Metastasizing aneurysmal dermatofibroma initially diagnosed as angiosarcoma confirmed by CD63::PRKCD fusion gene detection with nanopore sequencing.

Dermatofibroma (DF) is a benign tumor that forms pedunculated lesions ranging in size from a few millimeters to 2 cm, usually affecting the extremities and trunks of young adults. Histopathologically, DF is characterized by the storiform proliferation of monomorphic fibroblast-like spindle cells. In addition to neoplastic cells, secondary elements such as foamy histiocytes, Touton-type giant cells, lymphoplasmacytes, and epidermal hyperplasia are characteristic histological features. Several histological variants, including atypical, cellular, aneurysmal, and lipidized variants, have been reported; cases with variant histologies are sometimes misdiagnosed as sarcomas. We present a case of metastasizing aneurysmal DF that was initially diagnosed as an angiosarcoma on biopsy. A 26-year-old woman was referred to our hospital with a gradually enlarging subcutaneous mass in her lower left leg. Positron emission tomography-computed tomography revealed high fluorodeoxyglucose uptake not only in the tumor but also in the left inguinal region. On biopsy, ERG and CD31-positive atypical spindle cells proliferated in slit-like spaces with extravasation, leading to the diagnosis of angiosarcoma. Histology of the wide-resection specimen was consistent with DF, and lymph node metastasis was also observed. Nanopore DNA sequencing detected CD63::PRKCD fusion and copy number gain, although CD63 was not included in the target region of adaptive sampling. This report highlights the importance of recognizing the unusual clinical, radiological, and pathological features of DF to avoid misdiagnosis, and the potential diagnostic utility of nanopore sequencer.

Establishment and characterization of multiple patient-derived organoids from a case of advanced endometrial cancer.

Patient-derived organoids (PDOs) retain the original tumor's characteristics to a large degree and allow direct evaluation of the drug sensitivity, thereby emerging as a valuable resource for both basic and preclinical researches. Whereas most past studies stereotypically adopted a single PDO as an avatar of the patient, it remains to be investigated whether this assumption can be justified even for the tumor with spatial diversity. To address this issue, we established and characterized multiple PDOs originating from various sites of a patient with advanced uterine carcinosarcoma (UCS). Specifically, cancer cells were separately sampled from three sites; resected UCS tumor tissue, the peritoneal lavage fluid, and an intra-uterine brushing of the tumor. The three derived PDOs were morphologically undistinguishable, displaying typical carcinoma organoids-like appearance, but two of them proliferated at a faster rate. The primary tumor harbored mutations in TP53 and STK11 along with amplifications in CCNE1, ERBB2, and KRAS. These two mutations and the CCNE1 amplification were detected in all PDOs, while either KRAS or ERBB2 amplification was selectively observed in each PDO in a mutually exclusive manner. Observed intra-tumor heterogeneity in HER2 expression was differentially reproduced in the PDOs, which mirrored each PDO's sensitivity to HER2 inhibitors. Inter-PDO heterogeneity was also evident in sensitivity to standard cytotoxic agents. Lastly, a drug screening identified four candidate reagents commonly effective to all PDOs. Collectively, we showed that multiple PDOs could help reproduce the spatial diversity of a tumor and serve as a valuable resource in UCS research in many respects.

The diagnostic utility of cytology specimen in a case of EWSR1::NFATC2 sarcoma.

EWSR1::NFATC2 sarcoma, a rare round cell sarcoma constituting the majority of EWSR1::non-ETS sarcomas, has recently been defined in the latest WHO classification. To date, the cytological findings of EWSR1::NFATC2 sarcoma remain undocumented. We present the case of a 25-year-old man with a history of polyostotic fibrous dysplasia in the right leg, referred to our hospital with left thigh pain. Cytological findings included metachromasia, minimally pleomorphic round cells, and eosinophilic infiltration. There was no precursor fibrous dysplasia and the initial diagnosis was undifferentiated pleomorphic sarcoma. Following histologic review, we successfully performed immunocytochemistry and fluorescence in situ hybridization (FISH) on archival cytology specimens. The tumor cells were positive for NKX2-2, NKX3-1, and PAX7 and showed amplified 5' single signals of EWSR1 gene. Reverse transcriptase-polymerase chain reaction revealed an in-frame fusion of EWSR1 and NFATC2. This report describes the cytological features of EWSR1::NFATC2 sarcoma and highlights the diagnostic utility of archival cytology specimens.

Multidisciplinary management for primary uterine osteosarcoma, including gene panel testing: case report and literature review.

Primary osteosarcoma of the uterus (uOS) is rare, and its standard treatment has not yet been established. Herein, we present the case of a 50-year-old woman with uOS who demonstrated an improved prognosis after multiple surgeries to the metastatic sites. After the initial diagnosis of uOS, the patient showed recurrence and distant metastasis and hence expected to exhibit a poor prognosis. The patient underwent multiple surgical resections of the metastatic as well as primary tumors, which enabled the patient to survive for 24 months after the initial surgery. Considering that the median survival time of patients with uOS is approximately 6 months, the survival rate of our patient is noteworthy. Based on our observations, it is suggested that the resection of the primary and metastatic tumors might contribute to the extension of the survival period of the patient with chemo-resistant uOS.

Clinical Impact of Fine Needle Aspiration Cytology on Sentinel Node Biopsy after Preoperative Chemotherapy for Core Needle Biopsy-Proven Metastatic Lymph Nodes.

INTRODUCTION: Sentinel node biopsy (SNB) has been increasingly performed for patients with lymph node (LN)-positive (cN1) breast cancer that converted to LN-negative (ycN0) status after neoadjuvant chemotherapy (NAC). This study aimed to clarify the SNB avoidance rates using fine needle aspiration cytology (FNAC) for metastatic LNs after NAC. METHODS: This study included 68 patients with cN1 breast cancer undergoing NAC from April 2019 to August 2021. Patients with biopsy-proven metastatic clip-marked LNs (clipped LNs) underwent eight cycles of NAC. Ultrasonography (US) was performed to evaluate the effect of the treatment on the clipped LNs, and FNAC was performed after NAC. Patients with ycN0 status determined using FNAC underwent SNB. Those with positive results for FNAC or SNB underwent axillary LN dissection. Histopathology results and FNA were compared for clipped LNs after NAC. RESULTS: Of the 68 cases, 53 were ycN0 and 15 were clinically positive LNs after NAC (ycN1) on US. Further, 13% (7/53) of all ycN0 and 60% (9/15) of all ycN1 cases showed residual metastasis in the LNs on FNAC. CONCLUSION: FNAC was diagnostically useful for patients with ycN0 status on US imaging. Using FNAC for LNs after NAC helped avoid unnecessary SNB in 13% of the cases.

CDK4 overexpression is a predictive biomarker for resistance to conventional chemotherapy in patients with osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor, and its sensitivity to preoperative chemotherapy is a significant prognostic factor. The present study aimed to identify potential genomic markers for the prediction of chemosensitivity in patients with OS using a genomic approach. A total of 50 pediatric and adolescent patients diagnosed with high­grade OS were selected. Each pre­therapeutic biopsy sample was subjected to comparative genomic hybridization array analysis and targeted exome sequencing. Although no recurrent gene mutation was observed in chemoresistant tumors, copy number analysis detected recurrent gain of chromosome 12q14.1, which was significantly more frequent (5/21; 24%) in the poor responder cohort than in the good responder cohort (0/29; 0%; P<0.01). Subsequent expression analysis revealed that CDK4 was the only gene in the 12q14.1 gained region with an expression level that was positively associated with copy number gains. In order to elucidate the effect of CDK4 on drug sensitivity, CDK4­overexpressing OS cell lines were treated with cisplatin (CDDP); significant attenuation of CDDP sensitivity, demonstrated by increased cell viability and decreased expression of cleaved caspase­9, was induced by enforced expression of CDK4. In addition, treatment with CDK4/6 inhibitor palbociclib in CDK4­overexpressing U2OS cells facilitated apoptosis and a significant decrease in cell viability in a dose­dependent manner. In conclusion, the results of the present study showed that higher expression and amplification of CDK4 in tumors is a predictive biomarker for resistance to conventional chemotherapy in patients with OS and that palbociclib is a promising drug for this therapeutically challenging cohort.

Optimal surgical margin for infiltrative soft tissue sarcomas: Assessing the efficacy of excising beyond the infiltration.

BACKGROUND: Tumor infiltration in soft tissue sarcoma (STS) is known to correlate with an inadequate surgical margin and poor local control. This study aims to determine whether the radiological infiltration (R-inf) in STS cor relates with histological infiltration (H-inf) and to devise methods to determine a resection margin for infiltrative STS. METHODS: We reviewed the medical records of 145 patients with high-grade STS. We measured the R-inf on short-T1 inversion recovery or gadolinium-enhanced fat-suppressed (GdFS) magnetic resonance imaging. In addition, we assessed H-inf as the infiltrative growth of atypical tumor cells. The local control rate (LCR) was assessed using the Kaplan-Meier method. RESULTS: A statistically significant positive correlation was found between H-inf and R-inf (P < 0.0001). The R-inf obtained from the GdFS images exhibited a stronger correlation with H-inf than that obtained from the short-T1 inversion recovery images. Univariate and multivariate analyses revealed that a positive H-inf significantly correlated with a poor LCR. Moreover, the contaminated margins, which included intrainfiltration margins, significantly correlated with a poor LCR compared with the wide margins. CONCLUSIONS: R-inf as assessed by the GdFS images significantly correlates with H-inf, suggesting that we should exercise the infiltrative STS beyond their R-infs detected by the GdFS images.

Transformation of double-hit follicular lymphoma to plasmablastic lymphoma: a partial role of MYC gene rearrangement.

Follicular lymphoma (FL) is genetically characterized by BCL2/IGH translocation. Some FL cases histologically transform to high-grade lymphoma, and the majority of cases transform to diffuse large B-cell lymphoma. We report herein an unusual FL case that transformed to plasmablastic lymphoma (PBL) with MYC gene rearrangement as early as 12 months after FL diagnosis. IGH/MYC translocation, the most common cytogenetic abnormality seen in de novo PBL, was also detected in the transformed tumor (double-hit lymphoma). The patient became resistant to chemotherapy and died 4 months after transformation. We speculate that the "second hit" of MYC rearrangement played a crucial role in PBL transformation (PBL-T) in this case. Highly specific three-color FISH analysis demonstrated the presence of BCL2/IGH/MYC triple fusion signals on a single chromosome as we expected, but BCL2/IGH and IGH/MYC fusion signals also coexisted in a single nucleus. The PBL-T tumor was genetically heterogeneous, despite being histologically quite homogeneous PBL. Surprisingly, three-color FISH analysis revealed that the preceding FL tumor was also genetically heterogeneous, simultaneously harboring BCL2/IGH, IGH/MYC and BCL2/IGH/MYC fusion signals (i.e. double-hit lymphoma), despite being histologically quite homogeneous FL. This suggests that MYC rearrangement played a partial role in PBL-T. Genetic instability including MYC rearrangement in the preceding FL tumor would contribute to PBL-T and poor outcome in this case. This study will broaden our understanding of the pathogenesis of high-grade transformation of FL and help improve patient outcome.

Immunohistochemical characterization of renal tumors in patients with Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder associated with a germline mutation of folliculin (FLCN). The affected families are at a high risk for developing multiple renal cell carcinomas (RCC). Little is known about the immunostaining patterns of mutant FLCN-associated RCCs. We investigated 32 RCCs obtained from 17 BHD patients. The studied tumors included chromophobe RCCs (n = 15), hybrid oncocytic/chromophobe tumors (HOCT) (n = 14) and clear cell RCCs (n = 3). Almost all chromophobe RCCs and HOCTs revealed positive staining for S100A1, Ksp-cadherin and CD82. They stained either focally or diffusely for CK7, and were negative for CA-IX. All clear cell RCCs were positively stained for CA-IX and negative for CK7. These data confirmed that mutant FLCN-associated oncocytic and clear cell RCCs exhibited generally similar immunostaining patterns compared to their sporadic counterparts. Frequent positive staining for S100A1, Ksp-cadherin and CD82 in chromophobe RCCs and HOCTs indicated that these two types were relatively similar rather than distinctively different in their patterns of immunoreactivity. Characteristic peri-nuclear halos and polygonal cells with clear cytoplasm, which often misleads pathologists into the diagnosis of clear cell RCC, should be carefully examined using an immunohistochemical panel including CA-IX, Ksp-cadherin, CD82 and CK7.

Impact of infiltrative growth on the outcome of patients with undifferentiated pleomorphic sarcoma and myxofibrosarcoma.

BACKGROUND AND OBJECTIVES: Infiltrative growth, frequently observed in undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS), is often associated with a positive surgical margin as well as a local failure. The purpose of our study was to determine whether the radiographic growth patterns were associated with the outcomes of patients with UPS and MFS. METHODS: We reviewed 89 patients diagnosed with UPS or MFS and underwent initial surgery at our institute between 1994 and 2011. Growth patterns were assessed radiographically on preoperative MRI. Clinicopathological factors were collected and uni- and multivariate analyses were performed for survival. RESULTS: Infiltrative growth was observed in 21 patients (24%), which correlated with superficial tumors and positive surgical margin. Infiltrative growth correlated with poor disease-specific and distant failure-free survivals relative to non-infiltrative growth. Multivariate analysis confirmed that these factors remained as significant factors. Patients with non-infiltrative tumors resected inadequately exhibited slightly more favorable local control with postoperative radiotherapy, although no clinical benefit was seen for those with infiltrative tumors. CONCLUSIONS: Infiltrative growth was an adverse prognostic factor for not only local control, but also disease-specific and metastasis-free survival in patients with UPS and MFS. Radiotherapy could not salvage inadequately resected infiltrative tumors.

Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma.

Glioblastoma multiforme (GBM) is a highly invasive and chemoradioresistant brain malignancy. Temozolomide (TMZ), a DNA-alkylating agent, is effective against GBM and has become the standard first-line drug. However, the mechanism by which TMZ regulates the progression of GBM remains elusive. Here, we demonstrate that TMZ targets TAp63, a p53 family member, inducing its expression to suppress the progression of human GBM. High levels of TAp63 expression in GBM tissues after TMZ treatment was an indicator of favourable prognosis. In human GBM cells, TMZ-induced TAp63 directly repressed MYC transcription. Activation of this TAp63-MYC pathway by TMZ inhibited human GBM progression both in vitro and in vivo. Furthermore, downregulation of MYC mRNA levels in recurrent GBMs after TMZ treatment correlated with better patient survival. Therefore, our results suggest that the TAp63-mediated transcriptional repression of MYC is a novel pathway regulating TMZ efficacy in GBM.

IgG4-related periureteral fibrosis presenting as a unilateral ureteral mass.

IgG4-related sclerosing disease is a rare disease characterized by fibrosis and lymphoplasmacytic infiltration in various organs. Here, we report a rare case of IgG4-related fibrosis that presented as a unilateral ureteral mass in a 39-year-old man who presented with abdominal pain. Left hydronephrosis and a mass measuring 3 × 1.1 cm in the lower portion of the left ureter were found. As a ureteral malignancy could not be ruled out, the left ureter was resected partially. Pathologically, severe fibrosis and infiltration of plasma cells, lymphocytes, and eosinophils were found. No malignancy was found. Immunohistochemically, most of the plasma cells were IgG4-positive. The serum IgG4 level was also elevated (233 mg/dl). The histological characteristics were similar to those of retroperitoneal fibrosis, inflammatory pseudotumor, or idiopathic segmental ureteritis. It is important to consider IgG4-related sclerosing disease in the differential diagnosis of a unilateral ureteral mass.

Successful resection of schwannoma from an intercostal nerve causing bloody pleural effusion: report of a case.

We report a case of schwannoma arising from the 9th intercostal nerve, which caused a bloodstained pleural effusion. The patient, a 37-year-old woman, presented with left-sided back pain. A chest X-ray showed left pleural effusion, which was subsequently found to be bloodstained but without malignant cells. Chest magnetic resonance imaging showed a 76-mm tumor arising from the 9th intercostal nerve. The tumor and intercostal nerve were successfully resected. Histological examination revealed that the tumor comprised spindle cells with both Antoni types A and B patterns. There were necrotic changes and cystic degeneration, but no atypical or mitotic cells. Based on these findings, benign schwannoma was diagnosed. Schwannoma is rarely accompanied by bloody pleural effusion, which we assume was caused by partial tumor rupture. Magnetic resonance imaging proved very useful in localizing and characterizing the tumor in this case.

Giant intrapelvic solitary fibrous tumor arising from mesorectum.

We report a patient who had a giant pelvic solitary fibrous tumor (SFT) that was excised with the aid of aortic balloon occlusion. A 27-year-old woman was diagnosed, at another hospital, as having an inoperable intrapelvic tumor. On admission, computed tomography showed that the uterus, urinary bladder, and rectum were compressed anteriorly by a pelvic tumor with a maximum diameter of 16 cm. On magnetic resonance imaging, the tumor contained mesh-like structures showing strong intensity. Transanal needle biopsy was performed, and SFT was diagnosed by immunostaining. The tumor was supplied by feeding vessels from the inferior mesenteric artery and bilateral internal iliac arteries. Despite massive intraoperative hemorrhage, this giant tumor was excised with the help of aortic balloon occlusion. An intrapelvic SFT should be resected after careful preparation of countermeasures for hemorrhage.

Spontaneous regression of bone metastasis from renal cell carcinoma; a case report.

BACKGROUND: Spontaneous regression of metastatic renal cell carcinoma is rarely observed. CASE PRESENTATION: Metastatic renal cell carcinoma was identified in a 70-year-old male using computed tomography-guided percutaneous needle biopsy. Two months after the diagnosis, a partial resection of the sternal bone was performed. Pathological examination revealed granulated tissue with bleeding and necrosis but no carcinogenic cells. CONCLUSION: We report a pathologically identified case in which a sternal bone metastasis that was noticed two years after radical nephrectomy regressed completely and spontaneously.

Histological vascular invasion by tumors is a risk factor for distant metastasis in malignant fibrous histiocytoma.

BACKGROUND: The appearance of distant metastasis is a fatal sign in patients with soft tissue sarcoma. Therefore, we studied the risk factors associated with distant metastasis that appear in malignant fibrous histiocytoma. MATERIALS AND METHODS: The study group comprised sixty patients treated for malignant fibrous histiocytoma at our hospital between 1991 and 2002. We retrospectively studied whether age, tumor size, tumor site, developmental form, surgical margin, local recurrence, histological subtype, vascular invasion and histological grade are risk factors associated with the appearance of distant metastasis. RESULTS: A univariate analysis showed that, for those patients older than 70 years of age, insufficient surgical margin, the presence of local recurrence and vascular invasion are significant risk factors associated with the appearance of distant metastasis. A multivariate analysis showed only the presence of vascular invasion to be a significant risk factor as well. CONCLUSION: Histological vascular invasion by tumors is a risk factor associated with distant metastasis that appears in malignant fibrous histiocytoma. Taking early measures for patients with vascular invasion is necessary to improve the prognosis.