EGFR internal tandem duplications in fusion-negative congenital and neonatal spindle cell tumors.

Next-generation sequencing (NGS) assays can sensitively detect somatic variation, and increasingly can enable the identification of complex structural rearrangements. A subset of infantile spindle cell sarcomas, particularly congenital mesoblastic nephromas with classic or mixed histology, have structural rearrangement in the form of internal tandem duplications (ITD) involving EGFR. We performed prospective analysis to identify EGFR ITD through clinical or research studies, as well as retrospective analysis to quantify the frequency of EGFR ITD in pediatric sarcomas. Within our institution, three tumors with EGFR ITD were prospectively identified, all occurring in patients less than 1 year of age at diagnosis, including two renal tumors and one mediastinal soft tissue tumor. These three cases exhibited both cellular and mixed cellular and classic histology. All patients had no evidence of disease progression off therapy, despite incomplete resection. To extend our analysis and quantify the frequency of EGFR ITD in pediatric sarcomas, we retrospectively analyzed a cohort of tumors (n = 90) that were previously negative for clinical RT-PCR-based fusion testing. We identified EGFR ITD in three analyzed cases, all in patients less than 1 year of age (n = 18; 3/18, 17%). Here we expand the spectrum of tumors with EGFR ITD to congenital soft tissue tumors and report an unusual example of an EGFR ITD in a tumor with cellular congenital mesoblastic nephroma histology. We also highlight the importance of appropriate test selection and bioinformatic analysis for identification of this genomic alteration that is unexpectedly common in congenital and infantile spindle cell tumors.

Cutaneous VCL::ALK fusion ovoid-spindle cell neoplasm.

Cutaneous VCL::ALK fusion spindle (ovoid) cell tumor is unique. Recently emerged RAS::MAP tyrosine kinase fusion sarcomas more commonly involve subcutis, skeletal muscle and even bone. We share our experience with a novel cutaneous VCL::ALK spindle cell tumor. An 11-year-old male presented with a back pedunculated pink-red papule thought to be a pyogenic granuloma. Biopsy histopathology revealed an epithelial collarette with pedunculated tumor extending to deep dermis/subcutis interface. The combination of spindled and epithelioid cells, an ovoid myopericytoid appearance within myxoid to collagenous stroma, low to moderate MIB1 and focal S100 protein without SOX10 immunostaining, were suggestive of a novel RAS::MAPK tyrosine kinase fusion sarcoma that is well described. ALK immunostain being positive, a next-generation sequencing comprehensive fusion panel was performed to reveal a VCL::ALK fusion. While epithelioid fibrous histiocytoma shares this fusion and similar dermal location and collarette pedunculation, this and other entities were excluded by older patient age, deeper dermal involvement, ovoid-to-spindled morphology, central pericytoid vasculature, myxoid stroma, moderate cellularity with low to moderate MIB1 expression, superficial ulceration, and focal S100 protein expression. Complete excision was performed with favorable follow-up to date. This novel VCL::ALK fusion spindle (ovoid) cell tumor of the dermis is best considered as part of the recently emerged RAS::MAP tyrosine kinase fusion sarcomas.

Solitary fibrous tumor of the caruncle: a solitary location.

A 78-year-old Caucasian male presented with diplopia and decreased vision in the left eye for 1 month, in addition to a painless fleshy lesion in the inner corner of the left eye for 3-month duration. His best-corrected visual acuity was 20/40 and 20/50. Slit lamp examination revealed a left medial conjunctival and caruncular lesion, measuring 6 mm by 4 mm. Histology of the excised mass showed a cellular submucosal spindle cell neoplasm without cytologic atypia and rare mitoses, immunohistologically diffusely positive for CD34 and STAT6, and negative for SMA. Based on these findings, solitary fibrous tumor was diagnosed. With the combined diagnostic power of light microscopy and immunohistochemistry, SFTs are diagnosed increasingly and more accurately in the orbit. With this first case report of a caruncular SFT, we believe that SFTs should remain on the differential for mesenchymal tumors of the conjunctiva and caruncle.

A rare low-grade myofibroblastic sarcoma in lower jaw with the resemblance to benign lesions.

BACKGROUND: Low-grade myofibroblastic sarcoma (LGMS) is a rare solid infiltrative soft tissue tumor with a predilection for the head and neck region. CASE PRESENTATION: We report the diagnostic steps of a fast-growing lesion of the lower left jaw in a 45-year-old otherwise healthy woman. A first biopsy and subsequent histopathological examination showed potential differentials of a benign myofibroma, benign nodular fasciitis or an LGMS. This diagnostic overlap was a challenge for the decision of the further treatment approach. The treatment consisted of a segmental en bloc resection of the mandible including the second premolar, first and second molar. Histopathological examination of the resected tumor confirmed an LGMS. CONCLUSION: The histopathologic resemblance of LGMS to a range of benign and reactive tumors may lead to misdiagnosis and mistreatment. The rarity of LGMS explains the lack of established treatment protocols. This case shows the importance of adequate clinical decisions, expertise in the histopathology of rare tumors and interdisciplinary exchange to achieve state-of-the-art patient management.

Spindle cell tumor with CD34 and S100 co-expression and distinctive stromal and perivascular hyalinization showing EML4-ALK fusion.

Recently, a novel group of CD34+ and S100+ spindle cell tumors with distinctive stromal and perivascular hyalinization showing recurrent gene fusions involving RAF1, BRAF, NTRK1/2/3, and RET has been identified. ALK rearrangements have been rarely reported in this group of tumors. We report a 24-year-old woman with a 1.5-cm pink mass of the scalp. The tumor was made of spindle cells organized in fascicles or haphazardly arranged in a patternless architecture, with areas of stromal and perivascular hyalinization. The tumor cells diffusely expressed CD34 and S100, without SOX-10 expression. The tumor showed diffuse immunopositivity for ALK. RNA sequencing using next-generation sequencing (NGS) detected an EML4-ALK fusion. This case extends the spectrum of this newly described group of CD34+/S100+ spindle cell tumors at the molecular-genetic level. Dermatopathologists should be aware of this recent entity, as it may fall in the differential diagnosis of many other spindle cell tumors with CD34 expression. NGS-based techniques should be performed when facing spindle cell tumors with similar morphology and immunophenotype. Identification of kinase fusions is essential for the precise classification and better knowledge of these tumors, and for targeted therapy in rare aggressive cases.

Primary pulmonary hyalinizing spindle cell tumor with giant rosettes: A clinicopathological and immunohistochemical study of 2 cases.

Two cases of primary intrapulmonary hyalinizing spindle cell tumor with giant rosettes are presented. The patients are one woman and one man ages 37 and 42 years respectively. Both patients presented with non-specific symptoms of cough, dyspnea, and chest pain. Imaging revealed the presence of an intrapulmonary mass. One tumor was located in the left lower lobe while the other tumor was in the right upper lobe. Both patients underwent lobectomy. The tumors ranged from 2.4 to 3.0 cm in greatest dimension and were characterized by the presence of a bland spindle cell proliferation with areas of hyalinization and the presence of the so-called giant rosettes. Immunohistochemical stains were performed and the spindle cell component show positive staining for vimentin and negative staining for Bcl-2, CD34, STAT6, p40. Keratin immunohistochemical stain highlighted the entrapped alveolar epithelium while S-100 protein showed weak focal staining in the spindle cells. Both patients have remained alive and well without evidence of recurrence or metastasis for a period of 6 to 14 months post-surgical resection. The cases herein presented highlight the ubiquitous distribution of this tumor and underscores the importance of keeping this particular tumor in the differential diagnosis of spindle cell tumors of the lung.

S100 and CD34 positive spindle cell tumor with prominent perivascular hyalinization and a novel NCOA4-RET fusion.

We report a case of a 35-year old male patient with a tumor located in the deep dermis on his forearm. The lesion was completely excised but recurred 4 years later. The patient showed no signs of neurofibromatosis type 1. The morphology and immunophenotype of the tumor corresponded to the recently characterized group of soft tissue spindle cell lesions defined by a relatively uniform cytomorphology, patternless architecture, conspicuous stromal and perivascular hyalinization, S100 and CD34 coexpression and recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Using a 592-gene panel and massively parallel next-generation sequencing platform, we initially detected only NF1 gene mutation in our case. However, further molecular testing with Archer fusion assay revealed a novel NCOA4-RET gene fusion, adding it to the list of multiple kinase fusions originally reported in these tumors. Although break-apart FISH showed false negative result due to the presence of intrachromosomal rearrangement, RT-PCR confirmed the fusion transcript. Knowing the exact fusion is of great clinical importance especially for patients within the aggressive subset of these neoplasms that could be treated with selective kinase inhibitors. The presented case underscores the benefits of massively parallel sequencing as the types and number of gene fusions these tumors can potentially harbor render single-gene assays such as FISH impractical, and in this particular case, also insensitive.

Canine Gastrointestinal Spindle Cell Tumors Efficiently Diagnosed by Tissue Microarray-Based Immunohistochemistry.

Tissue microarray (TMA) is a time- and cost-saving technique allowing the simultaneous immunohistochemical evaluation of multiple tissue samples. The aim of this study was to assess the efficacy of TMA at classifying canine gastrointestinal spindle cell tumors as gastrointestinal stromal tumor (GIST), smooth muscle tumor (SMT), and non-GIST/non-SMT based on the expression of α-smooth muscle actin (α-SMA), desmin, and CD117. Thirty-four cases were investigated on TMAs, sampling 2 cores each. Immunohistochemistry was performed on TMAs and full sections, and the results were compared. Comparing full sections, TMA specificity and sensitivity were 100% and 93.8%, respectively, for α-SMA; 100% and 80.8% for desmin; and 100% and 100% for CD117. TMA allowed the identification of 6 of 6 GISTs, 25 of 26 SMTs, and 2 of 2 non-GIST/non-SMTs. One SMT was misdiagnosed as non-GIST/non-SMT. Based on these results, TMA-based immunohistochemistry is efficient at diagnosing canine gastrointestinal spindle cell tumors and might be applied on large caseloads in a research setting.

Biphenotypic sinonasal sarcoma: A series of six cases with evaluation of role of ß-catenin immunohistochemistry in differential diagnosis.

INTRODUCTION: Biphenotypic sinonasal sarcoma (BSNS) is a recently described mesenchymal tumor exclusive to the sinonasal region. It is a low grade sarcoma, displaying evidence of myogenic and neural differentiation. Role of ß-catenin immunohistochemistry in distinguishing it from its morphological mimics is not well-established. We conducted this study to identify cases of BSNS from our archives, and to examine immunopositivity for ß-catenin in them as well as in its close differential diagnosis. METHODS: All cases of nasal cavity and paranasal sinus mesenchymal neoplasms were identified. Histopathological features were reviewed. Cases showing smooth muscle actin (SMA) and S-100 immunopositivity, and typical morphology were reclassified as BSNS. ß-catenin immunoexpression was assessed. RESULTS: Twenty-one mesenchymal tumors, including 12 sinonasal hemangiopericytoma (SNHPC), five solitary fibrous tumors (SFT), three BSNS, and one synovial sarcoma were identified. Three SNHPC cases were reclassified as BSNS. BSNS patients included one male and five females, with mean age of 51years. Five BSNS cases (83.3%) showed nuclear ß-catenin immunopositivity. SNHPC cases also were ß-catenin positive (60%). CONCLUSION: BSNS is a rare sinonasal neoplasm, frequently misdiagnosed as SNHPC and SFT. ß-catenin immunopositivity is seen in majority of cases, indicating a role in pathogenesis. However, due to positivity in other tumors like SNHPC, it has limited role in differential diagnosis.

Uveal schwannoma in a brown-eyed dog.

An eleven-year-old, female spayed Boxer dog was diagnosed with a uveal schwannoma (formerly known as the spindle cell tumor of the blue-eyed dog or SCTBED) despite having a uniformly brown iris. The patient presented to emergency for ocular discomfort, and the right globe was subsequently enucleated due to glaucoma and submitted for histopathology. Upon histopathologic evaluation, a uveal schwannoma was diagnosed and confirmed with immunohistochemical staining. Complete metastatic evaluation 1 and 6 months after initial presentation did not reveal evidence of metastasis, and the dog remains systemically healthy. This case represents a unique variant of uveal schwannoma and is relevant because although the vast majority of these tumors occur in blue-eyed dogs, clinicians should not completely rule out this tumor as a differential based on the iris color.

Low-grade fibromyxoid sarcoma: Clinical, morphologic and genetic features.

Low-grade fibromyxoid sarcoma (LGFMS) is a bland spindle cell neoplasm that typically arises in the deep soft tissues of the proximal extremities or trunk of young adults. The majority of LGFMS are characterized by a recurrent (7;16)(q34;p11) translocation, resulting in the FUS-CREB3L2 fusion gene, which generates a chimeric protein with transcriptional regulatory activity. Small numbers harbor a FUS-CREB3L1 fusion resulting from t(11;16)(p11;p11), whilst rare cases harbor the EWSR1-CREB3L1 fusion. LGFMS is of low to moderate cellularity and consists of bland spindle cells with small, angulated nuclei and scant, wispy cytoplasm, arranged in a whorled growth pattern and typically showing abrupt transition from myxoid to fibrous areas. Immunohistochemical expression of MUC4 is a consistent finding. Hyalinized spindle cell tumor with giant rosettes (HSCTGR) is a morphological variant of LGFMS that shares the same balanced translocation, and is also immunoreactive for MUC4. A potential relationship between LGFMS and sclerosing epithelioid fibrosarcoma (SEF), a rare fibroblastic neoplasm that most commonly arises in the deep soft tissues of the lower extremities, limb girdles or trunk, has also been suggested. SEF is classically composed of nests and cords of epithelioid cells with clear or eosinophilic cytoplasm embedded within densely sclerotic stroma. In some cases, areas indistinguishable from LGFMS are present, and these have been shown to contain FUS-CREB3L2 fusion transcripts. The majority of pure SEF tumors harbor EWSR1 rearrangements, with EWSR1-CREB3L1 and more rarely EWSR1-CREB3L2 gene fusions more common than those involving FUS. MUC4 immunoreactivity is also seen in approximately 70% of SEF. Surgical resection of these tumors with clear margins is the treatment of choice. Correct diagnosis is important because of the significant potential for recurrence and late metastatic spread. We review LGFMS and SEF, discussing morphology and immunohistochemistry, genetics and molecular findings, and the differential diagnosis.

Nonmesothelial Spindle Cell Tumors of Pleura and Pericardium.

Spindle cell lesions of the pleura and pericardium are rare. Distinction from sarcomatoid mesothelioma, which has a range of morphologic patterns, can be difficult, but accurate diagnosis matters. This article provides practical guidance for the diagnosis of pleural spindle cell neoplasms, focusing on primary lesions.

RAF1-rearranged Spindle Cell Mesenchymal Tumor With Calcification and Heterotopic Ossification: A Case Report and Review of Literature.

We report an exceptional case of a spindle cell mesenchymal tumor with S100 and CD34 co-reactivity, which harbored a SLMAP::RAF1 fusion. To the best of our knowledge, this is the second case of a spindle cell mesenchymal tumor with S100 and CD34 co-reactivity with this specific fusion. Remarkable is the presence of calcification and heterotopic ossification in the center of our lesion, a feature that, to our knowledge, has not been described yet in RAF1-rearranged spindle cell mesenchymal tumors.

Malignant peripheral nerve sheath tumor of the uterine cervix: A case report and literature review.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare high-grade sarcomas arising from the peripheral nerves or peripheral nerve sheath cells. MPNSTs rarely occur in the soft tissue, especially in the uterine cervix. Few cases of cervical MPNST have been reported in the literature. The present study reports the case of a 36-year-old female patient who presented with vaginal bleeding. A cervical mass was detected by vaginal ultrasonography and the patient was diagnosed with MPNST via assessment of the morphological and immunohistochemical features of the tumor after surgery. The patient received chemotherapy and radiotherapy following surgery, and at 8 months post-treatment, had no recurrence or metastasis. Furthermore, the present study summarizes the characteristics of all reported cases of cervical MPNST and their potential differential diagnosis with other spindle cell tumors.

Pleomorphic leiomyosarcoma of the maxilla with metastasis to the colon: A case report.

BACKGROUND: Pleomorphic leiomyosarcomas make up around 8.6% of all leiomyosarcomas. They behave aggressively and often have poor prognoses. They can affect the gastrointestinal tract and retroperitoneum. To date, pleomorphic leiomyosarcoma involving the mesocolon have been reported in nine patients. CASE SUMMARY: The patient was a 44-year-old man with a history of pleomorphic leiomyosarcoma of the left maxilla with metastasis to the lung and liver. His most recent positron emission tomography-computed tomography (PET-CT) scan showed uptake in the ascending and transverse colons. A colonoscopy revealed a 5.0 cm × 3.5 cm × 3.0 cm pedunculated polyp in the ascending colon. The polyp was removed using hot snare polypectomy technique and retrieved with Rothnet. Histopathologic examination of the polyp showed a metastatic pleomorphic leiomyosarcoma. CONCLUSION: Uptake(s) on PET-CT in a patient with pleomorphic leiomyosarcoma should raise suspicion for metastasis.

Open Gastrostomy of a Gastric Leiomyoma Proximal to the Gastroesophageal Junction: A Case Report.

Gastric leiomyomas are benign, submucosal tumors found incidentally on unrelated imaging or during autopsy. The majority of leiomyomas are asymptomatic; however, patients can develop central ulcerations on the lesions leading to upper gastrointestinal (GI) bleeding. A 75-year-old female, with a past medical history of hypertension, hyperlipidemia, and a cerebrovascular accident, presented with complaints of melena, near-syncope events, lightheadedness, weakness, and hematemesis. A computed tomography (CT) of the abdomen with contrast found a heterogeneous low-attenuation mass of 4×4×3 cm3 within the gastric fundus and near the gastroesophageal (GE) junction. After an open gastrostomy and excisional biopsy, the mass was identified as a leiomyoma. This case report reviews the presentation, diagnostic assessments, and treatment of a gastric leiomyoma in a complex location proximal to the gastroesophageal junction. Gastric leiomyomas should be considered as a differential diagnosis for patients presenting with an upper gastrointestinal bleed.

Anterior uveal spindle cell tumor in a blue-eyed mixed-breed dog.

A female, eight-year-old, mixed-breed blue-eyed dog was presented for ophthalmic evaluation because its left eye had "changed color" one year previously. The before left eye was enucleated and submitted for evaluation. Histopathological analysis revealed an invasive neoplastic mass effacing most of the ventral aspect of the iris stroma. A diagnosis of an anterior uveal spindle cell tumor was made. Immunohistochemical results were strongly suggestive of a schwannoma, but some smooth muscle differentiation was also observed. Two and a half years after therapeutic enucleation there was no evidence of neoplasm recurrence or metastasis.

Metastatic uveal schwannoma of blue-eyed dogs.

A formalin-fixed left, blue eye, from a 9-year-old, spayed female beagle dog was submitted to the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) for light microscopic evaluation. The history included glaucoma and an abnormal appearance for 6 months and then the development of a uveal mass. The histologic diagnosis was a spindle cell tumor of blue-eyed dogs (SCTBED). In June of 2012, the dog was euthanized due to ailing health, and there was radiographic and postmortem examination evidence of neoplastic metastasis. This is the first reported case of this primary ocular neoplasm metastasizing, and we propose to rename SCTBED as a uveal schwannoma of blue-eyed dogs.

Biphenotypic Sinonasal Sarcoma: A Case Report and Review of Literature.

OBJECTIVES: Biphenotypic sinonasal sarcoma (BSNS), previously low-grade sinonasal sarcoma with neural and myogenic features, is a rare tumor of the sinonasal tract first described in 2012. Due to its rarity, limited literature is available in providing clinicians with a standardized treatment regimen, particularly in cases of positive surgical margins. This article aims to provide a clinical review of the currently available reported cases of BSNS, as well as presenting clinical, radiologic, and pathologic details of 2 novel cases. METHODS: Online electronic databases include PubMed and Embase where queried for reports of biphenotypic sinonasal sarcoma or low-grade sinonasal sarcoma with neural and myogenic features. Two previously unpublished cases were included in the results. Data including clinical presentation, epidemiologic data, radiologic evaluation, intraoperative details, histopathology, treatment modality, and postoperative follow-up information were included. RESULTS: A total of 100 previously published cases were identified in 12 prior articles. Mean age at presentation was 52.9 years. Extrasinonasal extension was observed in 27.4% of cases with most common site of extension being cribriform plate. Forty-seven cases included treatment details with surgical excision being the most common modality. Recurrence rates were identical for both surgical excision alone and surgical excision with adjuvant radiotherapy (33.3%). CONCLUSIONS: Biphenotypic sinonasal sarcoma is a slow-growing tumor that is amenable to surgical resection. Recurrence rates are similar between surgical excision and surgical excision with adjuvant radiation therapy, but limited data in reported cases preclude a determination of treatment superiority.

Male breast myofibroblastoma: Imaging features and ultrasound-guided core biopsy diagnosis.

Mammary myofibroblastoma is a rare mesenchymal neoplasm that typically presents in older men and women. Less commonly, these benign tumors may also occur in soft tissues located outside of the breast, in which case they are referred to as mammary-type myofibroblastomas. The histologic composition of this benign spindle cell tumor can be markedly varied. We present one such case of myofibroblastoma of the male breast, describing its sonographic appearance and its diagnosis using ultrasound-guided core biopsy.