Search

Solitary fibrous tumor (SFT) is a relatively rare mesenchymal fibroblastic tumor occurring most commonly in adults with no gender predilection. Although the pathological diagnosis of SFT is usually straightforward, some difficulties may occasionally arise mainly due to the wide morphological spectrum exhibited by this tumor. In the present paper we aimed to evaluate the unusual clinicopathological features in a series of 31 SFTs arising from parenchymal organs, superficial soft tissues and deep soft tissues. Our results emphasize that SFTs may occur anywhere, including unusual sites such as periosteum of the thoracic spine, mesorectal tissue, hepatic hilum, paravescial space, kidney and breast. Moreover, a wide morphological spectrum was observed in tumors included in our series. The most striking morphological features observed included: extensive lipomatous component, myxoid stromal changes, epithelioid cell component, metaplastic mature bone, neurofibroma-like, myxofibrosarcoma-like and pseudoalveolar-like areas. Additionally, multinucleated giant cells and sarcomatous dedifferentiation were also identified. Our paper emphasizes that SFT may occur in unusual anatomical locations and exhibits a wide morphological spectrum. Pathologists must be aware of these features to avoid confusion with other benign and malignant neoplasms that may show overlapping morphological features., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier GmbH.)

Sarcomas are mesenchymal-derived cancers with overlapping clinical and pathologic features and a remarkable histological heterogeneity. While a precise diagnosis is often challenging to achieve, systemic treatment of sarcomas is still quite uniform. In this scenario, next generation sequencing (NGS) may be exploited to assist diagnosis and to identify specific targetable alterations. However, the precise role of genomic characterization in these diseases is still debated. In the present study, we analyzed 18 samples from 11 low-incidence sarcomas using NGS technology. We also used an in-silico prediction tool to reclassify variants of unknown significance and then looked for potentially druggable alterations to match with targeted therapies. Our cohort presented several predictable findings (e.g. MYC amplification in radio-induced angio-sarcoma, COL1A1-PDGFB rearrangements in dermatofibrosarcoma protuberans) along with unexpected results (e.g. the reciprocal WT1-EWSR1 fusion in a desmoplastic small round cell tumor). One third of patients (6/18) displayed at least one actionable molecular alterations. Our experience confirms the potential role of NGS in the management of rare sarcomas. This tool may support the diagnostic process, but also detect targets for personalized therapies., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

STAT6 is usually considered to be a very sensitive and specific immunomarker for diagnosis of solitary fibrous tumor (SFT), being a surrogate of the NAB2-STAT6 fusion gene identified in most cases of this tumor. STAT6 expression has also been reported in rare cases of other soft tissue tumors, such as low-grade fibromyxoid sarcoma, myxoid/round cell liposarcoma, dedifferentiated liposarcoma and deep fibrous histiocytoma. The aim of this study was to report, for the first time, a case of mesenchymal chondrosarcoma showing diffuse aberrant immunohistochemical expression of STAT6. Molecular biology, showing the HEY1-NCOA2 fusion gene, was crucial to rule out SFT., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

A minority of mixed fibro-epithelial lesions of the breast lacks both fibroadenoma and phyllodes architectural patterns and have been previously labeled with different terms, including "hamartomas", "myoid/muscular hamartomas", "benign fibroadenomatous lesions" or "stromo-epithelial lesions of the breast". This study emphasizes the clinico-pathologic features of 5 cases of mammary benign fibro(stromo)-epithelial lesions sharing as a common morphologic theme the presence of minimally infiltrative margins due to the overgrowth of the stromal component into the surrounding fibro-fatty tissue. Notably the radiological features were suspicious for malignancy in 3 out of 5 cases. The following histologic features were seen in all cases: i) an epithelial component of benign glandular structures exhibiting the morphological spectrum of fibro-cystic disease; ii) a stromal component of bland-looking spindle cell myofibroblasts (vimentin + and α-smooth muscle actin +) set in a variably fibro-myxoid stroma. The present paper contributes to widen the morphological spectrum of the benign fibro-epithelial lesions of the breast, emphasizing the possibility that some cases, exhibiting a predominant myofibroblastic stromal component and minimally infiltrative margins, may be confused with other primary spindle cell mimickers of the breast. Accordingly, we propose the descriptive term "benign myofibroblastic/epithelial lesions of the breast with minimally infiltrative margins" for these previously underrecognized lesions., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Uveal melanoma is a rare disease but it is the most common primary intraocular malignant tumor in adults with poor late prognosis. About 50% of patients will develop liver metastasis far from the enucleation within 10-15 years. Our study examined SPANX-C expression levels in primary uveal melanoma both with and without metastasis to assess if they can be used to predict metastasis. This study included a total of 55 patients, 28 males and 27 females, with uveal melanoma. A significantly high expression of SPANX-C was seen in 19/23 (82.6%) patients with metastasis, and only in 11/32 (38.5%) patients without metastasis. In conclusion, we found that SPANX-C expression could play a role in tumor progression of uveal melanoma., (Copyright © 2019. Published by Elsevier GmbH.)

The diagnosis of spindle cell lesions of the breast parenchyma is challenging. Some of these lesions share the expression of CD34, posing differential diagnostic problems, especially in core biopsies. Recently, antibodies against the STAT6 C-terminal, are being used in paraffin-embedded tissues as a surrogate for identifying the NAB2-STA6 fusion gene which is considered a specific molecular marker for solitary fibrous tumor. Accordingly, we investigated the expression of STAT6 in a large series of uncommon spindle cell tumor-like and tumor lesions occurring primarily in the breast parenchyma. We collected 10 classic-type myofibroblastomas, 9 desmoid-type fibromatosis, 6 spindle cell metaplastic carcinoma, 5 benign fibroblastic spindle cell tumors, 3 solitary fibrous tumors, 7 pseudoangiomatous stromal hyperplasias, 2 reactive spindle cell nodules, 1 leiomyoma, 1 spindle cell lipoma, 1 case of inflammatory pseudotumor, 1 nodular fasciitis, 1 myxoma and 1 dermatofibrosarcoma protuberans. A diffuse and strong nuclear STAT6 expression was restricted only to solitary fibrous tumors, while the other lesions were negative or showed only weak cytoplasmic expression. The present study confirms that the demonstration of a diffuse and strong STAT6 nuclear staining is very helpful in distinguishing solitary fibrous tumor from other spindle cell mimics arising in the breast., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Recent immunohistochemical analyses have showed that cyclin D1 is expressed in soft tissue Ewing's sarcoma/peripheral neuroectodermal tumor (PNET) of childhood and adolescents, while it is undetectable in both embryonal and alveolar rhabdomyosarcoma. In the present paper, microarray analysis provided evidence of a significant upregulation of cyclin D1 in Ewing's sarcoma as compared to normal tissues. In addition, we confirmed our previous findings of a significant over-expression of cyclin D1 in Ewing sarcoma as compared to rhabdomyosarcoma. Bioinformatic analysis also allowed to identify some other genes, strongly correlated to cyclin D1, which, although not previously studied in pediatric tumors, could represent novel markers for the diagnosis and prognosis of Ewing's sarcoma/PNET. The data herein provided support not only the use of cyclin D1 as a diagnostic marker of Ewing sarcoma/PNET but also the possibility of using drugs targeting cyclin D1 as potential therapeutic strategies., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Making a correct diagnosis when dealing with a small round blue cell tumor (SRBCT) of children and adolescents may be relatively straightforward if the tumor arises in the typical clinical setting and the classic pathologic features are all recognizable. However it is widely known that diagnostic difficulties may arise because of: (i) many tumors share overlapping morphological and/or immunohistochemical features; (ii) considerable clinical, pathologic, and immunohistochemical variations do exist; (iii) the increasing use of small biopsies in daily practice makes the diagnosis of these neoplasms more challenging. Accordingly, immunohistochemical analyses are currently mandatory in establishing the correct diagnosis. In this regard there is the need to identify more sensitive and specific immunomarkers useful in the distinction of the several tumor entities. Over the last decades, several markers, such as CD99, WT1 protein, desmin, myogenin, NB84, and INI1 have been identified, providing a considerable help in recognition of the most common solid tumors (ESW/pPNET, rhabdomyosarcoma, neuroblastoma, Wilms' tumor, desmoplastic small round cell tumor; malignant rhabdoid tumor) in children and adolescents. However, at the same time, their unusual, unexpected expression can result in a misinterpretation of the immunohistochemical results, especially by pathologists who are not familiar with oncologic pediatric pathology. Therefore the present review focuses on the potential immunohistochemical pitfalls which should be kept in mind by pathologists to prevent diagnostic errors when dealing with SRBCTs., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

The protein cyclin D1 (CD1), which belongs to a family of proteins functioning as regulators of CDKs (cyclin-dependent kinases) throughout the cell cycle, has been immunohistochemically detected in a wide variety of human malignant tumors. The aim of the present study was to investigate immunohistochemically the expression and distribution of CD1 in the developing human peripheral sympathetic nervous system (PSNS) and in childhood peripheral neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas). The above mentioned fetal and neoplastic tissues represent an in vivo model in which undifferentiated neuroblastic cells undergo ganglion cell differentiation. During development, a strong nuclear expression of CD1 was restricted to neuroblasts, disappearing progressively from the maturing ganglion cells with increasing gestational age. In neoplastic tissues, CD1 immunoreactivity was restricted to neuroblastic cell component of all neuroblastomas and ganglioneuroblastomas, whereas it was absent or only focally detectable in maturing/mature ganglion cell component of differentiating neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. We conclude that CD1 is a reliable marker, which can be used routinely to stain neuroblastic cells in both developing and neoplastic tissues. Furthermore, our results indicate that CD1 expression in childhood peripheral neuroblastic tumors recapitulates the changes during normal development of PSNS, as previously reported for Bcl-2 oncoprotein, c-ErbB2, insulin-like growth factor 2, β-2-microglobulin, and cathepsin D. This is consistent with the current view that childhood peripheral neuroblastic tumors exhibit gene expression profiles mirroring those occurring during PSNS development., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Myogenesis is controlled by an elaborate system of extrinsic and intrinsic regulatory mechanisms in all development stages. The aim of this review is to provide an overview of the different stages of myogenesis and muscle differentiation in mammals, starting from somitogenesis and analysis of the different portions that constitute the mature somite. Particular attention was paid to regulatory genes, in addition to mesodermal stem cells, which represent the earliest elements of myogenesis. Finally, the crucial role of growth factors, molecules of vital importance in contractile regulation, hormones and their function in skeletal muscle differentiation, growth and metabolism, and the role played by central nervous system, are discussed., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Cyclin D1 amplification and/or overexpression contribute to the loss of the regulatory circuits that govern G1-S transition phase of the cell cycle, playing pivotal roles in different human malignant tumors, including breast, colon, prostate cancer, lymphoma, melanoma and neuroblastoma. In vitro studies have shown that cyclin D1 is overexpressed in Ewing's sarcoma (EWS)/peripheral Primitive Neuroectodermal Tumor (pPNET), but not in rhabdomyosarcoma cell lines. Only a few immunohistochemical studies are available on cyclin D1 expression in EWS/pPNET, which confirmed its expression only in a limited number of cases. The aim of the present study was a comparative immunohistochemical analysis of the expression and distribution of cyclin D1 in a large series of pediatric/adolescent soft tissue EWS/pPNETs and rhabdomyosarcomas (both embryonal and alveolar subtypes) to assess its potential usefulness in their differential diagnosis. Notably cyclin D1 was strongly and diffusely expressed in all cases (20/20) of EWS/pPNET, while it was lacked in all cases (15/15) of rhabdomyosarcomas. Immunohistochemical overexpression of cyclin D1 in EWS/pPNET is a novel finding which could be exploitable as a diagnostic immunomarker for this tumor. Although highly sensitive, cyclin D1 is not specific for EWS/pPNET, and thus it should not be evaluated alone but in the context of a wide immunohistochemical panel. Accordingly, we first emphasize that when pathologists are dealing with a small round blue cell tumor of soft tissues in pediatric/adolescent patients, a strong and diffuse nuclear expression of cyclin D1 is of complementary diagnostic value to CD99 and FLI-1 in confirming diagnosis of EWS/pPNET and in ruling out rhabdomyosarcoma., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

There is increasing evidence that WT1 protein expression is found not only at nuclear, but also at cytoplasmic, level in several developing and neoplastic tissues. In order to better understand the possible role of WT1 protein in human skeletal myogenesis and oncogenesis of rhabdomyosarcoma, we assessed immunohistochemically its comparative expression in a large series of human developing, adult and neoplastic skeletal muscle tissues. The present study shows that WT1 protein is developmentally expressed in the cytoplasm of human myoblasts from the 6 weeks of gestational age. This expression was maintained in the myotubes of developing muscles of the trunk, head, neck, and extremities, while it was down-regulated in fetal skeletal fibers from 20 weeks of gestational age as well as in adult normal skeletal muscle. Notably, WT1 immunostaining disappeared from rhabdomyomas, whereas it was strongly and diffusely re-expressed in all cases (27/27) of embryonal and alveolar rhabdomyosarcoma. The comparative evaluation of the immunohistochemical findings revealed that WT1 cytoplasmic expression in rhabdomyosarcoma may represent an ontogenetic reversal, and this nuclear transcription factor can also be considered an oncofetal protein which can be exploitable as an additional, highly sensitive immunomarker, together with desmin, myogenin and MyoD1, of this tumor. Moreover, our observations support the rationale for the use of WT1 protein-based target therapy in high risk rhabdomyosarcomas in children and adolescents., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

The aim of this review is to focus on the molecular factors that ensure the optimal development and maintenance of the mammary gland thanks to their integration and coordination. The development of the mammary gland is supported, not only by endocrine signals, but also by regulatory molecules, which are able to integrate signals from the surrounding microenvironment. A major role is certainly played by homeotic genes, but their incorrect expression during the spatiotemporal regulation of proliferative, functional and differentiation cycles of the mammary gland, may result in the onset of neoplastic processes. Attention is directed also to the endocrine aspects and sexual dimorphism of mammary gland development, as well as the role played by ovarian steroids and their receptors in adult life., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Several genes playing crucial roles in human development often reproduce a key role also during the onset and progression of malignant tumors. WT1, a transcription factor expressed with a dynamic pattern during human development, has either oncogenic or suppressor tumor properties. A detailed analysis of the immunohistochemical profile of WT1 protein in human developmental tissues could be exploitable as the rational for better understanding its role in cancerogenesis and planning innovative WT1-based therapeutic approaches. This review focuses on the dynamic immunohistochemical expression and distribution of WT1 protein during human ontogenesis, providing illustrations and discussion on the most relevant findings. The possibility that WT1 nuclear/cytoplasmic expression in some tumors mirrors its normal developmental regulation will be emphasized., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Despite Wilms tumor 1 (WT1) protein was originally considered as a specific immunomarker of Wilms tumor, with the increasing use of immunohistochemistry, there is evidence that other tumors may share WT1 protein expression. This review focuses on the immunohistochemical profile of WT1 protein in the most common malignant tumors of children and adolescents. The variable expression and distribution patterns (nuclear vs cytoplasmic) in the different tumors, dependent on the antibodies used (anti-C or N-terminus WT1 protein), will be emphasized by providing explicative illustrations. Potential diagnostic pitfalls from unexpected WT1 protein expression in some tumors will be discussed in order to avoid diagnostic errors, especially when dealing with small biopsies., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Myofibroblastoma (MFB) of the breast is a relatively rare, benign stromal tumor arising in the breast of both males and females. Several morphological variants have been recognized in the last two decades, including infiltrating, cellular, fibrous/collagenized, epithelioid/deciduoid-like cell, lipomatous and myxoid variants. Myxoid MFB is an extremely rare variant which can represent a potential diagnostic pitfall, posing differential diagnostic problems with other myxoid lesions occurring primarily in the breast parenchyma. We first report an unusual case of mammary MFB showing so extensive myxoedematous stromal changes that obscured the underlying neoplastic cells, rendering difficult its recognition as MFB. Tumor was composed of a few bland-looking spindled, stellate cells embedded in an abundant myxoedematous stroma containing thin and thick collagen fibers and numerous blood vessels with fibrin and foamy histiocytes deposits in their walls. Identification of a small-sized cellular area, with morphological and immunohistochemical features consistent with mammary-type MFB, was crucial for a correct diagnostic interpretation of the lesion. These unusual stromal and vascular features are likely morphological changes to which undergo long-standing mammary MFBs in response to ischemic, traumatic or inflammatory stimuli. Differential diagnostic problems with benign and malignant myxoid lesions of the breast parenchyma are discussed. The present case, for which the term "mammary MFB with extensive myxoedematous stromal changes" is proposed, contributes to widen the morphological spectrum of this unusual mammary tumor, suggesting that when pathologist is dealing with a hypocellular myxoedematous lesion of the breast, a MFB should be ruled out., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

There is increasing evidence that Wilms' tumor transcription factor-1 (WT1) is expressed in the cytoplasm of neoplastic cells from different benign and malignant tumors. Only a few studies on WT1 cytoplasmic immunolocalization are available in pediatric tumors. The aim of the present study was to investigate immunohistochemically the expression and distribution of WT1 in a large series of soft tissue fibroblastic/myofibroblastic lesions occurring in children and adolescents. Notably WT1 was not expressed in nodular fasciitis and desmoid-type (adult) fibromatosis, while it stained diffusely and strongly in several infantile-type fibromatoses, such as fibrous hamartoma of infancy, myofibroma/myofibromatosis, and lipofibromatosis. Interestingly, WT1 cytoplasmic expression was also found in all cases (10/10) of infantile fibrosarcomas examined. The present study shows that a diffuse WT1 cytoplasmic expression is of complementary diagnostic value to conventional myofibroblastic markers (α-smooth muscle actin; desmin) in confirming diagnosis of young-type fibromatoses or infantile fibrosarcoma and in ruling out both desmoid-type fibromatoses and nodular fasciitis. WT1 cytoplasmic expression in infantile fibrosarcoma is a novel finding which could be exploitable as an immunomarker for this tumor. Although highly sensitive, WT1 cytoplasmic immunostaining is not specific for infantile fibrosarcoma, and thus it should be evaluated in the context of a wide immunohistochemical panel when pathologists are dealing with spindle cell lesions of soft tissues in children and adolescents. Accordingly we recommend that a correct diagnosis of fibroblastic/myofibroblastic soft tissue lesion in pediatric patients is usually achieved on the basis of a careful correlation of morphological and immunohistochemical findings in the appropriate clinical context. The different cellular localization of WT1, namely nuclear, cytoplasmic or nucleo-cytoplasmic, in different benign and malignant tumors supports the hypothesis that this transcription factor plays a complex role in tumorigenesis, likely as a chameleon protein functioning as either a tumor suppressor gene or an oncogene, depending on cellular context., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Wilms' tumor protein (WT1) has been immunohistochemically detected in the cytoplasm of some developing, adult normal and neoplastic human tissues, suggesting its complex regulator activity in transcriptional/translational processes. Among neoplastic tissues, WT1 has been documented in the cytoplasm of benign and malignant vascular tumors and in rhabdomyosarcoma, while there are no available studies about its expression in myofibroblastic tumors. Accordingly, we studied immunohistochemically the potential expression of WT1 in mammary myofibroblastoma (MFB), a prototypical myofibroblastic tumor. A series of 18 cases of mammary MFB, including several morphological variants (classic, fibrotic, myxoid, lipomatous, Schwannian-like, and epithelioid variants), were tested with antibodies against the N-terminal of WT1. The most striking finding was a diffuse and strong WT1 cytoplasmic immunostaining restricted to the "epithelioid cell MFB", a rare and diagnostically challenging variant. Conversely the other variants of MFB, including the classic-type, were negative or only focally positive. The present study shows that mammary epithelioid cell MFB should be added to the list of mesenchymal tumors which express WT1 in the cytoplasm of neoplastic cells. Accordingly, we suggest that the detection of WT1 cytoplasmic immunoreactivity is of complementary diagnostic value to conventional myofibroblastic markers in identifying epithelioid cell myofibroblastoma., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Developmental expression of Wilms' tumor gene (WT1) and protein is crucial for cell proliferation, apoptosis, differentiation and cytoskeletal architecture regulation. Recently, a potential role of WT1 has been suggested in the development of neural tissue and in neurodegenerative disorders. We have investigated immunohistochemically the developmentally regulated expression and distribution of WT1 in the human fetal peripheral sympathetic nervous system (PSNS) and the gastro-enteric nervous system (GENS) from weeks 8 to 28 gestational age. WT1 expression was restricted to the cytoplasm of sympathetic neuroblasts, while it progressively disappeared with advancing morphologic differentiation of these cells along both ganglionic and chromaffin cell lineages. In adult tissues, both ganglion and chromaffin cells lacked any WT1 expression. These findings show that WT1 is a reliable marker of human sympathetic neuroblasts, which can be used routinely in formalin-fixed, paraffin-embedded tissues. The progressive loss of WT1 in both ganglion and chromaffin cells, suggests its potential repressor role of differentiation in a precise temporal window during the development of the human PSNS and GENS., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

The Wilms' tumor (WT1) gene and its protein product are known to exhibit a dynamic expression profile during development and in the adult organism. Apart from a nuclear expression observed in the urogenital system, its precise localization in other developing human tissues is still largely unknown. Accordingly, the aim of this study was to investigate immunohistochemically the temporal and spatial distribution of WT1 in epithelial and mesenchymal developing human tissues from gestational weeks 7-24. For this purpose we used antibodies against the N-terminal of WT1. As might be expected, WT1 nuclear expression was observed in mesonephric/metanephric glomeruli, metanephric blastema, celom-derived membranes (pleura, peritoneum, serosal surfaces) and sex cords. With regard to mesenchymal tissues, a similar nuclear staining was also obtained in the mesenchyme surrounding Müllerian and Wolffian ducts, as well as in the submesothelial mesenchymal cells of all celomatic-derived membranes. The most striking finding was the detection of strong WT1 cytoplasmic immunostaining in developing skeletal and cardiac muscle cells and endothelial cells. The tissue-specific expression of WT1, together with its different nuclear/cytoplasmic localization, both suggest that WT1 protein may have shuttling properties, acting as a protein with complex regulator activity in transcriptional/translation processes during human ontogenesis. The reported cytoplasmic expression of WT1 in human rhabdomyosarcomas and in many vascular tumors strongly suggests an oncofetal expression of this protein. Although not specific, WT1 cytoplasmic expression can be used as a marker of skeletal muscle and endothelial differentiation in an appropriate morphological context., (Copyright © 2012 Elsevier GmbH. All rights reserved.)