Pulmonary squamous cell carcinoma metastatic to the proximal interphalangeal joint of the right finger: report of a rare case and review of the literature.

Synovial metastasis is a rare condition with only a few cases reported in the literature. Synovial metastasis to the finger or toe joint is different from acrometastasis, which is defined as bone metastasis located distal to the elbow and knee. The most common site of synovial metastasis is the knee joint. Conversely, synovial metastasis to the finger or toe joints has, to our knowledge, been reported in one case only so far. Herein, we report the second case of synovial metastasis to the proximal interphalangeal joint of the right third finger in a patient with metastatic pulmonary squamous cell carcinoma and review the literature on synovial metastasis.

Cytomorphology of metastatic dedifferentiated/undifferentiated melanoma to the gallbladder: A case report and review of literature.

Dedifferentiated/undifferentiated melanoma (DM/UM) is a distinct subtype of malignant melanoma that tends to lose all melanocytic markers of differentiation. DM/UM pose major diagnostic challenges as they could be easily confused with UM sarcoma or carcinoma, thus necessitating the use of molecular studies such as Next Generation Sequencing (NGS) for detecting melanoma-compatible mutations to confirm such diagnosis. The capability of performing NGS molecular studies on small biopsy material with confirmation of adequacy via rapid on-site evaluation (ROSE) has tremendous value in diagnosing DM/UM. Herein, we present the first reported case of metastatic DM/UM to the gall bladder arising in a 60-year-old female with a prior history of right knee melanoma. We also shed light on the cytomorphology of DM/UM, review the literature on such a challenging entity, and emphasize the crucial role of molecular testing in their diagnosis.

Vascular Neoplasms With NFATC1/C2 Gene Alterations : Expanding the Clinicopathologic and Molecular Characteristics of a Distinct Entity.

Despite significant advances in their molecular pathogenesis, skeletal vascular tumors remain diagnostically challenging due to their aggressive radiologic appearance and significant morphologic overlap. Within the epithelioid category and at the benign end of the spectrum, recurrent FOS/FOSB fusions have defined most epithelioid hemangiomas, distinguishing them from epithelioid hemangioendothelioma and angiosarcoma. More recently, the presence of EWSR1/FUS :: NFATC1/2 fusions emerged as the genetic hallmark of a novel group of unusual vascular proliferations, often displaying epithelioid morphology, with alternating vasoformative and solid growth, variable atypia, reminiscent of composite hemangioendothelioma. In this study, we further our understanding and morphologic spectrum of NFATC -fusion positive vascular neoplasms by describing 9 new cases, including soft tissue locations and novel fusion partners. Combining with the initial cohort of 5 cases, a total of 14 patients were analyzed, showing slight female predilection and an age range of 10 to 66 (mean 42 y). Twelve patients had solitary lesions, while 2 had multifocal polyostotic (pelvic bones) disease. Overall, 12 lesions were intra-osseous and 2 in soft tissue. By targeted RNA Fusion panels or FISH, there were 6 cases of EWSR1::NFATC1 , 4 EWSR1::NFATC2 , 2 FUS::NFATC2 , 1 EWSR1 rearrangement, and 1 with a novel FABP4::NFATC2 fusion. Follow-up was available in 4 patients. One patient experienced 2 local recurrences, 11 and 15 years postdiagnosis, and one patient experienced progressive disease despite multimodality treatment (curettings, embolization, radiation) over 3 years. In summary, our extended investigation confirms that NFATC -related fusions define a distinct group of vascular neoplasms with variable architecture, epithelioid phenotype, and cytologic atypia, commonly located in the bone, occasionally multifocal and with potential for local recurrence and aggressive behavior but no metastatic potential. Molecular analysis is recommended in diagnostically challenging cases with atypical histology to exclude malignancy.

Loss of Histone H3K27 Trimethylation (H3K27me3) Expression as a Potential Diagnostic Pitfall in Sarcomatoid Carcinoma.

Loss of histone H3K27 Trimethylation (H3K27me3) immunohistochemical expression is commonly used as an ancillary test and a surrogate marker for the diagnosis of malignant peripheral nerve sheath tumor (MPNST). A potential histological mimic of MPNST is sarcomatoid carcinoma. Prompted by an index specimen of sarcomatoid carcinoma with H3K27me3 loss and the lack of literature on such phenomenon, we sought to determine the frequency of H3K27me3 loss of expression in a cohort of sarcomatoid carcinomas. Fifty specimens of primary and metastatic sarcomatoid carcinomas with spindle cell morphology mimicking MPNST were prospectively and retrospectively retrieved from our institutional archives and stained with an antibody to H3K27me3. H3K27me3 staining was lost in 4 of the 50 specimens (8%). These specimens included a primary sarcomatoid urothelial carcinoma of the bladder resection, two local recurrences (sarcomatoid squamous cell carcinoma of the larynx and oral cavity) as well as a metastatic sarcomatoid renal cell carcinoma. Next-generation sequencing performed on all four specimens demonstrated gene mutations and copy number alterations with TP53, FANC (FANCD2 and FANCI), and TERT being the most common gene mutations and CDKN2A/B copy number loss and 11q region amplification being the most common copy number gene alterations. Mutations involving NF1, SUZ12, or EED were absent in all tested specimens. In conclusion, H3K27me3 expression may be lost in as many as 8% of sarcomatoid carcinomas which can pose as a potential diagnostic pitfall, especially in challenging sarcomatoid carcinoma specimens with absent keratin staining.

Lack of FOS/FOSB Gene Rearrangements in Ischemic Fasciitis Indicates Distinct Pathogenesis from Proliferative Fasciitis and Proliferative Myositis.

Ischemic fasciitis is a pseudosarcomatous fibroblastic/myofibroblastic proliferation that shares several overlapping morphological features with proliferative fasciitis and proliferative myositis. Prompted by a recent study that demonstrated FOS gene rearrangements in proliferative fasciitis and proliferative myositis, suggesting that these lesions likely represent examples of "transient neoplasia," we examined a cohort of ischemic fasciitis for similar events. Nine cases of ischemic fasciitis were retrieved from our institutional archives for diagnosis verification, immunostaining for FOSB, and fluorescence in situ hybridization using validated FOS and FOSB break-apart probes. Additionally, RNAseq was performed on a subset of cases. In our cohort, eight out of nine cases of ischemic fasciitis were positive for FOSB IHC, but FISH studies were consistently negative for FOSB and FOS gene rearrangements in all cases. Additionally, RNA sequencing did not detect any gene fusions. These findings suggest that the pathogenesis of ischemic fasciitis is distinct from that of proliferative fasciitis and proliferative myositis.

Cytomorphology of a unique case of dedifferentiated chordoma involving a pleural effusion specimen.

Cytomorphology along with positive AE1/AE3 staining and Brachyury staining support the dignosis of metastatic dedifferentiated chordoma.

Expanding the molecular signatures of malignant ossifying fibromyxoid tumours with two novel gene fusions: PHF1::FOXR1 and PHF1::FOXR2.

AIMS: Ossifying fibromyxoid tumor (OFMT) is a rare enigmatic tumor of uncertain differentiation that can be classified as typical, atypical, and malignant subtypes based on cellularity, nuclear grade, and mitotic activity. The majority of OFMTs, regardless of the risk of malignancy, harbor genetic translocations. We report two malignant OFMTs, including one with evidence of dedifferentiation, with novel genefusions. METHODS AND RESULTS: Case 1 was a 63-year-old male with a dedifferentiated OFMT arising in the right wrist, while case 2 was a 41-year-old male with a malignant OFMT presenting as a posterior mediastinal mass. Case 2 showed multifocal expression with EMA and synaptophysin, while desmin and S100 were absent in both tumors. NGS sequencing studies detected PHF1::FOXR1 and PHF1::FOXR2 gene fusions in cases 1 and 2, respectively. Despite aggressive regimens, both progressed with wide spread metastases resulting in death within six years of diagnosis. CONCLUSIONS: We expand the genetic spectrum of OFMTs with two novel gene fusions, PHF1::FOXR1 and PHF1::FOXR2. These cases confirm the previously reported tendencies for OFMTs with rare variant fusions to demonstrate malignant behavior, unusual morphology, and non-specific immunophenotype.

Synchronous polyostotic solid variant of aneurysmal bone cyst involving thoracic vertebrae and harboring a novel AHNAK::USP6 gene fusion. A case report and review.

Aneurysmal bone cyst (ABC) is a benign bone neoplasm that usually affects the metaphysis of long bones and the posterior elements of vertebral bodies. The rearrangement of USP6 gene is present in most of primary ABC cases. Synchronous polyostotic presentation is extremely rare. All of the eight reported cases in literature have a classic ABC histomorphology, including dilated-blood filled cystic spaces separated by fibrous septa and composed of variably cellular bland fibroblasts with scattered osteoclast-like giant cells and reactive new bone formation. Herein, we report a case of a 29-year-old female with a synchronous polyostotic solid variant of ABC involving her T7-T11 posterior elements of her thoracic vertebrae with a novel AHNAK::USP6 fusion, detected by next-generation sequencing (NGS). This case is distinguished by its synchronous polyostotic presentation, solid rather than classic ABC morphology and novel AHNAK::USP6 fusion, which has not been previously reported in ABC or in any mesenchymal bone tumor.

Intradural Extramedullary Concurrent Schwannoma and Meningothelial Hyperplasia at C2-C3 Cervical Vertebrae: A Case Report and Review of Literature.

Concomitant schwannomas and benign meningothelial proliferations, including meningothelial hyperplasia or meningioma, rarely occur at the same location outside the setting of neurofibromatosis. Herein, we present a rare case of concurrent schwannoma and benign meningothelial hyperplasia concomitantly occurring in the cervical spine of a 69-year-old male patient with no history of any genetic disorder.

Expanding the Molecular Genetic Spectrum of Bone and Soft Tissue Fibrosarcomas: An Institutional Experience.

Introduction. Fibrosarcomas, once comprising the majority of unclassifiable spindle-cell sarcomas, are now regarded as a diagnosis of exclusion. Objectives. Prompted by an index report of neurotrophic receptor tyrosine kinase (NTRK)3 fusion in fibrosarcomas by Yamazaki et al bone/soft tissue tumors diagnosed as fibrosarcoma at our institution were evaluated in an attempt to expand the genetic spectrum of fibrosarcomas and identify therapeutically targetable cases. Methods. Institutional archives were searched for cases diagnosed as "fibrosarcoma" involving bone/soft tissue from 2000 to present. Twenty-one cases meeting inclusion criteria were identified, 10 of which had formalin-fixed paraffin-embedded tissue available for molecular testing. One case, at the submitting clinician's request, underwent outside deoxyribonucleic acid/ribonucleic acid (DNA/RNA) sequencing while the 9 remaining cases underwent in-house next-generation sequencing RNA fusion analysis. Results. At the time of diagnosis the mean age was 54.5 (range 14-88) with a male to female ratio of 1.5:1. Locations included soft tissue of the lower extremity (3), trunk (2), pelvis (2), head (1), upper extremity (1), and bone (1). Of the 10 cases, 1 demonstrated an FNDC3B-PIK3CA gene fusion and 1 demonstrated a BRAF (p.G469A) mutation and CDKN2A/B loss. Conclusion. In conclusion, our study demonstrated gene fusions in 1 (10%) of 10 fibrosarcomas diagnosed at our institution in the past 20 years, including FNDC3B-PIK3CA gene fusion. Additionally, 1 case harbored BRAF (p.G469A) mutation and CDKN2A/B loss with no evidence of gene fusion. NTRK rearrangements were not detected. The significance of these molecular aberrations is presently unclear and future studies are needed to establish whether these findings carry any clinicopathologic significance.

Thyroid paraganglioma in a patient with a history of carotid and vagal paraganglioma: metastatic or primary tumor?

Paragangliomas (PGs) are extremely rare multicentric neoplasms. Hereditary or familial PGs are associated with germline mutations in succinate dehydrogenase genes, seen in one-third of cases. Primary PGs of the thyroid are uncommon neuroendocrine neoplasms that account for 0.012% of all head and neck lesions. Although majority of these tumors are solitary, familial PGs are associated with synchronous tumors (carotid/vagal). We report an interesting case of primary thyroid PG in a patient with a previous history of a right carotid body, right vagal PGs and positive familial history, confining the differential diagnosis to recurrent lesions, which is the most common occurrence or new primary or a metastatic lesion. However, long interval and surgical anatomy suggests the diagnosis to be a primary lesion. In conclusion, although these lesions present multicentrically present at varying intervals, their occurrence at anatomically distinct sites should raise the concern for a new primary PG.

Prognosis of duodenal gangliocytic paraganglioma with lymph node metastasis: is follow-up >5 years required?

Gangliocytic paragangliomas (GP) are rare tumors encountered exclusively in the second portion of the duodenum. Duodenal gangliocytic paraganglioma (DGP) belongs to a subclass of neuroendocrine neoplasms, characterized with unique histologic features of carcinoid tumor, paraganglioma and ganglioneuromas. According to the recent World Health Organization classification of gastrointestinal neuroendocrine tumors (NETs), there is a debate to classify them either as low-grade NETs or as an independent entity. There are a few reports of regional lymph node (LN) metastasis that could argue DGP as a true neoplasm. However, majority of them had a benign course, raising the question of whether long-term follow-up is required. We report a case of a retroperitoneal LN involvement by metastatic GP and additionally performed a systematic review of the literature to determine the optimal follow-up, since no guidelines exist for this rare entity.

Novel MEAF6-SUZ12 fusion in ossifying fibromyxoid tumor with unusual features.

Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain differentiation that has the capacity for local recurrence and metastasis. Many OFMTs, including typical, atypical, and malignant tumors, have demonstrated recurrent gene fusions. The fusion partners reported to date share a common core function in that they play either a direct or indirect role in processes influencing histone modification. Herein, we report an OFMT with unusual morphology and non-specific immunoprofile harboring a novel MEAF6-SUZ12 fusion. A 34-year-old male presented with a slowly growing mass in the right antecubital fossa. Excision demonstrated a 6.9 cm partially encapsulated, tan-white, lobulated, and calcified lesion. Microscopic evaluation demonstrated cytologically bland spindle to ovoid cells arranged in a haphazard manner within a fibromyxoid background containing dense collagen, often with sclerotic nodules, and randomly distributed ossification. The tumor cells were diffusely positive for CD34 while essentially negative for S100, desmin, MUC4, SOX10, AE1/3, SMA, and EMA. Next-generation sequencing studies (sarcoma gene fusion next-generation sequencing panel with subsequent Sanger confirmation) performed on formalin-fixed paraffin-embedded tissue detected a fusion product between MEAF6 exon 4 (NM_001270875) and SUZ12 exon 2 (NM_001321207.1). The proposed mechanism of pathogenesis in OFMT, namely epigenetic dysregulation, is reinforced by the fact that both of these partner genes are involved in histone modification.

EWSR1-ATF1 Fusion in a Myoepithelial Carcinoma of Soft Tissue With Small Round Cell Morphology: A Potential Diagnostic Pitfall.

Myoepithelial tumors of soft tissue are rare mesenchymal neoplasms that overlap with their salivary gland and skin counterparts at both the histopathologic and molecular levels. EWSR1 gene rearrangements with various fusion partners represent a common genetic event in myoepithelial tumors of soft tissue, whether benign or malignant, and may prove useful as a diagnostic tool in difficult cases. However, the number of diagnostic entities with EWSR1 gene rearrangements has grown considerably in recent years, and there is significant morphologic and immunophenotypic overlap amongst this group, underscoring the importance of fusion testing to detect fusion partners that are characteristic of discrete diagnostic entities. Herein, we report a malignant myoepithelial tumor of soft tissue/myoepithelial carcinoma with an undifferentiated round cell morphology arising in a pediatric patient with a EWSR1-ATF1 gene fusion.

Subperiosteal Aneurysmal Bone Cyst with Florid Ossification: A Rare Subtype.

Aneurysmal bone cyst (ABC) is a well-characterized benign cystic lesion of the bone with common localization to the medulla of the long bones. Rarely, ABCs may arise within the subperiosteal region, which can be diagnostically challenging for both the radiologist and pathologist due to their aggressive radiologic appearance thus mimicking other malignant neoplasms. Herein, we present a rare case of subperiosteal ABC with prominent soft tissue involvement and florid reactive periosteal ossification and provide a short literature review on subperiosteal ABCs.

Low-grade fibromyxoid sarcoma: A rare case in an unusual location.

Low-grade fibromyxoid sarcoma, also known as Evans tumor, is a low-grade sarcoma that most commonly arises in the deep soft tissue of the proximal extremities or trunk in young adults. It is very rare in the viscera as a primary site, with only a few cases reported in the literature. Here, we present a case of Evans tumor occurring in an unusual and rarely reported location; an intrathoracic mass arising from the diaphragmatic pleura.

Intra-articular Extraskeletal EWSR1-Negative NR4A3-Positive Myxoid Chondrosarcoma: A Case Report.

CASE: Extraskeletal myxoid chondrosarcomas (EMCs) are rare soft-tissue malignancies. Intra-articular occurrence is even more rare. To our knowledge, this case is one of only 2 reported intra-articular EMC cases of the knee free of local recurrence and/or amputation at follow-up. This case is also distinctive for being fluorescence in-situ hybridization-negative for the typical EMC-balanced translocation t(9;22) which fuses EWSR1 with NR4A3, harboring instead a variant translocation resulting in fusion of NR4A3 with a less common gene fusion partner. CONCLUSION: This is a unique case of intra-articular EMC of the knee with a rare molecular fingerprint and an unusually positive outcome.