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Primary malignant bone tumors are uncommon and their accurate classification requires careful correlation of clinical, radiological, and pathologic findings. It is a heterogeneous group of tumors with a wide spectrum of morphology and their biological potential can be of low- or high-grade, depending on their risk for developing metastases. Over the past several decades, the classification of bone sarcomas has remained largely constant. However, some of the tumors have been reclassified and several new entities have emerged. In this review, we will focus on pleomorphic fibrosarcoma/UPS and dedifferentiated bone tumors, discuss their key diagnostic features, differential diagnosis, and their relation to prognosis.

An “unplanned excision” refers to soft tissue sarcomas excised without planning imaging studies and a diagnostic biopsy, resulting in the presence of residual disease and usually necessitating a re-excision procedure. We aimed to assess the impact of previous unplanned excisions on the intra-operative pathologic assessment at the time of re-excision, in terms of need to perform repeat assessments and the accuracy to predict margin status of the final pathologic specimen. Data was collected for all patients with extremity soft tissue sarcoma who had undergone wide local excision limb salvage surgery or amputation between 2012 and 2017. Intra-operative pathologic assessment with frozen sections was performed in all cases and was classified as negative, negative but close (

Salivary gland neoplasms are uncommon, and most exhibit epithelial differentiation. Mesenchymal neoplasms of the salivary gland are rare, and the incidence ranges from 1.9% to 5%. The aim of this study is to identify the types and clinical-pathological features of mesenchymal salivary neoplasm and review their differential diagnosis. A retrospective search for mesenchymal neoplasms of salivary glands from our institution's pathology archives from the 2004–2021 period and consultation files of one of the authors (AER) was performed. The clinical data were obtained from available medical records, and the histological slides and ancillary studies were retrieved and reviewed. We identified a total of 68 cases that form the study cohort. Thirty-five patients were male, and thirty-three patients were female, with a mean age of 48 years (range, 7 months–79 years), and the male to female ratio was 1:.94. Sixty-three (92.6%) of sixty-eight tumors were benign and included: 38 (56%) lipomas, 9 (13%) hemangiomas, 7 (10.3%) schwannomas, 3 (4.4%) neurofibromas, 3 (4.4%) lymphangioma, 2 (3%) solitary fibrous tumors, 1 (1.5%) myofibroma. Five of sixty-eight (7.4%) were malignant and included: 3 (4.4%) Adamantinoma-like Ewing sarcomas, 1 (1.5%) malignant peripheral nerve sheath tumor (MPNST), and 1 (1.5%) malignant solitary fibrous tumor. The involved sites included: parotid (55), submandibular gland (5), parapharyngeal space (5), buccal mucosa minor salivary gland (2), and sublingual gland (1). Sixty-seven patients underwent surgical resection. One patient with lymphangioma manifested a recurrence/persistence a week post-surgery. One patient with a parotid hemangioma developed post-operative numbness, and another patient developed chronic postauricular pain after surgery. Two patients with MPNST and one patient with adamantinoma-like Ewing sarcoma underwent neoadjuvant chemoradiation and were disease-free after treatment. The remaining 37 patients with available follow-up ranging from 7 days to 96 months (mean, 18 months) had a favorable outcome and were disease-free after treatment. Mesenchymal neoplasms of salivary gland are rare; most are benign and demonstrate adipocytic, endothelial, and schwannian differentiation; awareness of their development is important for adequate diagnosis. The mainstay of treatment is surgical excision, with the extent determined by tumor type. Adjuvant therapy is reserved for high-grade sarcomas and may be given in a neoadjuvant or adjuvant setting.

Rhabdomyosarcoma (RMS) encompasses a heterogeneous group of tumors with striated muscle differentiation. RMSs are classified as alveolar, embryonal, spindle cell /sclerosing and pleomorphic types and molecular analysis of these tumors has identified aberrations that are useful in their further subclassification. Spindle cell rhabdomyosarcoma (SpRMS) is uncommon and has been described with VGLL2 fusions, EWSR1/FUS-TFCP2 rearrangements, and myoD1 mutations - the mutations are associated with significantly different prognoses. Also, the NCOA2-MEIS1 fusion gene was recently described in two primary intraosseous RMS that contained spindle cell components. Herein, we report three cases of SpRMS harboring different novel fusion genes, one possessing EP300-VGLL3, a second with NCOA2-MEIS1 and CAV1-MET, and the third case had HMGA2-NEGR1 and multiple amplified genes. This article is protected by copyright. All rights reserved.

Aims Simple bone cysts are benign intramedullary tumours primarily involving the long bones in skeletally immature individuals. Several mechanisms have been proposed for their pathogenesis. Although the diagnosis is typically straightforward, the interpretation can be problematic, because of superimposed fracture causing them to resemble aneurysmal bone cysts and other tumours. EWSR1-NFATC2 or FUS-NFATC2 fusions, which are characteristic of a subset of aggressive round cell sarcomas, have been recently detected in simple bone cysts. The aim of this study was to examine the clinicopathological and molecular features in a series of simple bone cysts. Methods and results Using RNA-based next-generation sequencing and/or fluorescence in-situ hybridisation, we investigated the presence of EWSR1 or FUS rearrangements in nine simple bone cysts. The patients were five females and four males, aged 3-23 years (median, 14 years); the tumours ranged from 19 mm to 160 mm (median, 46 mm) in size, and involved the femur (n = 3), humerus (n = 2), fibula (n = 2), tibia (n = 1), and iliac wing (n =1). We identified three cases with EWSR1-NFATC2 fusion (showing identical breakpoints to those in EWSR1-NFATC2 sarcomas) and one additional case with FUS rearrangement. Unlike in EWSR1-NFATC2 sarcomas, immunohistochemical expression of NKX3.1 and NKX2.2 was absent in two simple bone cysts tested. Conclusions More than 40% of simple bone cysts harbour genetic alterations confirming that they are neoplastic, investigation of EWSR1 and/or FUS rearrangement may help to distinguish simple bone cysts from mimics, and NFATC2 rearrangement is not pathognomonic of malignancy.

Primary sarcomas of the larynx are rare and are associated with diagnostic and treatment challenges. Studies of these tumors are limited, and most examples have been reported as small series. To further increase our understanding of laryngeal sarcomas, we reviewed our experience of an adult cohort. A retrospective search for laryngeal sarcomas from our pathology archives and consultation files of one of the authors was performed. We studied 27 primary laryngeal sarcomas that included 25 males, and 2 females, with a mean age of 60 years (range 33–85). The cases included conventional chondrosarcoma (16), well-differentiated liposarcoma (2), clear cell chondrosarcoma (1), leiomyosarcoma (2), high grade myxofibrosarcoma (2), high grade myofibroblastic sarcoma (1), low-grade myofibroblastic sarcoma (1), malignant granular cell tumor (1), and Kaposi sarcoma (1). Data on treatment and follow-up was available in 17 and 16 cases, respectively. 12 patients underwent partial laryngeal resection; five had total laryngectomy, and the patient with Kaposi sarcoma received combined highly active antiretroviral therapy and chemotherapy. Three patients developed local recurrence, and two patients developed metastases. The remaining patients with follow up had a favorable outcome and were disease-free after treatment. The important differential diagnosis of spindle cell sarcoma is sarcomatoid squamous cell carcinoma, and their distinction often requires extensive sampling of the mucosal surface and immunohistochemical analysis. The mainstay of treatment for laryngeal sarcomas is surgical removal, with the extent dictated by tumor type and grade. Adjuvant therapy is reserved for high-grade sarcomas and may be given in a neoadjuvant or adjuvant setting.

Objectives Epithelioid sarcoma (ES) rarely arises in the nerve. To increase our understanding of this unusual tumor originating in the nerve, we describe the features of three cases and review the literature. Methods Clinical data, imaging, pathology, treatment, and follow-up are detailed. A systematic literature review was conducted. Results Two patients were male and one female; the median age was 24 years. The patients had neurologic symptoms, and the tumors arose in large nerves and ranged from 2.4 to 5.8 cm. The tumors were avid on positron emission tomography–computed tomography and showed increased signal intensity on T2-weighted magnetic resonance imaging. Centered in the nerve, the tumors grew with an infiltrative pattern and encased the nerve fascicles. All were treated with wide resection, and adjuvant treatment included combinations of chemotherapy and radiation. One recurred, and the limb was amputated. Metastases were documented to lymph nodes, lung, pleura, and skin. One patient died of disease after 54 months. Literature review including our cases showed that tumors stained with pancytokeratin (9/9), EMA (4/4), and CD34 (7/7); there was loss of INI1 in all six cases tested. Conclusions ES rarely arises in the peripheral nerve, and its infiltrative nature often requires morbid surgery. The differential includes a variety of benign and malignant epithelioid neoplasms.

Background Pseudocarcinomatous squamous hyperplasia (PSH) within the bone is uncommon and closely mimics well-differentiated squamous cell carcinoma (SCC). It arises from cutaneous or mucosal surfaces and grows directly into the bone. This study analyzes a large series of PSH and discusses the clinicopathologic features that facilitate its distinction from SCC. Design Cases were identified from the surgical pathology files between 1985 and 2020. Results The 31 cases included 21 males, 9 females, 1 unknown sex; who were 20 to 87 years old (average: 59 y). Sites included mandible-17, maxilla-5, toes-4, and 1 case from finger, femur, tibia, ischium, and unknown. Fourteen patients had a history of SCC, 13 treated with resection and chemoradiation and developed infected osteoradionecrosis, 4-medication-related osteonecrosis, 3-peripheral vascular disease, and diabetes mellitus, 3-trauma, 3-osteomyelitis, 3-unknown, and 1-hematologic malignancy. All cases exhibited severe osteomyelitis and nests of reactive keratinizing squamous epithelium that matured towards the bone surface, lacked significant atypia, or mitotic activity but permeated the medullary cavity. Patients with previous SCC developed PSH after 2 months to 8 years (average: 4 y). Nineteen of 30 patients had follow-up (2 to 48 mo, average: 17 mo); 6 patients experienced repeated debridements over 2 months to 1 year; no patient developed SCC. Conclusions PSH involving bone is infrequent, complicates severe osteomyelitis, and is often therapy related. The clinical findings are usually not concerning for malignancy, however, the histologic findings are an important diagnostic pitfall because they mimic SCC.

Giant cell tumor of bone is a locally aggressive, rarely metastasizing neoplasm. Evidence suggests that the neoplastic cells may be osteoblastic in differentiation. Standard treatment is surgical removal, but medical therapy with denosumab, an inhibitor of receptor activator of nuclear factor-κβ ligand, has become a component of patient management in select cases. Denosumab-treated giant cell tumor of bone (DT-GCTB) shows drastic morphologic changes including the presence of abundant bone. To further determine the relationship of the neoplastic cells to osteoblast phenotype, we performed a morphologic and immunohistochemical study on a series of DT-GCTB. Cases of DT-GCTB were retrieved from surgical pathology files, available slides were reviewed, and immunohistochemistry for H3.3 G34W, SATB2, and p63 was performed. The cohort included 31 tumors from 30 patients (2:3 male:female), ages 15 to 73 years (median=36 y). The morphology of post-denosumab-treated tumors ranged from tumors composed of an abundant bone matrix with few spindle cells to spindle cell-predominant tumors. Five had focal residual classic CGTB, and 2 manifested mild nuclear atypia. The majority expressed all markers: 86.2% for H3.3 G34W, 96.7% for SATB2, and 100% for p63. All markers stained the various tumor components including spindle cells and the cells on the surface of and within the treated tumor bone matrix. Most markers were also positive in reactive-appearing woven bone adjacent to tumor: 84.6% for H3.3 G34W, 100% for SATB2, and 68% for p63. These findings suggest that denosumab treatment of giant cell tumor of bone results in osteoblastic differentiation with bone production.

Summary The distinction between lipoma and atypical lipomatous tumor can be challenging in some cases. While detection of MDM2 gene amplification via fluorescence in situ hybridization (FISH) has been well established as a diagnostic tool to distinguish atypical lipomatous tumor and well-differentiated liposarcoma from benign mimics, MDM2 RNA in situ hybridization (RNA-ISH) has recently been proposed as an alternative diagnostic assay. During clinical workup for lipomatous tumors using MDM2 RNA-ISH, we noticed several dysplastic lipomas that were positive for MDM2 RNA-ISH but negative for MDM2 amplification by FISH. In this study, we examined a series of 11 dysplastic lipomas, all confirmed to be negative for MDM2 amplification by FISH. Positive MDM2 RNA-ISH was noted in 10 (91%) dysplastic lipomas. Single-nucleotide polymorphism array on one dysplastic lipoma identified the presence of homozygous deletion of 13q, including the RB1 gene locus with no evidence of MDM2 copy number gain. Our findings on the discordance between MDM2 FISH and MDM2 RNA-ISH highlight the potential utility and pitfalls of using MDM2 RNA-ISH in the distinction of atypical lipomatous tumor and related liposarcomas from dysplastic lipoma.

Summary Primary gastrointestinal liposarcoma is rare, and information regarding this entity is largely based on single case studies. We report on 8 patients with primary liposarcoma of the gastrointestinal tract and review the pertinent literature. The cohort includes 6 men and 2 women who ranged in age from 51 to 81 years (median 68.5). Two tumors arose in the stomach, 4 in the small intestine, and 2 in the large intestine. Tumors ranged in size from 2.5 to 14.5 cm (median 7 cm), originated in the submucosa or muscularis propria of the intestinal wall, and frequently protruded into the bowel lumen, resulting in mucosal ulceration and luminal obstruction. Six tumors were dedifferentiated liposarcomas, and 2 were well-differentiated liposarcoma. Surgical excision was performed on all tumors except for 1 case of dedifferentiated liposarcoma. On follow-up, 1 patient with dedifferentiated liposarcoma developed a lytic sacral lesion suspicious for metastasis 4 months after resection of the primary, and another underwent marginal resection and presented with recurrence 4 years later, had tumor re-resection, and was considered disease-free at 6 weeks postsurgery. A third patient with dedifferentiated liposarcoma was alive with unknown disease status at 17 months following surgery, and another patient with dedifferentiated liposarcoma was alive without evidence of disease at 30 months following surgery. No follow-up information on the remaining patients is available. Overall, liposarcomas of the intestinal tract are most frequently high-grade dedifferentiated tumors that are biologically aggressive and require surgical excision with widely negative margins to help reduce the risk of local recurrence and dissemination. Important in the differential diagnosis is malignant gastrointestinal stromal tumor. Care must be taken not to misdiagnose one entity for the other because the correct diagnosis carries important therapeutic implications.

Simple Summary Angiosarcomas (AS) are rare, highly aggressive sarcomas with limited therapeutic options. Genomic sequencing techniques have identified recurrent genetic abnormalities. Nevertheless, the association of these findings with etiology, site of origin, prognosis, and therapeutic implications is not well understood. We analyzed Next Generation Sequencing (NGS) and Whole Transcriptome Sequencing (WTS) data in a cohort of 143 AS cases. We identified distinct genomic biology according to the AS primary site. Head and neck AS cases primarily have Immunotherapy (IO) response markers and mutations in TP53 and POT1. On the other hand, breast AS is enriched for cell cycle alterations, predominately MYC amplification. Additionally, a microenvironment with abundant immune cells is present in a minority of cases but distributed evenly among primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS according to its biology at different primary sites. Abstract We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast (22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) (p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases (p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS.

Highlights • Inflammatory pseudotumor are non-neoplastic tumors of the abdomen. • They may be large and invasive. • They may cause significant morbidity and mortality. • There is limited information in the literature about management., Introduction There is a wide differential diagnosis for intraabdominal tumors. Surgical resection and microscopic analysis of tissue structure can identify tumor origin in most cases. Most rapidly growing invasive tumors are neoplastic. Inflammatory pseudotumors are a subcategory of intraabdominal tumors that are non-neoplastic and can be rapidly growing. Urachal cysts originate from the dome of the bladder; however they are typically not invasive. There is limited literature on the appropriate management of these tumors. Presentation A 37-year-old female presenting with symptoms of abdominal pain was found to have a large intraabdominal mass invading multiple organs. Core biopsies demonstrated inflammation. The mass grew significantly over the course of a year and patient's abdominal pain worsened. The patient was taken to the operating room for resection. Final pathology revealed reactive fibrous tissue with acute and chronic inflammation invading bladder, urethra, abdominal wall, appendix, and ovary. Intraoperative frozen section demonstrated low grade spindle cells with concern for inflammatory pseudotumor but final pathology demonstrated inflammation. Discussion Although benign, these tumors cause significant morbidity due to their size and level of organ invasion. Management should involve surgical resection as well as potential post-operative chemotherapy or NSAIDs based off clinical picture. We demonstrate the importance of close follow up for residual disease or recurrence of patients with inflammatory pseudotumors of the abdomen. Conclusion This case highlights difficulties in diagnosis of a tumor that has potential to cause significant morbidity. There is need for further research to discover the best management after surgical resection of these tumors.

The entity "pericytoma with t(7;12)" was described as a rare, distinct perivascular myoid neoplasm provisionally classified within the family of myopericytic tumors that demonstrates t(7;12)(p22;q13) translocation with resultant ACTB-GLI1 fusion and biologically was felt to behave in an indolent fashion. However, a recent study showed that tumors with this and similar translocations may have variable morphology and immunohistochemical phenotype with inconsistent myopericytic characteristics and a propensity for metastasis, raising questions regarding the most appropriate classification of these neoplasms. Herein, we report 3 additional patients with tumors harboring t(7;12) and ACTB-GLI1 fusion. The tumors arose in adults and involved the proximal tibia and adjacent soft tissues, scapula and adjacent soft tissues, and ovary. All tumors were composed of round-to-ovoid cells with a richly vascularized stroma with many small, delicate, branching blood vessels, where the neoplastic cells were frequently arranged in a perivascular distribution. Both tumors involving bone showed histologic features of malignancy. By immunohistochemistry, all tested tumors were at least focally positive for smooth muscle actin (3/3) and CD99 (patchy) (2/2), with variable staining for muscle-specific actin (2/3), S100 protein (1/3), epithelial membrane antigen (2/3), and pan-keratin (1/3); all were negative for desmin and WT1 (0/3). The 2 patients with bone tumors developed metastases (27 and 84 mo after diagnosis). Whether these tumors are best classified as malignant myopericytoma variants or an emerging translocation-associated sarcoma of uncertain differentiation remains to be fully clarified; however, our study further documents the potential for these tumors to behave in an aggressive fashion, sometimes over a prolonged clinical course.

Background Synovial sarcoma of the nerve is a rare entity with several cases and case series reported in the literature. Despite an improved understanding of the biology, the clinical course is difficult to predict. Objective To compile a series of patients with synovial sarcoma of the peripheral nerve (SSPN) and assess clinical and pathological factors and their contribution to survival and recurrence. Methods Cases from 2 institutions collected in patients undergoing surgical intervention for SSPN. Systematic review including PubMed and Scopus databases were searched for related articles published from 1970 to December 2018. Eligibility criteria: (1) case reports or case series reporting on SSPN, (2) clinical course and/or pathological features of the tumor reported, and (3) articles published in English. Results From patients treated at our institutions (13) the average follow-up period was 3.2 yr. Tumor recurrence was seen in 4 cases and death in 3. Systematic review of the literature yielded 44 additional cases with an average follow-up period of 3.6 yr. From pooled data, there were 10 recurrences and 7 deaths (20% and 14%, respectively). Adjuvant treatment used in 62.5% of cases. Immunohistochemical markers used in diagnosis varied widely; the most common are the following: Epithelial membrane antigen (EMA), cytokeratin, vimentin, cluster of differentiation (CD34), and transducin-like enhancer of split 1 (TLE1). Statistical analysis illustrated tumor size and use of chemotherapy to be negative predictors of survival. No other factors, clinically or from pathologist review, were correlated with recurrence or survival. Conclusion By combining cases from our institution with historical data and performing statistical analysis we show correlation between tumor size and death.

The classification of bone neoplasms composed of small round cells is experiencing a transformation after the discovery of various gene fusion rearrangements that determine diagnosis, behavior, and response to therapy. We present herein 4 new cases of small round cell tumor of the bone that harbor NFATc2 rearrangements involving either EWSR1 or FUS genes. We studied the clinical presentation, pathologic features, genetics (FISH, targeted RNA sequencing) and outcome in these 4 patients. We also reviewed the literature describing similar cases. All our patients were male. The median age at diagnosis was 33.5 years. All tumors presented in long bones of the extremities as a large destructive mass with a mean size of 12.5 cm. All cases were hypercellular with prominent collagenous stroma and consisted of small to medium size round cells arranged in cords, thin trabeculae, and pseudoacinar structures. Most cases showed focal or diffuse membrane staining for CD99; whereas S100, synaptophysin and chromogranin were negative. EMA showed cytoplasmic staining in one case. Genetic studies identified EWSR1-NFATc2 fusion in 3 cases, and FUS-NFATc2 fusion in one case. Two patients were treated with neoadjuvant chemotherapy using Ewing sarcoma regimens, and surgical excision was performed on 3 patients; necrosis was minimal. Follow-up is limited; after a median follow-up of 8.7 months, one patient developed local recurrence and metastases to the lungs. Poorly differentiated round cell sarcoma with EWSR1/FUS-NFATc2 fusions are uncommon. The tumors have consistent clinical findings, morphology, and immunoprofile that in combination are distinctive and differ from that of Ewing sarcoma. Importantly, these tumors do not respond to Ewing sarcoma chemotherapy regimens.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) is a common postoperative cardiovascular complication and is associated with short and long-term mortality. The objective of the study was to describe the contemporary management of patients with and without MINS after total joint and spine orthopedic surgery at a large tertiary care hospital. METHODS: Adults admitted for total joint and major spine surgery from January 2013 through December 2015 with ≥1 cardiac troponin (cTn) measurement during their hospitalization were identified. MINS was defined by a peak cTn above the 99(th) percentile of the upper reference limit. Demographics, medical comorbidities, and admission and discharge medications were reviewed for all patients. RESULTS: A total of 2,561 patients underwent 2,798 orthopedic surgeries, and 236 cases of MINS were identified. Patients with MINS were older (71.9 ± 10.9 vs. 67.0 ± 10.0, p

Objectives Amputation due to gangrene and arthroplasty for degenerative joint disease are common orthopedic procedures and are expected to increase as populations age. Histopathologic examination of these specimens can identify unsuspected diseases. Methods We reviewed gangrenous amputations and large joint arthroplasty specimens for diagnosis of unexpected lymphoma, January 2014 to January 2020. Pathology and medical records were reviewed to determine diagnosis, treatment, and outcome. Results Five cases (0.08%) of unexpected primary extranodal marginal zone lymphoma (MZL) centered in bone were identified in 1,624 amputations for gangrene and 4,163 arthroplasty specimens. The female-to-male distribution was 3:2. Median age was 71 years (range, 62-87). The 3 cases arising in the setting of gangrene involved the first toe phalanges and metatarsals, and the femoral head was involved in all cases of joint disease (2 cases). The bone showed variable (10%-80%) infiltration by dense populations of small lymphoid cells with MZL immunophenotype. One patient died from sepsis 18.5 months after diagnosis; all others are alive with a median follow-up of 27.45 months. Conclusions Histopathologic examination of nonneoplastic orthopedic specimens identifies unexpected primary bone extranodal MZL in a small percentage of cases. This neoplasm may be the result of chronic antigenic stimulation in some circumstances.

Undifferentiated sarcomas remain difficult to classify. Despite the remarkable advances in sarcoma classification made by the increased application of RNA sequencing in clinical practice, the unexpected result of a novel gene fusion raises further questions regarding the tumor histogenesis and subclassification. In this study, we present two high grade sarcomas with epithelioid phenotype occurring in the deep-soft tissues (shoulder, thigh) of young adults which based on the non-specific pathologic findings were deemed unclassified and subjected to targeted RNA sequencing for further diagnostic interpretation. The results showed an identical EWSR1 exon 7-SSX1 exon 5 fusion. The breakpoints in both genes represent similar hot spots as seen in Ewing sarcoma and synovial sarcoma, generating a fusion transcript predicted to be in frame, and to retain the same protein domains within the fusion oncoprotein. These results were further confirmed by FISH analysis for both break-apart and fusion come-together assays in both genes. Both tumors showed a round to epithelioid morphology associated with extensive stromal hyalinization and necrosis. One case showed scattered psammomatous calcifications. The tumors shared a similar immunoprofile, including reactivity for EMA, CK, TLE1, BCOR, and CD99, while negative for S100, SOX10, CD34, SMA, and desmin. Both cases showed MUC4 positivity (one diffuse, one patchy), while one case showed patchy ALK positivity. One patient developed lymph node metastases, while the other showed no evidence of disease at 6-month follow-up. Neither case fit in any known pathologic categories. Larger series are needed to interrogate if the presence of EWSR1-SSX1 fusion defines a novel pathologic entity of a sarcoma with epithelioid cytomorphology, sclerotic stroma, and epithelial differentiation immunohistochemically.

An 18-year-old man presented with a pathological fracture of the right proximal femur. Desmoplastic fibroma was diagnosed through histological studies. Surgical management involved extended intralesional curettage and fracture stabilization by open reduction with intramedullary nailing, using a short Gamma nail. At 42-month follow-up, the patient presented no limitations or recurrence. Internal fixation after prior intralesional curettage is a valid treatment strategy for pathological fractures in young patients. A short nail was chosen to prevent direct tumor cell seeding throughout the femur and future recurrence. Fracture consolidation was achieved because of the healing potential of a young patient.

Simple Summary For high-grade soft tissue sarcomas (STS), combined modality treatment with surgery and radiation therapy is the standard of care. The addition of chemotherapy has been shown to decrease the risk of local recurrence and improve survival. Evaluating treatment response with surrogate modalities such as MRI, CT and PET imaging have substantial limitations. Pathologic necrosis of the surgical specimen is a direct indicator of the effect of treatment on tumor cells. Studies in STS and other malignancies have shown that increasing rates of treatment-induced tumor necrosis correlate with improvement of oncological outcomes and survival. However, the relationship between pathologic response and outcomes of specific neoadjuvant treatments for STS remains indeterminate. We hypothesized that sequential neoadjuvant chemotherapy and radiation yields higher rates of pathologic complete response (pCR) than neoadjuvant radiation or chemotherapy alone. Our results indicate that neoadjuvant chemotherapy and radiation yields superior pCR compared to other neoadjuvant regimens. Abstract (1) Background: Pathologic necrosis of soft tissue sarcomas (STS) has been used to determine treatment response, but its relationship to neoadjuvant treatments remains indeterminate. In this retrospective, single institution study, we hypothesized that neoadjuvant chemoradiation (NA-CRT) yields higher rates of pathologic complete response (pCR) than neoadjuvant radiation (NA-XRT) or chemotherapy (NA-CT) alone. (2) Methods: Patients with extremity STS between 2011–2020 who received neoadjuvant treatment were included. pCR was defined as percent necrosis of the surgical specimen greater than or equal to 90%. (3) Results: 79 patients were analyzed. 51.9% of the population were male with a mean age of 58.4 years. 49.4% identified as Non-Hispanic White. Twenty-six (32.9%) patients achieved pCR while 53 (67.1%) did not. NA-CT (OR 15.82, 95% CI = 2.58–96.9, p = 0.003 in univariate (UVA) and OR 24.7, 95% CI = 2.88–211.2, p = 0.003 in multivariate (MVA), respectively) and NA-XRT (OR 5.73, 95% CI = 1.51–21.8, p = 0.010 in UVA and OR 7.95, 95% CI = 1.87–33.7, p = 0.005 in MVA, respectively) was significantly associated with non- pCR when compared to NA-CRT. The analysis also demonstrated that grade 3 tumors, when using grade 2 as reference, also had significantly higher odds of achieving pCR (OR 0.23, 95% CI = 0.06–0.80, p = 0.022 in UVA and OR 0.16, 95% CI = 0.04–0.70, p = 0.015 in MVA, respectively). (4) Conclusion: NA-CRT yields superior pCR compared to other neoadjuvant regimens. This extends to higher grade tumors.

Chondrosarcomas represent the second most common group of primary bone sarcomas. Their pathologic subcategorization is based on morphology and biological behavior and has been recently revised to better harmonize risk of metastasis with diagnostic terminology. Many of the different entities are associated with specific genetic aberrations, and their identification can be essential to accurate diagnosis. Patient management depends on the correct integration of key pathological, molecular, and imaging data.

Chondrosarcoma, Ewing sarcoma, osteosarcoma, multiple melanoma/plasma cell myeloma, metastases, undifferentiated high-grade pleomorphic sarcoma, fibrosarcoma, chondroma/enchondroma, Langerhans cell histiocytosis/eosinophilic granuloma, desmoplastic fibroma, aneurysmal bone cyst, giant cell tumor, fibrous dysplasia, and osteoid osteoma are the most common histological type of pelvic bone tumors. This chapter will illustrate the gross and histological features of these tumors; highlight the ancillary testing of diagnostic, prognostic, and predictive markers, and the collaborative opportunities between pathologists and orthopedic surgeons to improve the quality, safety, and value of patient care.

Reactive angiogenesis is commonplace, occurs in many circumstances, and is important in the repair of injured tissue. Histologically, it is characterized by newly formed capillaries arranged in a lobular architecture and lined by plump endothelial cells. We have encountered a form of reactive angiogenesis not well described; composed of large endothelial cells with abundant clear cytoplasm that causes diagnostic challenges. The cohort includes 10 patients, aged 4 to 61, mean 40 years; 7 males, 3 females. One case involved bone (ilium), and 9 involved soft tissue: fingers (n=2), toes (n=2), hip joint (n=1), shoulder (n=1), thigh (n=2), and anal mucosa (n=1). Clinically, the patients had chronic ulcers, osteomyelitis, or localized infection. All cases exhibited a lobular proliferation of capillaries lined by large polyhedral endothelial cells that obscured the vessel lumens and were admixed with acute and chronic inflammation. The endothelial nuclei were vesicular with small nucleoli and the cytoplasm was abundant and clear or palely eosinophilic. The endothelial cells were stained with CD31 and ERG (7/7 cases), CD34 (6/6), FLI1 (4/4), and were negative for keratin and CD68 (6/6). Periodic acid-Schiff stain and periodic acid-Schiff stain-diastase on 3 cases did not demonstrate glycogen. Using a polymerase chain reaction, no Bartonella henselae was found in all 6 cases tested. Reactive angiogenesis with clear cell change unassociated with Bartonella spp. has not been described. It causes diagnostic challenges and the differential diagnosis includes benign and malignant tumors, as well as unusual infections. It is important to distinguish between these possibilities because of the significant impact on treatment and prognosis.

Amyloidoma is a solitary mass of amyloid protein that arises in patients with or without evidence of systemic amyloidosis, and can be found in a variety of different organ systems. Herein, we describe three cases of localized biopsy-positive amyloidomas with no evidence of systemic involvement-primary amyloidoma. Our cases include a patient with a paraspinal soft tissue amyloidoma, a patient with multiple primary amyloidomas involving the thoracic cavity and flank, and a patient with insulin-injection induced amyloidoma of the left shoulder. We present these cases to provide further insights into the clinical presentation of this uncommon clinical entity. We review the pathophysiology of amyloidosis and discuss our cases in the context of previous reports of amyloidoma.

Dedifferentiated chordoma is a rare chordoma subtype characterized by a high-grade sarcoma juxtaposed to conventional chordoma. We identified a series of dedifferentiated chordomas, reviewed clinicopathologic features, performed next-generation sequencing in select cases, and analyzed all related English-language publications. Our series included 7 men and 3 women (age 15 to 80 y [median: 54 y];1% of1000 chordomas surveyed). The tumor (2.8 to 24.5 cm [median: 5.8 cm] in size) presented de novo or as recurrence (including postradiotherapy) in sacrum (n=5), skull base (n=2), lumbar spine (n=1), thoracic/mediastinum (n=1), and lung (n=1; as metastasis). Histologically, the dedifferentiated component (3% to 95% [median: 60%]) was pleomorphic-to-fibrosarcomatous, juxtaposed to conventional (n=8) or chondroid (n=2) component. By immunohistochemistry, the conventional/chondroid component consistently expressed cytokeratin and brachyury, whereas the dedifferentiated component showed loss of both. We identified a sacral conventional chordoma with INI1 loss, with one of the lung metastases showing biphasic histology with loss of cytokeratin and brachyury in the dedifferentiated component. Sequencing identified tumor suppressor mutations in 4 tumors, including TP53 mutations in the dedifferentiated component in 3 tumors. Of 7 patients with follow-up, 6 developed metastases; 4 died at 15 to 99 months (median: 24 mo) after dedifferentiated chordoma diagnosis. Collectively, of 87 dedifferentiated chordoma patients described in 1913-2020 (including 10 herein), the median overall survival was 20 months. In summary, dedifferentiated chordoma involves diverse sites and presents de novo, postradiotherapy, or as recurrence/metastasis months-to-years after initial diagnosis. The dedifferentiated component shows loss of brachyury and cytokeratin staining and harbors recurrent TP53 mutations, implicating tumor suppressor dysregulation in chordoma dedifferentiation.

Giant cell tumor of bone (GCT) is a benign locally aggressive neoplasm composed of mononuclear cells admixed with innumerable osteoclast-type giant cells. H3F3A gene mutations producing mutant histone protein product H3.3 have been identified in 96% of GCT; mutant H3.3 is reliably demonstrated by immunohistochemistry. GCT may contain woven bone and rarely, neoplastic cartilage nodules which causes diagnostic challenges with aggressive neoplasms such as osteosarcoma. We describe the features of GCT with cartilage matrix and report the next-generation sequencing findings in a subset of tumors. Seventeen cases of GCT with cartilage matrix form the cohort: 7 males and 10 females, 13 to 55 (mean: 25) years old. Tumors involved the fibula (6), femur (6), and patella, tibia, humerus, S1, and scapula (1 case each). Tumors were radiolucent, circumscribed, lytic, and expansile. All contained classic GCT, foci of cartilage matrix, and trabeculae of woven bone. Immunohistochemistry showed diffuse staining for H3.3 in 9/9 cases and 1 case was positive for S100 and SOX9 in the cartilage areas. Next-generation sequencing showed a mutation in the H3F3A gene in 6/6 cases. On follow-up, 2 patients who underwent resection showed no disease after 12, and 7 months, respectively. Three patients had recurrences 10, 12, and 27 months after curettage; there were no metastases. GCT with cartilage matrix is uncommon. The cartilage matrix is associated with woven bone suggesting the neoplastic cells may differentiate into chondrocyte-like and osteoblast-like cells. Recognition of this neoplasm is important to prevent misdiagnosis and overtreatment of affected patients.

We present 5 cases of intraosseous hibernoma, a rare benign tumor of brown fat. Our literature review reveals that the average age at presentation is 58.6 years, and 69.7% of patients are female. Lesions are most often located in the spine and pelvis. Computed tomography usually demonstrates sclerotic changes, although lesions can be lytic. Magnetic resonance imaging findings include heterogeneous T2 hyperintensity. Technetium 99m-methyl diphosphonate bone scan reveals variable radiotracer uptake, whereas 18F-labeled fluoro-2-deoxyglucose (FDG) PET-CT shows mild uptake. Intraosseous hibernoma should be considered when imaging demonstrates a fat-containing lesion in bone, especially one exhibiting FDG avidity.

Background. Epithelioid hemangioendothelioma (EHE) is an uncommon malignant endothelial neoplasm that most commonly arises in soft tissue, bone, lung, and liver. Crohn’s disease (CD) is an inflammatory bowel disease of unknown etiology that is frequently associated with complications including strictures, fistulas/fissures, and neoplasms. Case description. A 43-year-old woman with a 6-year history of severe CD presented with anal pain and bleeding. She had prior partial colectomy for a stricture and a diverting ileostomy for perianal fissures and stricture. Colonoscopy showed severe chronic active colitis, stricture at 30 cm of anal verge, and a perianal fistula. The patient underwent total proctocolectomy. The colonic mucosa exhibited segmental ulceration and irregular thickening of the colon wall. Beneath an ulcer of the anal canal within the muscularis propria was a 1.2-cm poorly circumscribed, firm, white-tan mass. The mass was composed of cords and groups of large epithelioid endothelial cells with intracytoplasmic vacuoles enmeshed in a myxohyaline stroma. Immunohistochemically, the tumor cells were positive for ERG, CD31, and CAMTA1 and focally positive for keratin and SMA. Next-generation sequencing revealed a WWTR1-CMATA1 fusion. The morphology, immunoprofile, and molecular genetics were diagnostic of EHE. Discussion. Long-standing inflammatory bowel disease is associated with significant risk for developing neoplasms, usually carcinomas, which can be indistinguishable radiologically and clinically from nonneoplastic complications. These tumors are often identified as an incidental finding in specimens resected for clinically severe disease. This is the first report of EHE arising in the bowel affected by CD, and it mimicked mural fibrosis and fissures.

ObjectiveTo present the current terminology and natural history of neurofibromatosis 1 (NF1) cutaneous neurofibromas (cNF).MethodsNF1 experts from various research and clinical backgrounds reviewed the terms currently in use for cNF as well as the clinical, histologic, and radiographic features of these tumors using published and unpublished data.ResultsNeurofibromas develop within nerves, soft tissue, and skin. The primary distinction between cNF and other neurofibromas is that cNF are limited to the skin whereas other neurofibromas may involve the skin, but are not limited to the skin. There are important cellular, molecular, histologic, and clinical features of cNF. Each of these factors is discussed in consideration of a clinicopathologic framework for cNF.ConclusionThe development of effective therapies for cNF requires formulation of diagnostic criteria that encompass the clinical and histologic features of these tumors. However, there are several areas of overlap between cNF and other neurofibromas that make distinctions between cutaneous and other neurofibromas more difficult, requiring careful deliberation with input across the multiple disciplines that encounter these tumors and ultimately, prospective validation. The ultimate goal of this work is to facilitate accurate diagnosis and meaningful therapeutics for cNF.

Highlights • Myoepithelial carcinoma of the vulva and epithelioid sarcoma has overlapping histological, immunohistochemical and genetic features. • Similarities between two diagnoses in aggressive vulvar cancer should be noted as a sarcoma-based chemotherapy regimen should be considered. • We recommend immediate surgical resection with bilateral superficial and deep inguinal lymph node dissections in these aggressive cancers. • Identification of SMARCB1-deficiency trials of targeted therapies such as EZH2 inhibitors which show promise in halting further progression., Introduction Myoepithelial carcinoma and proximal-type epithelioid sarcoma of the vulva are two rare malignancies with known aggressive behavior. In addition to a similar clinical course, these two disease entities also have significant histologic and pathologic overlap. Given the rarity of these malignancies, there is limited literature on the appropriate treatment regimen. Nevertheless, there is a consensus that early surgical resection is beneficial in both cases. Presentation We present a case of a patient who was initially diagnosed with myoepithelial carcinoma of the vulva with a differential later expanded to include possible epithelioid sarcoma. Discussion We demonstrate the importance in early identification of a SMARCB1 deficiency. Additionally, we suggest an appropriate treatment regimen for these patients going forward. Specifically, we encourage consideration of bilateral superficial and deep inguinal lymphadenectomies. Furthermore, sarcoma based chemotherapy regimens in the appropriate clinical setting may be beneficial in treating SMARCB1 deficient tumors. Additionally, there are now clinical trials involving EZH2 Inhibitors which may offer benefit for similar patients going forward. Conclusion This case highlights the difficulty in making a definitive diagnosis, and the importance in identifying a SMARCB1 deficiency as it will affect treatment options and may allow for enrollment in ongoing clinical trials.

Background Indeterminate dendritic cell tumor (IDCT) is an extremely rare hematologic disorder with poorly understood pathogenesis. Occasionally encountered by hematologists, unusual presentations of IDCT have not been reported in the spine literature. Methods We report a 51-year-old man who presented with a 3-month history of progressively worsening axial thoracic back pain radiating to his sides. Magnetic resonance imaging revealed a 3-cm enhancing mass at the T9 vertebral body with an exophytic component causing significant canal stenosis. Initial percutaneous biopsy revealed histiocytic sarcoma. Results The patient underwent exploratory thoracotomy and en bloc resection of the lesion with T8-10 fusion. Final pathology results revealed IDCT with fibrosis. IDCT immunostaining was partially positive for Langerhans cell marker (positive for S100 and CD1a, but lacked Birbeck granules and Langerin stain) and partially positive for blastic plasmacytoid dendritic cell neoplasm. Additionally, it was positive for CD45, CD68, and CD163. Lymphadenopathy was absent in this patient. Conclusions Although first reported in the 1980s, IDCT has been omitted from most classifications owing to its rarity. Hematologists have debated the cell of origin; it is believed to comprise pre–Langerhans cells, as Birbeck granules are acquired after migration to the epidermis. IDCT remains of indeterminate origin. We report the first case of spinal IDCT. Familiarity with the histologic features is warranted to ensure accurate diagnosis and appropriate treatment.

Bone-forming tumors are defined by neoplastic cells that differentiate along the lines of osteoblasts that deposit neoplastic bone. The morphology and biological spectrum of bone-forming tumors is broad, and their accurate diagnosis requires the careful correlation of their clinical, morphologic, and radiologic characteristics. Immunohistochemical and molecular analyses have an important role in select instances. At present, the identification of neoplastic bone largely depends on histologic analysis, which can be subjective. The major types of osteosarcoma are defined according to their morphology, origin within or on the surface of the bone, and their histologic grade.

Hemangioma of the bone is a benign neoplasm of endothelial cells that form blood vessels. It is one of the most common tumors of bone and has been found in vertebral bodies in approximately 10% of the adult population. The lesions can be classified according to their morphology and number. They include conventional capillary or cavernous hemangioma, diffuse cystic angiomatosis, and hemangioma/lymphangioma with massive osteolysis (Gorham-Stout syndrome, aka disappearing bone disease). Conventional hemangioma is often asymptomatic and is more frequent in adult women. Vertebral bodies are the most common location, followed by the craniofacial bones and metaphyses of long bones. Imaging of hemangioma is characterized by coarse trabeculations. Asymptomatic lesions may not require treatment. Prognosis is excellent.

Vascular tumors of the joint are rare; they are defined as neoplastic proliferations of cells with endothelial phenotype that arise in periarticular structures, especially the synovium. The majority of cases reported in the literature are synovial hemangiomas. The knee joint is the most common location. Angiosarcoma of the joint is extremely rare. Clinically, intra-articular hemangioma can cause pain, tenderness, swelling, and hemarthrosis. Phleboliths can be identified on plain radiographs. MRI shows an intra-articular or juxta-articular soft tissue mass of intermediate signal intensity on T1-weighted images and of high signal intensity of T2-weighted images. Microscopically, the tumors can be composed of capillary, cavernous, or mixed arteriovenous types. Current treatment is surgical excision via arthroscopy, or open excision if the lesion is diffuse. Preoperative embolization may be effective for diffuse lesions.

Purpose To retrospectively describe the clinical characteristics, management, and outcomes of a series of patients with solitary fibrous tumor (SFT) of the orbit and to evaluate signal transducer and activator of transcription 6 (STAT6) as a diagnostic marker. Methods Review of a retrospective, noncomparative, consecutive series of patients treated at a single institution with a histopathologic diagnosis of SFT. Demographic, clinical, and imaging data were collected, and paraffin-embedded tissue sections were stained to evaluate for the presence of STAT6 and other pertinent markers. Results Twenty-one patients were identified. Most presented with painless progressive proptosis or eyelid swelling for less than 6 months. Imaging revealed well-circumscribed, firm, variably vascular contrast-enhancing lesions with low to medium reflectivity on ultrasound. Four tumors were histopathologically malignant. All tumors were primarily excised, and 1 patient required exenteration. Two patients were treated with adjuvant radiation therapy. Six patients had recurrent disease of which 3 underwent repeat excision, and 2 were observed. No metastatic disease or attributable deaths were observed. All lesions with available tissue stained positively for both CD34 and STAT6. Conclusion This is the largest single institution case series of orbital SFT with clinicopathologic correlation and the largest series to confirm the presence of STAT6 in orbital lesions. The management of SFT remains challenging due to unpredictable tumor behavior, and complete excision is the generally recommended treatment. It remains unclear whether a subset of asymptomatic patients with histopathologically benign disease can be durably observed without negative sequelae.

Background Angiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas. Methods We performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue. Results We have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities. Conclusions This case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy.

In this article, we describe a case of conventional epithelioid hemangioendothelioma (EHE) arising within an extra-adrenal myelolipoma. This composite neoplasm arose in the mediastinum of a 51-year-old female. The tumor was composed of a large myelolipoma that contained nodules of EHE consisting of CD31-positive epithelioid endothelial cells that grew in solid cords and were enmeshed in a basophilic hyalinized stroma. Both EHE and myelolipoma are characterized genetically by alterations of WWTR1. We demonstrated the expression of CAMTA-1 chimeric protein by immunohistochemistry both in the neoplastic endothelial cells of EHE and some of the endothelial cells lining the blood vessels in the myelolipoma. To the best of our knowledge, this is the first report of a malignant vascular neoplasm arising in association with myelolipoma.

Warthin tumor (WT) is the second most common benign salivary gland neoplasm and has characteristic cytologic and histologic findings. Fine-needle aspiration is a common and useful preoperative diagnostic technique, which sometimes leads to ischemic injury resulting in the infarction of these lesions. Infarcted WT may demonstrate variable gross and histologic alterations that may render the diagnosis challenging, particularly during intraoperative frozen section evaluation. In this study, we collected 11 resection specimens from 9 patients with infarcted WT. Seven patients were men and 2 were women, ranging from 49 to 85 years (mean, 69). All the patients had fine-needle aspiration before the resection. Macroscopically, the tumors were tan-white and contained soft, yellow, exudative material. The histologic findings were variable and included necrosis, ghosts of papillae, squamous metaplasia, cholesterol clefts, foamy macrophages, multinucleated giant cell reaction, necrotizing granulomas, and fibrosis. Each case predominantly demonstrated 1 or 2 of these histomorphologic features. In the permanent sections, additional sampling revealed foci of residual viable WT in 8 cases. Three cases were completely infarcted; however, they all had ghost-like papillae in which the architecture of WT was evident. Infarcted WT may present a diagnostic challenge during intraoperative frozen section evaluation. Associated morphologic alterations may preclude a definitive diagnosis of WT and may mimic malignancy. Awareness of the gross and microscopic features associated with infarcted WT is important, particularly for accurate frozen section evaluation of these salivary gland tumors.

We discuss two of the most common conditions of bone seen in general pathology practice. We review the causes and pathophysiology of osteomyelitis and osteonecrosis. We discuss their imaging characteristics and histological features as well as some of the problems in diagnosis faced by a pathologist.

Background As specialists in perioperative medicine, anesthesiologists are well equipped to design and oversee the preoperative patient preparation process; however, the impact of an anesthesiologist-led preoperative evaluation clinic (PEC) on clinical outcomes has yet to be fully elucidated. The authors compared the incidence of in-hospital postoperative mortality in patients who had been evaluated in their institution’s PEC before elective surgery to the incidence in patients who had elective surgery without being seen in the PEC. Methods A retrospective review of an administrative database was performed. There were 46 deaths from 64,418 patients (0.07%): 22 from 35,535 patients (0.06%) seen in PEC and 24 from 28,883 patients (0.08%) not seen in PEC. After propensity score matching, there were 13,964 patients within each matched set; there were 34 deaths (0.1%). There were 11 deaths from 13,964 (0.08%) patients seen in PEC and 23 deaths from 13,964 (0.16%) patients not seen in PEC. A subanalysis to assess the effect of a PEC visit on deaths as a result of failure to rescue (FTR) was also performed. Results A visit to PEC was associated with a reduction in mortality (odds ratio, 0.48; 95% CI, 0.22 to 0.96, P = 0.04) by comparison of the matched cohorts. The FTR subanalysis suggested that the proportion of deaths attributable to an unanticipated surgical complication was not significantly different between the two groups (P = 0.141). Conclusions An in-person assessment at the PEC was associated with a reduction in in-hospital mortality. It was difficult to draw conclusions about whether a difference exists in the proportion of FTR deaths between the two cohorts due to small sample size.

The Stewart-Treves syndrome is a rare and deadly entity, which is defined as angiosarcoma arising in the setting of chronic lymphedema. It typically presents in women who develop lymphedema in the upper extremity secondary to axillary lymph node dissection for breast cancer surgery. It is extremely uncommon in the lower extremities as a result of idiopathic chronic lymphedema. Here, we present the case of a 63-year-old female patient with idiopathic chronic lymphedema of the lower extremities having morbid obesity (BMI 82.6) and multiple comorbidities. She developed multiple confluent, hemorrhagic and necrotic elevated purple-black papules in the lower extremities, for which the initial diagnosis was cellulitis. Because there was no improvement with antibiotics, a lower extremity ultrasound and biopsy was performed which showed multiple masses in the left inner upper calf with solid and cystic components. The pathology results of the punch biopsies were consistent with angiosarcoma. Immunohistochemical studies revealed positivity for CD31, FLI-1, and a high Ki-67 proliferation rate. Because of the patient's weight and medical comorbidities, no further extensive diagnostic tests were performed to detect metastatic disease, and because of contraindications, no further medical treatment was provided. The patient subsequently died 1 month after diagnosis.

Summary Background VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma. Methods This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0–1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2–10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual. Findings Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1–19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6–79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1–90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths. Interpretation Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials. Funding Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.

Background Osteomas are benign lesions of bone, most frequently seen in the paranasal sinuses; however, they are typically asymptomatic and without complication. We report a rare case of large frontal sinus osteoma with intracranial extension, associated with meningitis and the development of seizures. Case Description The patient is a 38-year-old man with a prolonged history of headache and seizures, who was seen by multiple specialists previously, all of whom deferred treatment. After years of worsening seizure activity, he finally underwent surgical resection of the lesion at our institution in a joint operation with neurosurgery and otolaryngology. We examine his course, presentation, and management, and examine the literature for cases of complicated sinus osteomas. Conclusions This represents the fourth reported case of frontal sinus osteoma associated with meningitis. We believe this case demonstrates the value of a robust differential and a multidisciplinary approach.

We report a first case of paraneoplastic human chorionic gonadotropin (HCG) production in a dedifferentiated liposarcoma with rhabdosarcomatous differentiation in an 83-year-old man with a retroperitoneal mass, unilateral scrotal enlargement, and a serum HCG level of 843 IU/L. Core biopsy of the retroperitoneal mass revealed rhabdomyosarcoma. Orchiectomy revealed a paratesticular dedifferentiated liposarcoma with rhabdosarcomatous differentiation. Fluorescence in situ hybridization analysis performed on both the retroperitoneal and paratesticular masses revealed amplification of MDM2. The retroperitoneal tumor was interpreted as metastatic dedifferentiated liposarcoma with the dedifferentiated component represented by rhabdomyosarcoma. HCG production is a common feature of testicular germ cell tumors, less common in carcinomas, and extremely rare in sarcomas. Accordingly, sarcomas secreting HCG are a potential diagnostic pitfall, and raise the differential diagnosis of germ cell tumors and a variety of carcinomas. HCG production by carcinomas is a known poor prognostic finding, however the significance of its production in sarcomas is unknown.

Lipomatous metaplasia is an uncommon phenomenon. After identifying the presence of a band of adipocytes in the superficial reticular dermis underlying two excisions for basal cell carcinoma, we prospectively reviewed all skin specimens accessioned in our laboratory over a 6-month period and identified eight additional cases. In each example there was a band of adipocytes in the upper dermis, at the level of solar elastosis that was widely separated from the subcutaneous fat by a normal appearing reticular dermis. The cells were positive for S100 and negative for CD163. No connection between the superficial band of adipocytes and the subcutaneous or periappendageal fat was seen. The alterations were flat in configuration without polypoid changes. Eyerich et al. reported lipomatous metaplasia in the dermis of a patient with acute generalized exanthematic pustulosis and psoriasis, and postulated this to be a postinflammatory phenomenon. Fatty metaplasia occurs within a variety of cutaneous neoplasms including nevi, adnexal tumors and peripheral nerve sheath tumors. However, superficial dermal fatty metaplasia beneath cutaneous neoplasms is a newly described phenomenon and we suspect this process represents fatty metaplasia within solar elastosis and that it may occur more frequently than recognized.

Dedifferentiated liposarcoma (DDL) of the spermatic cord is rare, with limited data regarding morphology and prognosis. We analyzed the morphologic spectrum of DDL of the spermatic cord and its clinical significance in 42 patients from 1990 to 2014. The median age of the patients was 70.5 years (range: 43 to 90 y). The median tumor size was 10.9 cm (range: 3 to 30 cm). Six cases were low-grade DDL, 28 were high-grade DDL, and in 8 cases both coexisted. Five cases had osteosarcoma, and 2 had leiomyosarcoma differentiation. Low-grade DDL had a fibrosarcoma-like (n=11), myxofibrosarcoma-like (n=2), and fibrosarcoma and inflammatory-like (n=1) pattern. High-grade DDL had a fibrosarcoma-like (n=22), undifferentiated pleomorphic sarcoma-like (n=7), myxofibrosarcoma and undifferentiated pleomorphic sarcoma-like (n=4), fibrosarcoma and undifferentiated pleomorphic sarcoma-like (n=2), and myxofibrosarcoma-like (n=1) pattern. Resection margins were positive in 22, negative in 13, and unknown in 7 cases. MDM2 was positive in 24/24 cases. Two patients received neoadjuvant radiotherapy (1 with chemotherapy). Patients received postoperative radiation (n=13), reexcision (n=5) with radiation (n=3), chemotherapy (n=2), chemotherapy and radiation (n=1), no therapy (n=11), and unknown (n=6). Follow-up information was available in 31 patients (mean: 54.2 mo; median: 38.5 mo; range: 2 to 180 mo). Seven patients developed local recurrence. Two patients had systemic metastases and succumbed to disease. Recurrence developed at an average of 40.9 months (median: 24 mo; range: 12 to 100 mo) after resection. Average follow-up in patients without recurrence was 45.2 months (median: 25 mo; range: 2 to 180 mo) (P=0.87). Margin status, size, and grade did not correlate with recurrence (P>0.05). Thus, DDL of the spermatic cord includes a spectrum of morphologic patterns. Complete excision is difficult at first attempt. Local recurrence is common, and relatively few patients develop systemic disease.

Myocardial necrosis in the perioperative period of noncardiac surgery is associated with short-term mortality, but long-term outcomes have not been characterized. We investigated the association between perioperative troponin elevation and long-term mortality in a retrospective study of consecutive subjects who underwent hip, knee, and spine surgery. Perioperative myocardial necrosis and International Classification of Disease, Ninth Revision –coded myocardial infarction (MI) were recorded. Long-term survival was assessed using the Social Security Death Index database. Logistic regression models were used to identify independent predictors of long-term mortality. A total of 3,050 subjects underwent surgery. Mean age was 60.8 years, and 59% were women. Postoperative troponin was measured in 1,055 subjects (34.6%). Myocardial necrosis occurred in 179 cases (5.9%), and MI was coded in 20 (0.7%). Over 9,015 patient-years of follow-up, 111 deaths (3.6%) occurred. Long-term mortality was 16.8% in subjects with myocardial necrosis and 5.8% with a troponin in the normal range. Perioperative troponin elevation (hazard ratio 2.33, 95% confidence interval 1.33 to 4.10) and coded postoperative MI (adjusted hazard ratio 3.51, 95% confidence interval 1.44 to 8.53) were significantly associated with long-term mortality after multivariable adjustment. After excluding patients with coronary artery disease and renal dysfunction, myocardial necrosis remained associated with long-term mortality. In conclusion, postoperative myocardial necrosis is common after orthopedic surgery. Myocardial necrosis is independently associated with long-term mortality at 3 years and may be used to identify patients at higher risk for events who may benefit from aggressive management of cardiovascular risk factors.