BACKGROUND AND AIMS:Chronic intestinal pseudo-obstruction (CIPO) occurs in up to 40% of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). While enteric nervous system abnormalities have been documented, 15%-38% of CIPO cases show normal histology, suggesting alternative pathogenic mechanisms. We aimed to investigate smooth muscle pathology in MELAS-associated CIPO. METHODS:Comprehensive pathological examination including light and electron microscopy was performed on autopsy material from a 52-year-old male with MELAS (m.3243A > G mutation) and recurrent intestinal obstruction symptoms. Gastrointestinal tissue from the entire digestive tract was analyzed and compared with age-matched control tissue. KEY RESULTS:Histological examination revealed widespread vacuolization and pallor of gastrointestinal smooth muscle throughout the digestive tract (esophagus, stomach, duodenum, and colon). Electron microscopy demonstrated abundant abnormal mitochondria in smooth muscle cells and, notably, marked loss of myofilaments in the colonic muscle. The ultrastructural preservation was limited by postmortem changes (autolysis, occurring approximately 4 h after death) and the re-embedding technique from formalin-fixed paraffin-embedded tissue; however, the striking difference was evident compared to age-matched controls. Similar abnormalities were observed in the Auerbach plexus. CONCLUSIONS AND INFERENCES:This represents the first report of myofilament loss in MELAS-associated CIPO, suggesting that mitochondrial dysfunction may directly impair smooth muscle contractile apparatus beyond previously described neuronal abnormalities. These findings provide novel insights into CIPO pathogenesis and may inform therapeutic strategies emphasizing early enteral nutrition interventions that bypass affected gastrointestinal segments.

A 75-year-old woman presented with nausea, exertional dyspnea, and right-sided chest pain. Chest imaging showed a right hilar mass with right pleural effusion. Initial assessment favored primary lung cancer with carcinomatous pleuritis. However, laboratory tests at admission revealed markedly elevated levels of total protein with hypoalbuminemia, resulting from monoclonal IgG-kappa (κ) gammopathy (IgG: 7,700 mg/dL). Thoracentesis demonstrated an exudative effusion; pleural fluid cytology and transbronchial tumor biopsy confirmed small cell lung cancer (SCLC). Anemia, markedly increased serum free κ light chain levels, and atypical plasmacytosis in the bone marrow confirmed the presence of multiple myeloma. She was then diagnosed with extensive-stage SCLC and concomitant multiple myeloma. Dose-reduced carboplatin plus etoposide was initiated for SCLC with clinical improvement and no severe acute toxicity; treatment for myeloma was planned after stabilization of SCLC. This case highlights that extreme hypergammaglobulinemia in a patient with suspected lung cancer should trigger prompt evaluation for multiple myeloma. Dual malignancy can coexist and may be overlooked if clinicians focus on a single diagnosis.

Calcifying aponeurotic fibroma (CAF) is a rare benign but locally aggressive mesenchymal tumor that primarily occurs in the distal extremities of children and adolescents. It typically presents as a slow-growing, painless, poorly circumscribed mass, often of prolonged duration. Radiographs may reveal a soft-tissue mass with a variable extent of fine stippled calcifications. On magnetic resonance imaging, CAF usually appears as an ill-defined subcutaneous mass with low to intermediate signal intensity on T1-weighted sequences and heterogenous high signal intensity on T2-weighted sequences. Areas of calcification exhibit low signal intensity on all pulse sequences. Intense heterogeneous enhancement is seen after intravenous contrast administration. Histologically, CAF is characterized by a fibromatosis-like component and a nodular calcified component. By immunohistochemistry, the tumor cells are variably positive for smooth muscle actin, muscle-specific actin and CD99 but negative for desmin and β-catenin. Moreover, frequent expression of ETS transcription factor ERG (ERG) and epidermal growth factor (EGF) has been demonstrated. Recent molecular studies have identified the presence of a recurrent fibronectin 1 (FN1)-EGF gene fusion. Surgical excision is the treatment of choice for CAF, but local recurrence is common due to its infiltrative nature. This review provides an updated overview of the clinical, radiological, morphological, immunohistochemical and molecular genetic features of CAF and discusses the differential diagnosis of this uncommon condition.

Chondromyxoid fibroma (CMF) is a rare benign cartilaginous neoplasm that most frequently occurs in the metaphysis of long bones in adolescents and young adults. The most common symptom is pain and/or swelling in the affected area. Radiographs typically show a well-defined, eccentric lytic lesion with sclerotic margins and scalloped or lobulated borders. Unlike other cartilaginous neoplasms, matrix calcification is uncommon. On magnetic resonance imaging (MRI), CMF usually exhibits low to intermediate signal intensity on T1-weighted sequences and heterogenous high signal intensity on T2-weighted sequences. Contrast-enhanced MRI demonstrates intense homogeneous, heterogeneous or peripheral enhancement. Histologically, CMF is composed of lobules of stellate to spindle-shaped cells in a myxoid background. The periphery of the lobules is generally hypercellular, imparting a characteristic zonal architecture. Recent molecular studies have identified alteration of glutamate metabotropic receptor 1 (GRM1) gene, and GRM1 positivity by immunohistochemistry has emerged as a reliable surrogate marker for this molecular event. Curettage or en bloc resection is the treatment of choice, with a non-negligible risk for local recurrence. This review provides an updated overview of the clinical, radiological, histological, immunohistochemical and molecular genetic features of CMF and discusses the differential diagnosis of this unusual neoplasm.

Epithelioid sarcoma (EPS) is an ultra-rare malignant mesenchymal neoplasm of uncertain differentiation that comprises two distinct clinicopathological subtypes: classic and proximal. Classic EPS most commonly occurs in the distal upper extremity of adolescents and young adults, whereas proximal-type EPS most often affects the truncal regions of young to middle-aged adults. Both classic and proximal-type EPSs exhibit aggressive clinical behavior, including a higher risk of local recurrence and regional lymph node or distant metastasis. Histologically, classic EPS is characterized by irregular nodules composed of epithelioid and spindled cells, while proximal-type EPS consists of multinodular distributions and sheets of large polygonal cells. EPS has a distinctive immunoprofile with characteristic expression of cytokeratins and epithelial membrane antigen. Loss of nuclear expression of SMARCB1 protein occurs in the vast majority of cases. Moreover, SMARCB1 homozygous deletions have also been observed in both subtypes. Surgery is the mainstay treatment approach for localized EPS. Systemic treatment options for metastatic or unresectable locally advanced disease are very limited. The withdrawal of tazemetostat has created a significant gap in available treatment options. In this review, we provide an overview of the current knowledge on the clinical and radiological features, histopathology, immunohistochemistry, pathogenesis, and management of EPS.

Fibronectin 1 (FN1), located on chromosome 2q35, encodes fibronectin, a high molecular weight glycoprotein of the extracellular matrix. Several histologically overlapping chondroid matrix-producing tumors are known to harbor FN1 rearrangements, including soft tissue chondroma, synovial chondromatosis, calcifying aponeurotic fibroma, calcified chondroid mesenchymal neoplasm and phosphaturic mesenchymal tumor. Over the past 10 years, fusions involving the FN1 gene have also been identified in other mesenchymal neoplasms such as lipofibromatosis and inflammatory myofibroblastic tumor. The current World Health Organization Classification of Soft Tissue and Bone Tumors suggests that FN1-rearranged lesions are typically benign or intermediate. This review provides an updated overview of the clinical, histological and molecular genetic features of FN1-rearranged mesenchymal neoplasms and discusses their relationships with one another.

Introduction: Axillary lymph node metastasis is a major prognostic factor for breast cancer. In rare cases, metastatic lesions may undergo necrosis. Case Presentation: A 69-year-old woman with a history of rheumatoid arthritis and ovarian tumor surgery was diagnosed with right-sided breast cancer (cT1N1M0) following abnormal screening mammography. Core needle biopsy revealed invasive ductal carcinoma (estrogen receptor: >95%, progesterone receptor: <1%, human epidermal growth factor receptor 2: 2+ [fluorescence in situ hybridization-negative], MIB-1: 18%). Fine-needle aspiration (FNA) cytology of an enlarged axillary lymph node confirmed metastasis. Mastectomy and axillary dissection were performed approximately 3 months after the FNA procedure without preoperative treatment, suggesting a temporal relationship between aspiration and subsequent necrosis. Histopathological analysis revealed no viable cancer cells in the lymph nodes but uniform eosinophilic necrosis with partial epithelial-like structures in one node. Immunohistochemistry showed positivity for epithelial membrane antigen, AE1/AE3, estrogen receptor, and GATA3, and histiocytes surrounding the necrotic area were positive for cluster of differentiation 68 and 163. These findings suggested that the metastatic carcinoma had undergone necrosis, likely triggered by FNA. The Oncotype DX score was 33; however, the patient chose endocrine therapy alone. No recurrence has been observed at the time of writing, 18 months after surgery. Conclusion: This case highlights a rare instance of necrosis in a metastatic lymph node, possibly induced by FNA. Immunohistochemistry is essential to confirm the diagnosis and avoid misinterpretation as a granulomatous or infectious process.

This study investigated the association between CD73 expression and malignant progression in NF1-associated peripheral nerve sheath tumors and evaluated its potential as a diagnostic marker. Histopathological differentiation of atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP) and low-grade malignant peripheral nerve sheath tumors (MPNST) in patients with NF1 remains challenging. Therefore, reliable adjunctive markers are needed to improve diagnostic accuracy. CD73 is an ectoenzyme with ecto-5'-nucleotidase activity. Recent studies have also suggested that CD73 may promote tumor invasion by facilitating extracellular matrix remodeling, independent of immune suppression. To investigate the role of CD73 in NF1-associated tumors, we analyzed CD73 expression in 57 NF1-associated tumors, including 39 benign neurofibromas (NF), 7 ANNUBP, and 11 MPNST, using immunohistochemistry and reverse transcription- quantitative PCR (RT-qPCR) in selected cases. Most tumors arose in the skin or subcutaneous tissue. Among the four histological subtypes of NF, solitary and diffuse types were mostly negative for CD73 expression (19/20 cases), whereas plexiform and mixed types, which are associated with a higher risk of malignant transformation, more frequently exhibited positive expression. Most ANNUBP cases (6/7 cases) demonstrated low or negative CD73 expression, whereas all MPNST cases were positive, with the majority showing high expression (9/11 cases). CD73 expression was significantly higher in MPNST than in solitary and diffuse types of NF and ANNUBP. RT-qPCR analysis consistently demonstrated a stepwise increase in NT5E(CD73) mRNA expression progressing from benign solitary and diffuse types of NF (0.74 ± 0.33) to ANNUBP (2.93 ± 0.57) and MPNST (9.26 ± 4.89). These findings suggest that CD73 expression increases in association with higher tumor grade and malignant progression in NF1-associated peripheral nerve sheath tumors and may serve as a useful adjunctive marker in pathological diagnosis, particularly in cases where distinguishing ANNUBP from MPNST is challenging.

Giant cell-rich tumors of soft tissue present a significant diagnostic challenge due to pronounced morphological overlap, particularly in limited tissue samples. This review provides a streamlined update on the clinicopathological and molecular features of nine distinct entities: nodular fasciitis, juvenile xanthogranuloma, phosphaturic mesenchymal tumor, tenosynovial giant cell tumor, giant cell fibroblastoma, giant cell-rich solitary fibrous tumor, giant cell tumor of soft tissue, keratin-positive giant cell-rich tumor, and undifferentiated pleomorphic sarcoma. While these neoplasms are unified by a prominence of multinucleated giant cells, recent genomic insights have identified signature, diagnostically defining molecular drivers. We highlight characteristic gene fusions, including USP6, NTRK1, FN1, CSF1, COL1A1-PDGFB, NAB2-STAT6, and HMGA2-NCOR2, as well as entities characterized by non-recurrent or highly complex genomic alterations. Synthesizing these data, this review underscores the critical role of advanced molecular testing in resolving diagnostic ambiguities, refining tumor classification, and guiding targeted therapeutic strategies.

INTRODUCTION:Pelvic squamous cell carcinoma (SCC) originating from a dermoid cyst (DC) is extremely rare. Here, we report the first case of SCC that developed in the anterior rectal area. CASE PRESENTATION:A 46-year-old man was initially diagnosed with rectal SCC by endoscopic biopsy, and multimodal image findings demonstrated direct invasion of the urinary system. Accordingly, total pelvic exenteration with bilateral lymph node dissection was performed with robotic assistance, and the patient was discharged without severe postoperative complications. Histological assessment revealed that the cancer originated in a DC with direct invasion of the seminal vesicle. CONCLUSIONS:Pelvic DC-derived SCC is rare but possesses high malignant potential. Because of the difficulty in preoperative diagnosis, diagnostic excision may be selected if complete resection is possible. Importantly, robot-assisted surgery enables precise management and might be an optimal strategy for preventing cancer dissemination by rupture during surgery.

Plexiform fibrohistiocytic tumor (PFHT) is a rare locally aggressive and rarely metastasizing mesenchymal neoplasm that most commonly arises in the upper extremities of children and young adults. It typically presents as a small, slow-growing, painless, dermal or subcutaneous mass. Magnetic resonance imaging (MRI) often reveals a plaque-like or infiltrative lesion with intermediate signal intensity on T1-weighted sequences and high signal intensity on T2-weighted sequences. Contrast-enhanced MRI demonstrates moderate or avid enhancement. Histologically, PFHT is characterized by a multinodular or plexiform proliferation of a variable admixture of histiocyte-like cells, osteoclast-like giant cells and elongated spindle cells. Immunohistochemically, the histiocyte-like and osteoclast-like giant cells express CD68, CD163 and CD11c, whereas the spindle cells are focally positive for smooth muscle actin. Most notably, cyclin D1 immunostaining demonstrates nuclear expression in the histiocyte-like and osteoclast-like giant cells as well as spindle cells. Wide local excision with long-term follow-up is generally considered optimal management for conventional cases. This review provides an updated overview of the clinical, radiological, histological, immunohistochemical, cytogenetic and molecular genetic features of PFHT and discusses the differential diagnosis of this enigmatic neoplasm.

INTRODUCTION:Paget's disease of the breast is generally associated with breast cancer involving the epithelium of the nipple and frequently extends into the areola or surrounding epidermis. Although it classically presents as a nipple lesion, recent diagnostic frameworks recognize that Paget's disease may rarely occur without overt nipple involvement. We report a rare case of Paget's disease of the breast without a nipple lesion. CASE PRESENTATION:The patient was a 73-year-old woman who was referred to the dermatology department at our hospital for investigation of a ring-shaped area of erythema on her right areola that had been treated with topical steroids for a month at a local dermatology clinic with no improvement. A skin biopsy led to a diagnosis of Paget's disease of the breast, and she was referred to our department. Mammography and ultrasonography did not show any intramammary lesions, while MRI suggested possible limited ductal involvement near the nipple. However, the exact extent of the disease could not be reliably delineated preoperatively. A right mastectomy was performed. Postoperative pathology confirmed Paget cells in the erythematous area and ductal carcinoma in situ within the breast, without demonstrable histological continuity between the two lesions. CONCLUSIONS:When a patient presents with a refractory lesion in the areolar region, even in the absence of nipple involvement, the possibility of Paget's disease of the breast should be considered, and a skin biopsy should be performed for appropriate diagnosis.

Myxoid pleomorphic liposarcoma (MPLPS) is an exceedingly rare and recently recognized adipocytic neoplasm that primarily occurs in children and young adults and shows a strong predilection for the mediastinum. Clinically, MPLPS demonstrates aggressive behavior and exhibits a high propensity for systemic spread and a worse overall survival. Some cases have been associated with Li-Fraumeni syndrome. Histologically, MPLPS is composed of a variable mixture of myxoid and pleomorphic liposarcoma-like components. Immunohistochemically, the tumor cells show diffuse expression of CD34 and p16 and loss of nuclear RB expression. MPLPS lacks DNA damage inducible transcript 3 (DDIT3) rearrangements and MDM2 proto-oncogene (MDM2) amplifications but shows tumor protein p53 (TP53) mutations and RB transcriptional co-repressor 1 (RB1) deletions. Moreover, recent studies have demonstrated that the most consistent molecular feature of MPLPS is genome-wide loss of heterozygosity. Surgical excision with negative margins is the mainstay of treatment for localized MPLPS. The treatment of advanced/metastatic MPLPS still poses a huge therapeutic challenge. This review provides information about the clinicoradiological features, pathogenesis, histopathology, and management currently available for MPLPS. In addition, we discuss the differential diagnosis of this novel entity.

BACKGROUND/AIM:We previously reported that Pyra-Metho-Carnil (PMC) suppresses macrophage differentiation in co-culture with mutant (mt) Kirsten rat sarcoma (KRAS) tumors. In this study, we used integrative proteomics and identified a KRAS-regulated membrane and exosomal protein, 5'-nucleotidase ecto (NT5E)/CD73, as a key candidate linking KRAS signaling to macrophage-associated tumor immune microenvironment (TIME) remodeling. We investigated whether PMC modulates CD73-associated pathways during macrophage differentiation. MATERIALS AND METHODS:THP-1 cells were differentiated with phorbol 12-myristate 13-acetate (PMA) and treated with PMC or a CD73 inhibitor (CD73i). Three-dimensional (3D) co-culture assays were performed using HKe3 wild-type (wt) KRAS or HKe3 mt KRAS spheroids. Macrophage infiltration into spheroids was evaluated by live-cell imaging and immunohistochemistry (IHC) of co-cultured spheroid sections. Using clinical colorectal cancer (CRC) specimens, the co-localization of CD73+ tumor cells and CD68+ macrophages was examined. RESULTS:IHC of co-cultured spheroid sections revealed that PMC treatment reduced THP-1-derived macrophage infiltration into mt-KRAS spheroids. Notably, while CD73i reproduced only the effect on macrophage infiltration, PMC demonstrated a more comprehensive antitumor effect by suppressing both CD73-mediated infiltration and direct tumor cell proliferation. Analysis of clinical mt-KRAS CRC tissues revealed significant clustering of CD73+ tumor cells and CD68+ macrophages specifically at the invasive fronts. In contrast, such infiltration was minimal in non-invasive regions or wt-KRAS tissues. CONCLUSION:These findings suggest that PMC suppresses macrophage infiltration and promotes TIME reprogramming through mechanisms associated with CD73 regulation. Therefore, by targeting tumor growth and immune evasion, PMC offers superior therapeutic value over conventional CD73i in mt-KRAS CRC, where CD73 expression correlates with clinical macrophage clustering.

Lipofibromatosis (LPF) is a locally aggressive but non-metastasizing mesenchymal tumor that primarily occurs in the hands and feet of infants and young children. It typically presents as a slow-growing, painless, poorly demarcated subcutaneous mass. Magnetic resonance imaging reveals the lesion to be a poorly defined mass with a mixture of adipose and fibrous components. Variable enhancement is seen after intravenous contrast administration. Histologically, LPF displays a distinctive admixture of mature adipose tissue and short fascicles of bland spindle cells. By immunohistochemistry, the spindle cells are moderately or diffusely positive for CD34 and CD99, focally positive for smooth muscle actin but typically negative for S-100 protein, desmin, β-catenin and pan-tropomyosin receptor kinase (TRK). Recent molecular studies have shown a variety of fusions involving epidermal growth factor receptor (EGFR) ligands or EGFR itself or other receptor tyrosine kinases, suggesting a shared deregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway. Complete surgical excision with preservation of adjacent neurovascular structures is the treatment of choice for LPF. This review provides an updated overview of the clinical, radiological, histological, immunohistochemical, cytogenetic and molecular genetic features of LPF and discusses the relationship to LPF-like neural tumor.

Bizarre parosteal osteochondromatous proliferation (BPOP) is a rare benign surface-based bone lesion that primarily occurs in the hands and feet of young and early middle-aged adults. The lesion presents as a firm, usually painless mass of variable duration. Radiographs reveal a well-defined, pedunculated or sessile mass arising from the cortical surface of bone without altering the architecture of the underlying cortex. On magnetic resonance imaging, BPOP shows low to intermediate signal intensity on T1-weighted images and variable signal intensity on T2-weighted images. Marked enhancement is often seen after intravenous contrast administration. Histologically, the lesion is composed of an admixture of cartilage, bone and fibrous tissue. Between the cartilage and bone is a characteristic basophilic stroma, so called "blue bone". Immunohistochemistry does not play a significant role in the diagnosis of BPOP. Cytogenetic studies have demonstrated recurrent chromosomal abnormalities, including t(1;17)(q32-42;q21-23), inv(7)(q21.2-22q31.3-32) and inv(6)(p25q15). Most recently, gene rearrangements of collagen type I alpha 1 chain (COL1A1) or collagen type I alpha 2 chain (COL1A2) have been identified in a significant subset of cases. Surgical resection is the treatment of choice for symptomatic BPOP, but its local recurrence rate is relatively high. This review provides an updated overview of the clinicopathological, radiological, cytogenetic and molecular genetic features of BPOP and discusses the differential diagnosis of this uncommon lesion.

Intracranial mesenchymal tumor FET::cyclic adenosine monophosphate response element-binding fusion-positive is a soft tissue tumor with an extremely rare intracranial occurrence. Histological diagnosis is sometimes difficult, requiring confirmation of characteristic fusion genes. The patient was a 45-year-old male who presented with a chief complaint of pain and an abnormal sensation in the right trigeminal nerve area, in whom a neoplastic lesion in Meckel's cave was noted. The preoperative diagnoses included meningioma and schwannoma. The tumor was extirpated as much as possible, and the tumor tissue showed a high proliferative potential with rhabdoid features, raising the suspicion of a rhabdoid meningioma. However, immunostaining was positive for desmin and cluster of differentiation 99, suggesting the possibility of angiomatoid fibrous histiocytoma. For diagnosis, Ewing sarcoma breakpoint region1 gene-cyclic adenosine monophosphate response element-binding 1 fusion and Ewing sarcoma breakpoint region1 gene-activating transcription factor 1 fusion were examined at our institution, but were undetectable and did not lead to a diagnosis. Genomic profiling with FoundationOne CDx (Foundation Medicine, Cambridge, MA, USA) confirmed Ewing sarcoma breakpoint region1 gene-cyclic adenosine monophosphate response element modulator fusion and a diagnosis of intracranial mesenchymal tumor FET::cyclic adenosine monophosphate response element-binding fusion-positive was made. Diagnosis of intracranial mesenchymal tumor FET::cyclic adenosine monophosphate response element-binding fusion-positive requires both histological examination and confirmation of the fusion gene. Genomic profiling using the FoundationOne CDx is also useful when the fusion gene cannot be sufficiently confirmed at an individual's institution.

Fibroma of tendon sheath (FTS) is a benign fibroblastic/myofibroblastic neoplasm that primarily occurs in the fingers and hands of young and middle-aged adults. The lesion typically presents as a small, firm, slow-growing, painless nodule. Ultrasonography usually shows a focal nodular mass with homogeneous hypoechogenicity. Magnetic resonance imaging reveals a well-defined nodular mass with decreased signal on all pulse sequences. No or minimal peripheral enhancement is often seen after intravenous contrast. Histologically, the lesion is well circumscribed and consists of bland spindle cells in a dense collagenous stroma with slit-like thin-walled vessels at the periphery. A cellular variant of FTS has also been described and shows at least a focal morphological overlap with nodular fasciitis. Immunohistochemistry does not play a significant role in the diagnosis of FTS. Cytogenetic studies have demonstrated the presence of 11q rearrangements. A significant subset of cellular variants of FTS are characterized by ubiquitin specific peptidase 6 (USP6) rearrangements, with a variety of fusion partners. Complete surgical excision is the treatment of choice. This review provides an updated overview of the clinical, radiological, histological, cytogenetic and molecular genetic features of FTS and discusses the differential diagnosis of this uncommon entity.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that results from tumors that secrete fibroblast growth factor 23 (FGF23). This leads to chronic hypophosphatemia. Burosumab, an anti-FGF23 antibody, is an effective treatment when surgery is not possible; however, it complicates FGF23 measurements and postoperative monitoring. We describe the first case report of TIO in which the responsible tumors were discovered during burosumab therapy and successfully resected. Despite tumor removal, the serum FGF23 levels remained elevated. In the postoperative monitoring of patients treated with burosumab, physicians should focus on the serum and urine levels of phosphate rather than FGF23.