Central nervous system germ cell tumors are uncommon and include germinomas, teratomas, and other nongerminomatous germ cell tumors. Mature teratomas are usually cured by complete resection, but rare patients later develop a histologically distinct malignant germ cell tumor. We report a man who presented at age 20 years with a cystic pineal lesion. Gross-total resection at age 21 years showed a mature teratoma with bronchogenic differentiation and no overt immature or malignant component on H&E. Serial postoperative MRI for 3 years showed no recurrence. Eleven years after surgery, he developed headache, gait disturbance, and confusion due to a 4.6-cm pineal mass with obstructive hydrocephalus. Serum alpha-fetoprotein was normal, whereas beta-human chorionic gonadotropin (β-hCG) was elevated. The resected tumor showed sheets of large round cells with clear cytoplasm and dense lymphocytes. Immunohistochemistry demonstrated strong nuclear OCT4 and SALL4 and membranous c-KIT, with focal β-hCG-positive syncytiotrophoblastic giant cells. No nongerminomatous germ cell tumor component was identified, supporting a diagnosis of germinoma with focal syncytiotrophoblastic giant cells. After this diagnosis, retrospective evaluation of the initial tumor showed multifocal, patchy OCT4 immunoreactivity in scattered cells along the ciliated respiratory-type epithelial lining. SALL4, c-KIT, and PLAP were focally positive in corresponding regions. These findings raised the possibility of an occult germ cell marker-positive population, although no discrete expansile germinoma component was identified. This case illustrates that metachronous germinoma can develop after a long disease-free interval following resection of a mature teratoma and highlights the value of retrospective pathologic evaluation and long-term surveillance.
Glioblastoma is the most common primary malignant central nervous system (CNS) tumor; however, its microenvironment, including tumor-associated microglia/macrophages (TAMs), is not fully understood. Although ionized calcium-binding adaptor molecule 1 (IBA-1) is expressed in various microglial phenotypes in the healthy human brain, CD163 is a marker of activated/phagocytic microglia. Tissues from 34 patients with glioblastoma were analyzed, and 17.6% of cases were CD163-dominant. CD163-dominant patients showed better overall survival than IBA-1-dominant patients (p = 0.019). CD163 dominance was identified as an independent prognostic factor for overall survival (hazard ratio [HR], 0.17; p = 0.011). Compared with the IBA-1-dominant group, CD163-dominant tumors showed more CD4-positive cell infiltration (p = 0.005), fewer ameboid TAMs (p = 0.021), and fewer non-microvascular proliferation (non-MVP) vessels (p = 0.012). No significant differences were found in patient characteristics, such as age, sex, tumor location, or extent of resection. The CD163-to-IBA-1 ratio of TAMs is a significant independent prognostic factor in glioblastoma, suggesting that the activation status of these cells and their interactions with the vascular endothelium and T cells influence tumor progression. These findings highlight TAMs as potential therapeutic targets for glioblastoma.
CIC-rearranged sarcoma is a rare, aggressive tumor entity with a dismal outcome. We describe a patient with a history of B-cell acute lymphoblastic leukemia (B-ALL), presenting to our hospital with seizures and left-sided upper limb weakness. Brain imaging revealed a localized right frontal mass, which was surgically resected. Initial pathological analyses suggested a secondary malignant neoplasm, not otherwise specified. However, the tumor's methylome was profiled and analyzed using the DKFZ brain tumor classifier to reach a diagnosis of CIC-rearranged sarcoma, confirmed by FISH study. The patient received the ICE protocol, alongside focal radiotherapy. The patient experienced a local recurrence 14 months post-diagnosis. The brain tumor classifier significantly improved the efficiency of diagnosing this rare tumor in a pediatric patient. However, effective therapeutic regimens for CIC-rearranged sarcomas remain unavailable.
Japanese encephalitis (JE) is a mosquito-borne viral infection of the central nervous system for which no specific antiviral treatment is available. We report the case of a 79-year-old man residing in Kumamoto Prefecture, southwestern Japan, with JE who presented with fever, impaired consciousness, and respiratory failure, and subsequently died of multiple organ failure despite early supportive care. Magnetic resonance imaging (MRI) revealed characteristic bilateral thalamic lesions, leading to an early clinical suspicion of JE before serological confirmation. Neuropathological findings, particularly, the involvement of the thalamus, substantia nigra, hippocampus, and anterior horn of the spinal cord, were consistent with previously reported cases of JE, while also demonstrating a broader distribution of lesions than suggested by antemortem MRI. As most cases of JE occur in unvaccinated individuals, vaccination should be considered in middle-aged and older adults, particularly, those with low antibody titers against the JE virus.
We report an autopsy case of a man in his early 80s who was found deceased, submerged in a bathtub at home. He had no history of regular medical care or smoking. One month before death, he experienced vomiting, malaise, and reduced appetite; however, due to limited clinical information, it was unclear whether he exhibited symptoms suggestive of cerebellar dysfunction. The autopsy showed fibrinous pericarditis resulted from left atrial metastasis from lung squamous cell carcinoma (LSCC) originating in the left lower lobe, which was determined to be the cause of death. Neuropathological examination exhibited no gross abnormalities in the cerebrum or brainstem; however, mild atrophy of the cerebellar vermis, extending from the lobulus centralis to the culmen, was observed. Histologically, focal loss of Purkinje cells accompanied by gliosis was noted, predominantly affecting the superficial layers of the superior vermis and simple lobule, while other cerebellar regions were largely preserved. Mild-to-moderate CD8-positive T-lymphocyte-predominant perivascular infiltration was present in the cerebellar white matter and leptomeninges, whereas no significant inflammation was detected in the cerebrum or brainstem. No abnormal protein aggregates (phosphorylated tau, α-synuclein, polyglutamine, or p62) were identified in the cerebellum. Postmortem serum testing revealed the presence of anti-amphiphysin antibodies. Collectively, although the clinical manifestations were unclear and a definitive diagnosis remains difficult, these findings support a pathological diagnosis of paraneoplastic cerebellar degeneration (PCD) associated with previously undiagnosed LSCC. Although autopsy data are limited, the preferential involvement of the superficial superior vermis may represent an early-stage pattern of PCD. This case highlights the importance of autopsy with detailed neuropathological examination in patients with malignancy, even when cerebellar symptoms are mild or absent and imaging or gross abnormalities are lacking. To our knowledge, this is the first reported autopsy case of anti-amphiphysin antibody-associated PCD in association with LSCC.
Colony stimulating factor-1 receptor-related disorder (CSF1R-RD) is a rare, autosomal dominant neurodegenerative disease caused by loss-of-function variants in the CSF1R gene, leading to microglial dysfunction and progressive white matter degeneration. Therapeutic strategies targeting microglial pathways, including activation of triggering receptor expressed on myeloid cells 2 (TREM2), have been proposed to compensate for impaired CSF1R signaling. Iluzanebart (VGL101), a monoclonal antibody TREM2 agonist, has shown promise in preclinical models. We report a longitudinal clinical course, neuroimaging findings, genetic analysis, and postmortem neuropathological examination of a 52-year-old patient with genetically confirmed CSF1R-RD (c.2507G>A, p.Ser836Asn). The patient received iluzanebart as part of a Phase 2 clinical trial. Clinical progression, MRI changes, and histopathological features at autopsy were systematically analyzed. Despite treatment, the patient experienced progressive cognitive decline, neuropsychiatric symptoms, motor impairment, and seizures, culminating in death. Serial neuroimaging demonstrated worsening white matter degeneration and brain atrophy without evidence of therapeutic response. Neuropathological examination revealed characteristic features of CSF1R-RD, including severe myelin loss, axonal spheroids, infiltration of Iba1-positive cells with macrophage-like morphology, and cortical neuronal abnormalities. There was no histological evidence of treatment-related benefit or harm. This case represents the first clinicopathological assessment of iluzanebart in CSF1R-RD and demonstrates no observable clinical, radiological, or neuropathological improvement. These findings highlight the challenges of targeting microglial dysfunction in advanced disease and suggest that TREM2 activation alone may be insufficient to alter disease progression.
We report the first autopsy-proven case of colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy harboring the CSF1R mutation c.2320T>C (p.Cys774Arg). The patient, a man in his 40s, exhibited progressive neuropsychiatric symptoms with predominant frontal white matter lesions and corpus callosum atrophy. Neuropathological examination revealed frontal-predominant demyelination with a relatively low number of axonal spheroids compared with typical cases, as well as the absence of intracranial calcifications. In addition, prominent cerebral amyloid angiopathy was observed despite an APOE ε3/ε3 genotype. These findings expand the clinicopathological spectrum of CSF1R-related leukoencephalopathy and highlight variability in pathological features associated with different CSF1R mutations.
Gliosarcoma of the central nervous system (CNS) is a rare and aggressive neoplasm exhibiting biphasic differentiation into glial and mesenchymal components. We report a primary gliosarcoma with mesenchymal differentiation resembling follicular dendritic cell sarcoma (FDCS). A 72-year-old man presented with a rim-enhancing lesion in the left frontotemporal parenchyma. Histologically, the tumor was biphasic, comprising a glioblastoma (GBM) component of diffusely infiltrative GFAP- and Olig2-positive oligodendroglial-like cells with microvascular proliferation, and an FDCS component composed of cohesive sheets, nests, and fascicles of CD21-, CD23-, and CD35-positive plump spindle cells. NGS analysis performed on the microdissected components revealed shared PTEN p.N48S mutations with high variant allele frequencies and MGMT promoter methylation, suggesting a monoclonal origin. Furthermore, the two components exhibited divergent genetic profiles: the glial component was characterized by an FGFR1 mutation, PDGFRA fusion, KIT/KDR amplification, and a whole-arm 1p/19q codeletion, whereas the sarcomatous component harbored an ERBB4 p.S853F mutation. These alterations predominantly converged on the RAS-MAPK and PI3K-AKT-mTOR signaling pathways. No IDH1/2 mutations, EGFR gene amplification, or TERT promoter mutations were detected in either component. This case represents the first documented instance of primary gliosarcoma with FDCS differentiation, thereby expanding its known differentiation spectrum. Furthermore, it demonstrates the necessity of separately analyzing each histological component in the diagnosis of challenging cases.
A surgical case of lymphoplasmacyte-rich (LPR) meningioma that arose in the region of the clivus of an 81-year-old woman is reported. The tumor consisted largely of a dense and diffuse infiltration of mature lymphocytes and a smaller number of plasma cells. Mainly in the peripheral region of the tumor, small sheets or clusters of large polygonal cells having vesicular nuclei and palely eosinophilic cytoplasm were observed. Some of these cells formed cellular whorls. These cells showed immunoreactivity for progesterone receptor, epithelial membrane antigen, somatostatin receptor type 2A, epithelial cadherin, and podoplanin, thus confirming the diagnosis of LPR meningioma. Although lymph follicles having germinal centers were not evident, the distributions of lymphocytes and plasma cells were heterogeneous, and plasma cells occasionally appeared to surround lymphocytic aggregates. Some intratumoral venules showed features of "high endothelial venules." These findings suggested that a dense accumulation of lymphocytes and plasma cells in LPR meningioma was not a simple inflammatory cell infiltration but might represent formation of "tertiary lymphoid structures." Whereas some inflammatory cells showed cytoplasmic immunoreactivity for programmed cell death ligand-1, meningioma cells did not express it.
Glioblastoma (GBM) is an aggressive CNS malignancy with extensive tumor growth and invasion. Highly proliferating cells require an increased intracellular iron concentration to maintain cell metabolism. We assessed the expression of transferrin receptor 1 (TFR1), the principal iron transporter, in GBM and ascertained its clinicopathological significance, implication in pathobiology, and therapeutic potential. Ninety-four cases of adult-type hemispheric GBM were included, along with 60 cases of IDH-mutant astrocytic and oligodendroglial tumors (grade 2-4) for comparison. The protein and mRNA expression were assessed by immunohistochemistry and qRT-PCR, respectively. We used U87MG and LN229 cell lines for in vitro analysis. TFR1 expression was significantly higher in GBM than in other IDH-mutant/lower-grade diffuse gliomas at mRNA and protein level. The non-tumor brain was negative on immunohistochemistry, and strong immunoreactivity was present only in GBM, indicating its diagnostic significance. SiRNA-mediated knockdown of TFR1 was associated with reduced cell survival, proliferation, migration, invasion, and increased apoptosis in vitro. Ferroptosis induction by RSL3/FIN56 led to increased TFR1 expression and ROS generation. The pro-ferroptotic effect of these drugs could be reversed by TFR1 knockdown. Hence, TFR1 appears to be crucially implicated in the cell survival and proliferation and ferroptosis sensitivity of malignant cells. Temozolomide in combination with siRNA-mediated gene silencing showed a significantly higher antitumor effect than the drug or silencing alone. This may be one of the important therapeutic vulnerabilities of GBM. High TFR1 expression was associated with shorter overall survival in all gliomas together but not in GBM separately.
A variety of malignancies can be found in the sinonasal tract including the nasal cavity, paranasal sinuses, and skull base. Many of these are attributed to viruses, for example, carcinomas with the presence of transcriptionally active high-risk human papillomavirus, as well as Epstein-Barr virus associated malignant lymphoepithelial carcinoma and haematolymphoid neoplasias. Olfactory neuroblastoma (ONB) is a rare malignant tumor of the olfactory fossa with an unknown etiology. We present the first comprehensive virus study of ONB. By targeted next-generation sequencing for 41 DNA viruses, we investigated the presence of papillomaviruses, herpesviruses, polyomaviruses, and parvoviruses, among others, in 12 ONBs. In addition, herpesvirus presence was evaluated by qPCR. Low-risk HPV6 was detected in one sample. Human endogenous retroviruses were positive in all samples, supporting successful library preparation and sequencing, considered as an internal quality control. No other virus findings were observed. The present broad-scale virus study did not reveal abundant presence of viral DNA in ONB suggesting a limited viral role in its etiology. Nevertheless, our cohort exhibited a finding of low-risk HPV, which has been associated with increased risk of cancer progression of inverted sinonasal papilloma in the same anatomic site advocating for further research. Trial Registration: §31/07.03.2019.
Although the regenerative capacity of the mammalian brain is quite weak, internal neural stem/progenitor cells (NSPCs) in the brain can provide new neurons into the brain lesions. Leukocytes, particularly T cells, infiltrate injured brain tissue and participate in immune reactions and have a large impact on the progress of the lesion. However, the effect of T cells on the regeneration of brain tissue remains unclear. Trimethyltin (TMT) is an organotin that has selective neurotoxicity on granule neurons in the hippocampal dentate gyrus. TMT-induced hippocampal lesion is mostly regenerated because adjacent NSPCs can provide new granule neurons. In this study, using TMT-injected mice as a model of brain tissue regeneration, the influence of T cells on hippocampal tissue regeneration was investigated. When TMT was injected into nude mice lacking T cells, they exhibited shortened immobility time in the tail suspension test, indicating improved functional outcomes. Immunohistochemical analysis revealed improved granule neuron replenishment and enhanced survival and differentiation of new neurons in nude mice. Microglial reaction characterized by phagocytosis and astrocytic reaction with brain-derived neurotrophic factor (BDNF) expression were enhanced in nude mice. Hippocampal tissue regeneration was impaired when nude mice were repopulated with total lymphocytes or with CD4- or CD8-positive cells. Repopulations of T cells altered microglial reactions; however, changes in astrocytes were not reproduced. These results suggest that both helper and cytotoxic T cells inhibit hippocampal tissue regeneration by preventing neuronal replenishment. T cells also affect lesion clearance by microglia and astrocytic BDNF expression; however, their effect is stronger on microglia. These findings provide novel insights into the immune regulation of brain tissue regeneration.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder characterized by a late onset and slow progression caused by a premutation (55-200 CGG repeat) in the fragile X mental retardation (FMR1) gene. Here, we report the case of a Japanese patient with FXTAS which is the first case autopsied in Japan. The patient was a 74-year-old man with a family history of fragile X syndrome at the time of death. The clinical features included postural tremors, mild cognitive decline, and ataxia. Magnetic resonance imaging (MRI) showed a high-intensity lesion in the bilateral middle cerebellar peduncles and deep white matter around the ventricle on T2-weighted images. A gene analysis revealed that the patient had a pre-mutation of the CGG expansion (83 CGG repeats) in the FMR1 gene. Neuropathologically, ubiquitin- and p62-positive intranuclear inclusions were widely present, especially in the hippocampus. The middle cerebellar peduncle (MCP), where the "MCP sign" was seen on MRI, showed marked spongiosis with accompanied demyelination and axon loss, and a similar pathology was seen in the cerebral and cerebellar white matter. In an electron microscopy study, intranuclear inclusions were found to consist of a non-membrane-bound filamentous material. The clinical, MRI, and neuropathological findings were similar to those of neuronal intranuclear inclusion disease. Awareness of the disease is gradually increasing, and the number of autopsy cases is likely to increase, contributing to the elucidation of the pathology and development of treatments.
Primary central nervous system (CNS) neuroblastoma, FOXR2-activated (CNS-NB-FOXR2), is a rare embryonal tumor characterized by neuroblastic differentiation and structural rearrangement of the FOXR2 gene. Previously grouped under CNS primitive neuroectodermal tumors (PNET), this entity has been reclassified based on genome-wide DNA methylation profiling. In this study, we present the detailed clinicopathological and immunohistochemical features of two pediatric cases diagnosed at our center. The first case involved a six-year-old with a left frontal mass; the second was a one-year-old with a large bifrontal lesion. Radiologically, both cases mimicked other embryonal tumors or high-grade gliomas. Histologically, tumors displayed small round blue cell morphology with neuroblastic features, including Homer-Wright rosettes and ganglionic differentiation. Immunohistochemistry demonstrated diffuse positivity for OLIG2, synaptophysin, and L1CAM, with negative expression for GFAP, EMA, and IDH1 R132H. FOXR2 showed nuclear positivity in both cases, supporting the diagnosis. Both cases exhibited diffuse L1CAM positivity-a rare finding with limited evidence in the existing literature. Although DNA methylation profiling could not be performed, the diagnosis was supported by characteristic morphology and immunohistochemistry profile. This report highlights key diagnostic features and potential mimics of CNS neuroblastoma, FOXR2-activated, and underscores the utility of immunohistochemistry in low-resource settings. Recognizing this entity is essential for accurate classification and appropriate therapeutic planning. Further studies are warranted to explore targeted therapies, including MEK inhibitors, which may hold promise based on emerging molecular data.
IDH-mutant gliomas most commonly harbor the canonical IDH1 p.R132H mutation, followed by less common mutations involving IDH1 p.R132 or IDH2 p.R172 codons. We present a case of a 32-year-old male found to have a left temporal brain tumor with regional enhancement on brain MRI, for which he underwent resection. Histologic sections showed an infiltrating astrocytic tumor with increased mitotic activity and elevated Ki67 (MIB1) labeling. The tumor was negative for IDH1 p.R132H mutant protein expression with retained ATRX expression. 1p/19q was intact by FISH analysis, and next-generation sequencing identified a previously unreported IDH2 (p.R172_H173delinsSN) likely pathogenic variant. A diagnosis of astrocytoma, IDH-mutant, CNS WHO grade 3 was rendered. Subsequent tumor methylation profiling performed at the National Institutes of Health matched with high confidence to the class "IDH glioma, subclass astrocytoma" and confirmed lack of MGMT promoter hypermethylation. He received adjuvant concurrent radiation and temozolomide. Surveillance brain MRI at 32 months post resection demonstrated no evidence of interval tumor progression. We present a case of IDH-mutant astrocytoma with a somewhat atypical molecular presentation, including a previously uncharacterized IDH2 mutation, retained ATRX expression, and lack of MGMT promoter hypermethylation. Though it has not been biochemically or functionally validated, tumor methylation profiling is supportive of this previously uncharacterized IDH2 variant as tumorigenic.
In order to prepare specimens to clarify the anatomical localization of intracerebral hematomas (ICHs), we examined 18 autopsy cases ranging from 1 day to 2.5 months after onset: Five cases of hypertensive ICH (two cases of putaminal hematoma, one case of thalamic hematoma, one case of mixed-type hematoma, and one case of cerebellar hematoma), two cases of subarachnoid hemorrhage with ICH, three cases of cerebral amyloid angiopathy-related hemorrhage, two cases of ICH associated with blood coagulation abnormalities, and six cases of brain death with ICH (brain death period: 10 h to 13 days). Paraffin blocks containing hematomas that have hardened and have poor formalin penetration can be easily sectioned at 6 μm thickness by using Histoheme, an ammonia-based softening reagent. By mounting the sections on MAS-coated glass slides or New Silan III-coated glass slides, we were able to minimize the peeling of hematomas from the slides. Conventional staining (Klüver-Barrera staining, Elastica-Masson Goldner staining) showed decreased staining of the brain tissue surrounding the hematoma due to the effects of edema, making the localization of the hematoma unclear. Synaptophysin (SYP) immunostaining was visualized with 3,3'-diaminobenzidine tetrahydrochloride (DAB)-CoCl2 and double stained with eosin azur 50 (EA50) (DAB-CoCl2 SYP + EA50). This method revealed gray matter as black and fresh to relatively recent hematoma as red, and clearly demonstrated the anatomical localization of the hematoma without any reduction in staining due to edema. In contrast, hematomas in cases more than 29 days after onset showed heterogeneous staining in red or green, and the boundary between the brain tissue and the hematoma was unclear. However, with double staining using DAB-CoCl2 SYP and Masson Goldner staining, the hematoma stained dark red, and the boundary with the brain tissue was more clearly visible than with DAB-CoCl2 SYP + EA50.
We investigated changes in O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in 21 patients with malignant gliomas who underwent two or more surgeries. Tumor specimens from multiple surgeries were analyzed using methylation-specific polymerase chain reaction (MS-PCR) and immunohistochemistry (IHC) for MGMT. Patients were divided into two groups: Group A (13 recurrent cases with therapeutic intervention) and Group B (8 cases of recurrence without therapeutic intervention or planned two-stage surgeries). MGMT methylation status was compared between initial and recurrent specimens, and in Group A, progression-free survival (PFS) and overall survival (OS) were analyzed according to MGMT methylation status at both initial and recurrent surgeries. By MS-PCR, changes in Group A were as follows: methylated to unmethylated in 23.1%, unchanged in 61.5%, and unmethylated to methylated in 15.4%. In Group B, changes were methylated to unmethylated in 12.5%, unchanged in 87.5%, and no cases of unmethylated to methylated. The difference in proportions between the groups was not significant (p = 0.13). By IHC, changes in Group A were methylated to unmethylated in 7.7%, unchanged in 53.8%, and unmethylated to methylated in 38.5%. In Group B, changes were methylated to unmethylated in 12.5%, unchanged in 87.5%, and no cases of unmethylated to methylated. The difference in proportions between the groups was significant (p = 0.034). Excluding one grade 3 case, in the 12 patients of Group A, median OS from treatment initiation differed by MGMT status assessed by immunohistochemistry in recurrent specimens (26.5 vs. 90.0 months, p = 0.043). These findings suggest that immunohistochemical assessment may capture spatial heterogeneity of MGMT status that is not readily detected by MS-PCR, and that therapeutic intervention may be associated with dynamic changes in MGMT methylation status. Furthermore, MGMT status assessed by IHC in recurrent specimens was associated with overall survival, indicating its potential prognostic relevance.
The ruptured blood vessels of a 57-year-old Japanese man who had died 5 days after bilateral hypertensive thalamic hemorrhage (HTH) were investigated by preparing 9 paraffin-embedded tissue blocks, all containing the hematomas. Each block was cut serially into 6-μm-thick sections. The first of every 18 sections was stained with Victoria blue and hematoxylin-eosin, the second with elastica-Goldner, and the third with phosphotungstic acid-hematoxylin. Several additional stainings, including immunostaining for α-smooth muscle actin and synaptophysin, were performed as necessary. In the large hematoma on the right, 18 cross-sections of ruptured blood vessels, comprising 12 arteries and 6 veins, were observed in the area supplied by the thalamoperforate arteries, thalamogeniculate arteries, and some of the posterior choroidal arteries. With an anteroposterior distribution, these ruptured vessels were observed in the middle third to posterior third of the thalamus, with arteries especially concentrated in the middle third. The small hematoma on the left was distributed mainly in the internal capsule. Two cross-sections of ruptured arteries, one of which had ruptured on the internal capsule side, were observed in the lateral part of the ventral posterolateral nucleus of the thalamus. In the hematomas, degeneration of medial smooth muscle cells due to arteriolosclerosis was observed in 14 cross-sections of ruptured arteries encountered, one of which showed a ruptured dissecting aneurysm. Microaneurysm or lipohyalinosis was not evident in any of them as well as the other non-ruptured arteries within the hematomas. The arteries surrounding the hematomas showed fibrinoid degeneration, lipohyalinosis, disruption of the internal elastic lamina, and degeneration and loss of smooth muscle cells in the media. Even though serial sections were examined at the rupture sites, no aneurysm-like structure was found. We concluded that HTH essentially arises from arterial wall fragility due to hypertension, and that aneurysm formation may not be essential.
Immune-mediated necrotizing myopathy (IMNM) is a subtype of idiopathic inflammatory myopathies (IIMs) characterized by severe muscle weakness and refractory response to immunotherapy. Recent studies proposed a role for necroptosis in IMNM-associated myonecrosis. This study aims to investigate the potential diagnostic value of phospho-mixed lineage kinase domain-like protein (pMLKL), the executive molecule of necroptosis, for IMNM. Sero-positive and -negative IMNM patients and various myopathies with myonecrosis diagnosed in Huashan Hospital during October 2020 to October 2022 were enrolled in this study. Comprehensive immunohistochemical staining including pMLKL was performed. The spatial distribution of pMLKL was assessed by qualitative and semi-quantitative scoring. Upregulation of pMLKL on sarcolemma was seen in both IIMs and non-IIMs (nIIMs) with distinct spatial patterns and varying positive rates. In IMNM and nIIM, it radiates outward from the center of myonecrosis and is upregulated on the surrounding non-necrotic myofibers, while in dermatomyositis, it is extensively upregulated around microinfarcts but not expressed within them. IMNM patients showed a 93.48% pMLKL expression rate, surpassing other IIMs (50%) and nIIMs (47.9%) (p < 0.0001). The concurrent upregulation and colocalization of pMLKL, MHC-I, and MAC on non-necrotic myofibers lack consistency. The frequent upregulation of pMLKL in IMNM suggests a potential correlation between necroptosis and the etiology as well as progression of IMNM. Nevertheless, its upregulated expression across diverse myopathic conditions attenuates its efficacy as a diagnostic myopathological biomarker for IMNM.
