Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function.

The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines, we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells down-regulate glycolytic mechanisms. These studies demonstrate that discrete perturbations of mitochondrial respiratory chain function impact in vivo tumor growth in a context-specific manner with differential impacts on primary and metastatic tumors.

ALK Immunoexpression is Specific for Inflammatory Myofibroblastic Tumor Among Vulvovaginal Mesenchymal Neoplasms.

Gynecologic tract origin of inflammatory myofibroblastic tumor (IMT), a receptor tyrosine kinase fusion driven tumor with malignant potential, is uncommon and mostly involves the uterine corpus where misclassification as a smooth muscle tumor may occur due to overlapping morphologic features. With rare exception, uterine IMT involves ALK rearrangements and exhibits ALK immunoexpression. Molecularly confirmed vulvovaginal IMT has not been reported, but several low-grade mesenchymal tumors in this region exhibit myxoid stroma and/or inflammatory infiltrates that may resemble IMT. The aims of this study were to define the diagnostic specificity of ALK immunoexpression for IMT among a broad spectrum (107 cases) of vulvovaginal mesenchymal tumors in the differential diagnosis of IMT and to report the clinicopathologic features of vulvovaginal IMT identified in our archives or via retrospective ALK staining of otherwise classified vulvovaginal tumors. Review of archives from 5 different centers revealed a single case of vulvar IMT in a 62-yr-old woman. The 2.5 cm well-circumscribed tumor exhibited the typical microscopic features of IMT, namely a loose fascicular distribution of bland spindle cells within a myxoid stroma, accompanied by an infiltrate of plasma cells, lymphocytes, and eosinophils. The tumor cells exhibited expression for smooth muscle actin, desmin, h-caldesmon, and ALK. Break-apart fluorescence in situ hybridization confirmed the presence of ALK rearrangement. The patient did not receive any treatment and is alive without disease 32 mo later. No evidence of ALK expression was detected in any of the other 107 vulvovaginal tumors, which included 14 aggressive angiomyxomas, 2 superficial angiomyxomas, 12 angiomyofibroblastomas, 8 cellular angiofibromas, 15 smooth muscle neoplasms, 10 peripheral nerve sheath tumors, 20 fibroepithelial polyps, and a variety of other low grade mesenchymal tumors. Although vulvovaginal ALK- rearranged IMT is exceedingly rare, the behavior remains to be fully understood. ALK immunohistochemistry, which appears specific for IMT in this anatomic site, is advised in the evaluation of vulvovaginal mesenchymal tumors exhibiting myxoid stroma and/or an inflammatory infiltrate.

Calcifying fibrous tumor: a rare case in the foot.

Calcifying fibrous tumor is a rare fibroblastic tumor with distinctive histological presentation that shows benign characteristics. To our knowledge, there are no prior reports that have documented imaging findings of calcifying fibrous tumor in the distal lower extremity. We report the case of a 25-year-old man who presented with a mass in the medial aspect of the right foot that was first noted 4 years earlier. Medical attention was sought due to perceived increase in size as well as increasing pain in the right foot. The patient had no limitations in activity but reported worsening discomfort while walking. An anteroposterior radiograph obtained at first presentation demonstrated a large calcified soft mass in the medial aspect of the foot. Contrast-enhanced MRI showed a mildly enhancing 6.5 cm × 2.5 cm × 8.5 cm mass, hypointense on T1- and T2-weighted images, infiltrating the adjacent abductor hallucis and flexor digitorum brevis muscles. Histopathology demonstrated multiple irregular fragments of white-tan firm tissue with a gritty cut surface, positive for CD34 on immunohistochemistry and consistent with calcifying fibrous tumor. Although rare in the extremities, this diagnosis should be considered in patients with a calcifying soft tissue mass. Low signal intensity with low-grade enhancement on MRI as well as stable disease course could prompt a diagnosis of calcifying fibrous tumor even in previously unmanifested locations.

Botryomycosis: a rare mimic of sarcoma as an initial presentation of acquired immunodeficiency syndrome.

Botryomycosis is a rare granulomatous response to chronic bacterial infection most frequently associated with Staphylococcus aureus. This disease, which predominantly affects immunocompromised patients, may present with cutaneous, visceral, or soft tissue manifestations. Soft tissue involvement typically has an aggressive mass-like appearance on imaging which can be concerning for malignancy. In immunocompromised patients, botryomycosis can resemble fungal infection both clinically and histologically; therefore, definitive diagnosis requires tissue sampling along with histological and microbiological analysis. Presented here is a 25-year-old man with an enlarging intramuscular soft tissue mass of the right forearm as his first presentation of undiagnosed acquired immunodeficiency syndrome (AIDS). MR imaging showed a mildly T2 hyperintense and enhancing mass with infiltrative margins extending through tissue planes. Biopsy of the mass revealed Staphylococcus aureus-associated botryomycosis, which improved with nonsurgical treatment employing antibiotics. Unfortunately, the patient subsequently expired from other manifestations of his new AIDS diagnosis. This case describes the MR and PET-CT appearance of botryomycosis and also underscores that infection can mimic sarcoma, particularly in the setting of immunodeficiency.

Primary Cutaneous Malignant Perivascular Epithelioid Cell Tumor Mimicking Undifferentiated Pleomorphic Sarcoma: A Report of a Rare Entity.

ABSTRACT: Primary cutaneous malignant perivascular epithelioid cell tumor (PEComa) is a rare and potentially aggressive neoplasm. In this article, we report the case of a 34-year-old man who initially presented with a 3-cm mass involving the skin and soft tissue of the right shoulder that, over 3 months, enlarged to 12 cm. Histologic examination of the mass revealed an infiltrative neoplasm with features resembling an undifferentiated pleomorphic sarcoma, including sheets of pleomorphic cells with abundant atypical mitoses and necrosis. Immunohistochemical evaluation showed features suggestive of PEComa. Next-generation sequencing revealed pathogenic homozygous deletions of TSC2 and TP53 genes and numerous large-scale copy number changes. Taken together, the findings supported malignant PEComa. This case demonstrates only the seventh example of malignant cutaneous PEComa. Although cutaneous PEComa is chiefly a benign mesenchymal neoplasm, in rare cases, it can rapidly transform into a malignant and infiltrative sarcoma, requiring prompt surgical management.

Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation.

Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1-/- SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.

Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma.

BACKGROUND: Soft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited. METHODS: Here, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients. RESULTS: We uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors. CONCLUSIONS: Our study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.

Lipoblastomas presenting in older children and adults: analysis of 22 cases with identification of novel PLAG1 fusion partners.

Lipoblastomas are benign neoplasms of embryonal white fat that typically present in the first 3 years of life and show a lobular arrangement of maturing adipocytes with variable degrees of myxoid change. We systematically studied the clinicopathologic and genetic features of lipoblastomas arising in older children and adults. Cases with a diagnosis of lipoblastoma or maturing lipoblastoma in patients >3 years of age were retrieved from our archives. Immunostaining for CD34 and desmin and molecular studies (FISH, RNA sequencing) were performed. Twenty-two cases (8F; 14M) were identified in patients ranging from 4 to 44 years of age (median 10 years). Sites included extremity (n = 15), head and neck (n = 4), and trunk (n = 3) with tumor sizes varying from 1.6 to 17.5 cm (median 5). Only three tumors had histologic features of "conventional" lipoblastoma. The majority of tumors (n = 14) were composed of variably sized lobules of mature adipose tissue partitioned by thin fibrous septa ("maturing"). The remaining five cases consisted predominantly of bland spindled to plump ovoid cells embedded in a fibrous stroma, with a vaguely plexiform arrangement of small myxoid and adipocytic nodules ("fibroblastic"). CD34 was diffusely positive in all cases tested (21/21), while desmin immunoreactivity was identified in 12 of 21 cases (diffuse = 7, focal = 5). PLAG1 rearrangements were identified in 13 tumors in the entire cohort (59%), including all 5 fibroblastic tumors. RNA sequencing detected eight PLAG1 fusion partners, of which two were known (CHCHD7 and COL3A1) and six were novel (SRSF3, HNRNPC, PCMTD1, YWHAZ, CTDSP2, and PPP2R2A). Twelve cases had follow-up (1-107 months; median 21 months), and no recurrences were reported. Lipoblastomas may occur in older children and adults and may be difficult to recognize due to their predominantly adipocytic or fibrous appearance. Awareness that lipoblastomas may occur in older patients, careful evaluation for foci showing more typical morphologic features, ancillary immunohistochemistry for CD34 and desmin, and molecular genetic studies to identify PLAG1 rearrangements are the keys to recognizing these tumors.

Fibroma-like perivascular epithelioid cell tumor: a rare case in a long bone.

Fibroma-like perivascular epithelioid cell (PEComa) tumor is an extremely rare family of mesenchymal tumors composed of cells co-expressing melanocytic and myogenic markers. To date, 13 cases of primary bone PEComa have been reported in the literature and five reported fibroma-like PEComas were found in the soft tissues of patients with tuberous sclerosis (TSC). However, no fibroma-like PEComa has been reported in bone, either sporadic or TSC-associated. Here we report the case of a 22-year-old man with known TSC, who presented for evaluation of an asymptomatic mass in his left fibula diaphysis that had been present for 5 years. He had no activity-related pain, numbness, weakness, or limitations in range of motion. Both 3-T MRI and CT demonstrated a tumor originating from the midshaft middiaphyseal fibula. Axial T1-weighted and fat-saturated T2-weighted fast spin echo images showed a well-defined lesion in the fibula with extension into the surrounding soft tissues. Whole body bone scan was negative for metastasis using technetium-99m. Renal ultrasound was unremarkable with no evidence of angiomyolipoma. Histopathology demonstrated isolated spindle cells in a dense collagenous matrix. By immunohistochemical staining, tumor cells were positive for HMB-45 and MiTF and partially positive for alpha-smooth muscle actin supporting a diagnosis of fibroma-like PEComa of the midshaft fibula. Although fibroma-like PEComa of bone is very rare, a bone tumor in the setting of TSC should raise suspicion for the diagnosis, in particular if histology demonstrates rare epithelioid cells in a densely fibrotic stroma.

Primary osteosarcoma of the parietal bone.

Osteosarcoma is the most common primary bone tumor and usually involves the long bones. Osteosarcoma of the skull, on the other hand, is relatively rare. Here, we present a 29-year-old man with a growing mass in the skull he first noticed after a fall while skateboarding. The initial clinical diagnosis was hematoma. While undergoing an evacuation surgery for a hematoma, a suspicious mass was detected which was biopsied. Histopathological evaluation showed high-grade osteosarcoma. The patient was referred to our hospital where he underwent definitive resection followed by adjuvant chemotherapy. His course was complicated by wound infection. Even though osteosarcoma of the skull is a rare finding, it should be suspected in a patient with a skull mass, and the history of prior head trauma does not exclude the diagnosis.

Genetic and molecular reappraisal of spindle cell adamantinoma of bone reveals a small subset of misclassified intraosseous synovial sarcoma.

Adamantinoma represents a distinct group of bone tumors showing both mesenchymal and epithelial differentiation most commonly involving the tibial diaphysis. Most adamantinomas contain a fibro-osseous component and an epithelial component consisting of squamous or basaloid cells. Adamantinomas are considered malignant neoplasms requiring en bloc excision that frequently recur locally and can rarely metastasize. Rare adamantinomas show an epithelial component consisting predominantly of monomorphic spindle cells, which, combined with an epithelial immunophenotype, can mimic monophasic synovial sarcoma. Synovial sarcoma is very rare in bone. It is considered a high-grade sarcoma that typically necessitates chemotherapy. However, the relationship between spindle cell adamantinoma and intraosseous synovial sarcoma has not been investigated. The current study was prompted by identification of a presumed spindle cell adamantinoma of the tibia with diffuse keratin expression that harbored a SS18 gene region rearrangement. FISH of eight additional bone tumors initially classified as spindle cell adamantinoma based on clinicoradiopathologic findings revealed one additional case with SS18 rearrangement. Histologically, both intraosseous synovial sarcoma and spindle cell adamantinoma demonstrated uniform fusiform nuclei with scant cytoplasm, short fascicles and low mitotic activity. The adamantinomas, but not the synovial sarcomas, were more likely to show overt epithelial differentiation in the form of pseudoglands or squamous nests. Immunohistochemistry of all cases, irrespective of SS18 status, showed diffuse keratin positivity in the spindle cell component, and less consistent EMA positivity. Clinical follow-up was available in both intraosseous synovial sarcomas, one of which recurred and the other metastasized. Two of the six spindle cell adamantinomas with follow-up metastasized. The above findings highlight the morphologic and immunophenotypic overlap between spindle cell adamantinoma and intraosseous synovial sarcoma of the tibia. Investigation of SS18 status to exclude synovial sarcoma is suggested prior to rendering a diagnosis of spindle cell adamantinoma.

Atypical lipomatous tumour/well-differentiated liposarcoma and de-differentiated liposarcoma in patients aged ≤ 40 years: a study of 116 patients.

AIMS: Limited data exist on atypical lipomatous tumour (ALT)/well-differentiated liposarcoma (WDL) and de-differentiated liposarcoma (DDLPS) in children and young adults. METHODS AND RESULTS: Cases of ALT/WDL/DDLPS arising in patients aged ≤ 40 years were collected from multiple institutional and consultation archives. A total of 116 cases of ALT/WDL (75) and DDLPS (41) were identified, representing fewer than 5% of these tumours seen at our institutions during this time-period. The patients (59 male/57 female) ranged in age from 8 to 40 years. Sites included deep central (abdomen/retroperitoneum/pelvis/groin) (n = 60), extremity (n = 42), trunk (n = 5), head/neck (n = 8) and mediastinum (n = 1). De-differentiated patterns included: high-grade pleomorphic sarcoma, myxofibrosarcoma-like, heterologous rhabdomyoblastic differentiation, low-grade spindle cell sarcoma and homologous lipoblastic differentiation. Forty-one patients experienced a local recurrence and 11 patients with DDLPS developed metastasis. ALT arising in the extremities had lower recurrence rates than deep central WDL (5-year recurrence-free survival 88.9% versus 59.0%; P = 0.002), while patients with deep central DDLPS experienced significantly more adverse events compared to WDL at this site (5-year event-free survival 11.9% versus 59.0%) (P < 0.0001). Seven (of eight) head/neck tumours had follow-up available; five recurred, and one patient (DDLPS) with recurrence also experienced a metastasis. The single mediastinal tumour (DDLPS) recurred and metastasised. CONCLUSION: ALT/WDL and DDLPS occurring in patients aged ≤ 40 years is rare, but exhibits similar morphological features to its counterparts in older adults, including potential for heterologous and homologous de-differentiation in the latter. Although case numbers are limited, tumours arising in the head and neck exhibit high rates of adverse events, suggesting that classification as WDL rather than ALT is more appropriate.

Progression of dialysis-related amyloidoma towards pathologic fracture.

Amyloidosis is the extracellular deposition of amyloid protein fibrils, and this condition may be hereditary or acquired. Patients undergoing long-term hemodialysis are particularly at risk for developing acquired amyloidosis. A rare form of amyloidosis is an amyloidoma or amyloid tumor, which occurs when amyloid focally deposits in a section of the musculoskeletal system, most commonly in the osteoarticular system. Here, we present a case of a hemodialysis-related amyloidoma of the left femoral neck in an 80-year-old woman with end-stage renal disease on hemodialysis for 8 years. The purpose of this report is to provide an account of the unique clinical, imaging, and histopathologic manifestation of a dialysis-related amyloidoma that progressively enlarges over a 2-year period. This report also highlights some prophylactic measures that may reduce the risk of developing an associated pathologic fracture.

Significance of H3K27me3 loss in the diagnosis of malignant peripheral nerve sheath tumors.

The diagnosis of malignant peripheral nerve sheath tumors can be challenging and other spindle cell sarcomas commonly enter in the differential diagnosis. Loss of trimethylation at lysine 27 of histone-H3 (H3K27me3) by immunohistochemistry was recently described in malignant peripheral nerve sheath tumors. However, its specificity remains controversial. We therefore studied 82 synovial sarcomas, 39 malignant peripheral nerve sheath tumors, and 10 fibrosarcomatous dermatofibrosarcoma protuberans for H3K27me3 loss by immunohistochemistry. The diagnoses were based on morphology, immunophenotype, and genetics based on WHO classification. H3K27me3 immunohistochemistry was scored by two pathologists based on fraction of cells with nuclear staining (score 0 to 3+). Loss of H3K27me3 (score 0) was seen in 44% of malignant peripheral nerve sheath tumors and 9% of synovial sarcomas yielding positive and negative predictive values of 71% and 77%, respectively. Loss of H3K27me3 was seen in 10% of fibrosarcomatous dermatofibrosarcoma protuberans, yielding positive and negative predictive values of 94 and 29% in the differential diagnosis of malignant peripheral nerve sheath tumor versus fibrosarcomatous dermatofibrosarcoma protuberans. Partial loss (score 1-2) was common in all three tumor types. Among malignant peripheral nerve sheath tumors, there was no significant association between H3K27me3 loss and gender, tumor site, or size, and progression-free or overall survival. Patients with tumors with H3K27me3 loss were younger than those with tumors with retained H3K27me3 expression (P=0.011). H3K27me3 expression was lost in 50 and 31% of sporadic and Neurofibromatosis-associated malignant peripheral nerve sheath tumors, respectively (P=0.25).Complete H3K27me3 loss is a moderately sensitive and relatively specific marker for the diagnosis of malignant peripheral nerve sheath tumor when the differential diagnosis includes synovial sarcoma and fibrosarcomatous dermatofibrosarcoma protuberans. Partial loss has limited diagnostic utility. H3K27me3 status does not show significant association with clinical outcome in malignant peripheral nerve sheath tumors.

Recurrent GNAQ mutations in anastomosing hemangiomas.

Anastomosing hemangiomas are recently described benign vascular lesions that occur chiefly in the genitourinary tract and paravertebral soft tissues. Owing to their rarity and unusual cytoarchitectural features, anastomosing hemangiomas are frequently confused with low-grade angiosarcomas. The specific genetic alterations underlying these lesions are currently unknown. We performed capture-based next-generation DNA sequencing analysis on 13 anastomosing hemangiomas and identified frequent somatic mutations in the heterotrimeric G-protein alpha-subunit, GNAQ. Nine of 13 cases (69%) harbored a somatic mutation at GNAQ codon 209, a known hotspot that is commonly mutated in uveal melanoma and blue nevi, as well as various congenital vascular proliferations. No other pathogenic or likely pathogenic mutations were identified in these genetically simple lesions. The finding of a recurrent driver mutation in the G-protein signal transduction pathway provides strong evidence that anastomosing hemangiomas are indeed clonal vascular neoplasms.

Composite hemangioendothelioma with neuroendocrine marker expression: an aggressive variant.

Aberrant expression of neuroendocrine markers is extremely rare in endothelial neoplasms, with only a single report describing three cases. Although originally classified as conventional angiosarcoma, further assessment of these tumors revealed a strikingly composite morphology composed of retiform and epithelioid elements reminiscent of composite hemangioendothelioma, a rare subtype of hemangioendothelioma. To further investigate these findings, available materials from 11 morphologically distinctive endothelial tumors showing neuroendocrine marker expression were retrieved from our archives. Immunohistochemistry for CD31, CD34, FLI-1, synaptophysin, chromogranin, D2-40, ERG, keratin (OSCAR), and CAMTA1 was performed. Total RNA from five cases were extracted and subjected to whole transcriptome sequencing. Clinical follow-up was obtained. These tumors were found to arise in five males and six females in patients from 9 to 55 years in age (median 47 years). They arose both in superficial (wrist, ankle, scalp, hip, and foot) and deep (periaortic tissues, C5 vertebra, pulmonary vein, and liver) locations. All contained elongated, retiform vascular channels lined by hyperchromatic 'hobnail' endothelial cells and a solid growth of uniform epithelioid cells reminiscent of epithelioid hemangioendothelioma. Hemangioma-like foci also lined by hobnail endothelial cells were frequently present. Mitotic activity was typically <1/10 HPF, and necrosis or areas of conventional angiosarcoma was absent. The results of immunohistochemistry were: CD31 (10/10), FLI-1 (10/10), ERG (9/9), CD34 (5/10), D2-40 (7/10), synaptophysin (11/11), chromogranin A (1/11), CD56 (5/11), keratin (0/11), and CAMTA1 (0/6). Sequencing analysis showed one case with PTBP1-MAML2 and one case with EPC1-PHC2 fusion transcripts; fusion transcripts were not identified in the remaining cases. Follow-up (8 cases) revealed local recurrence in one patient and metastatic spread in four individuals (bone, lung, liver, and brain). One person died of disease. Although the morphological features of these tumors are characteristic of composite hemangioendothelioma, this distinctive subset with neuroendocrine differentiation more often involves deep locations and displays more aggressive behavior than typically described in other cases of composite hemangioendothelioma.

Composite hemangioendothelioma with neuroendocrine marker expression: an aggressive variant.

This corrects the article DOI: 10.1038/modpathol.2017.83.

SATB2 Expression Is Sensitive but Not Specific for Osteosarcomatous Components of Gynecologic Tract Carcinosarcomas: A Clinicopathologic Study of 60 Cases.

The novel marker special AT-rich sequence binding protein (SATB2) is highly sensitive for mesenchymal tumors with osteoblastic differentiation. However, SATB2 expression in gynecologic tract carcinosarcoma has not been previously explored. Given the potential prognostic and therapeutic implications of heterologous carcinosarcoma in the gynecologic tract, this study investigates the utility of SATB2 in identifying osteosarcomatous elements. A multi-institution database review identified consecutive cases of gynecologic tract carcinosarcoma including both heterologous and homologous types. Clinicopathologic parameters were recorded. Nuclear SATB2 immunoreactivity was scored from 1 representative whole-slide section from each case. Sixty gynecologic tract carcinosarcoma were identified (uterine corpus=47, ovary=11, fallopian tube=1, cervix=1) including 32 heterologous type (7 osteosarcoma, 3 mixed osteosarcoma/chondrosarcoma, 6 chondrosarcoma, 12 rhabdomyosarcoma, 4 mixed chondrosarcoma/rhabdomyosarcoma) and 28 homologous type. Patient ages ranged from 41 to 90 yr (average 67.9 yr). Mostly diffuse strong SATB2 positivity was present in 10/10 (100%) cases containing osteosarcoma. In these cases, SATB2 positivity was seen in malignant cells intimately associated with osteoid or bone [3/10 (30%) of these cases additionally showed patchy weak/moderate SATB2 staining in areas of nonosteogenic sarcoma elsewhere in the same tumor]. SATB2 positivity was present in 30/50 (60%) cases lacking osteosarcoma, predominantly as patchy moderate staining within undifferentiated sarcoma. No cases showed SATB2 positivity in chondrosarcoma or rhabdomyosarcoma components. SATB2 is a highly sensitive marker for osteosarcomatous differentiation in gynecologic tract carcinosarcoma, and is also highly specific when used to differentiate osteosarcoma from chondrosarcoma and rhabdomyosarcoma elements in these tumors. However, a positive SATB2 result may lack specificity for differentiating osteosarcoma from an undifferentiated sarcoma component.

Interobserver Reproducibility Among Gynecologic Pathologists in Diagnosing Heterologous Osteosarcomatous Component in Gynecologic Tract Carcinosarcomas.

Distinguishing hyalinized stroma from osteoid production by a heterologous osteosarcomatous component can be challenging in gynecologic tract carcinosarcomas. As heterologous components in a carcinosarcoma may have prognostic and therapeutic implications, it is important that these are recognized. This study examines interobserver reproducibility among gynecologic pathologists in the diagnosis of osteosarcomatous components, and its correlation with expression of the novel antibody SATB2 (marker of osteoblastic differentiation) in these osteosarcomatous foci. Digital H&E images from 20 gynecologic tract carcinosarcomas were reviewed by 22 gynecologic pathologists with a request to determine the presence or absence of an osteosarcomatous component. The 20 preselected cases included areas of classic heterologous osteosarcoma (malignant cells producing osteoid; n=10) and osteosarcoma mimics (malignant cells with admixed nonosteoid matrix; n=10). Interobserver agreement was evaluated and SATB2 scored on all 20 cases and compared with the original diagnoses. Moderate agreement (Fleiss' κ=0.483) was identified for the 22 raters scoring the 20 cases with a median sensitivity of 7/10 and a median specificity of 9/10 for the diagnosis of osteosarcoma. SATB2 showed 100% sensitivity (10/10) and 60% (6/10) specificity in discriminating classic osteosarcoma from osteosarcoma mimics. Utilizing negative SATB2 as a surrogate marker to exclude osteosarcoma, 73% (16/22) of the reviewers would have downgraded at least 1 case to not contain an osteosarcomatous component (range, 1-6 cases, median 1 case). Gynecologic pathologists demonstrate only a moderate level of agreement in the diagnosis of heterologous osteosarcoma based on morphologic grounds. In such instances, a negative SATB2 staining may assist in increasing accuracy in the diagnosis of an osteosarcomatous component.

Intraneural glomus tumor of "uncertain malignant potential" and with BRAF mutation in the median nerve - an unusual case.

A glomus tumor of uncertain malignant potential is defined as a glomus tumor with some, but not all, criteria for malignancy and without a known metastasis. Here, we present a rare example presenting in the median nerve in a 40-year-old woman with a long history of severely impaired left median nerve function. A large panel of immunohistochemical stains excluded other diagnoses, and the designation of a "uncertain malignant potential" was based on the high proliferative activity, the tumor size and location, and the lack of WHO malignancy criteria such as marked nuclear atypia, necrosis, or atypical mitoses. A BRAF mutation was found in the tumor. Although extremely rare, both benign and malignant glomus tumors may present in large peripheral nerves and should therefore be considered in the differential diagnosis.
.