosis in this tumor group. Therefore, screening for p53 mutations is not a useful prognostic indicator in fibrous tumors with borderline pattern at microscopic examination.