Defect in degradation of glycogenin-exposed residual glycogen in lysosomes is the fundamental pathomechanism of Pompe disease.

Pompe disease is a lysosomal storage disorder that preferentially affects muscles, and it is caused by GAA mutation coding acid alpha-glucosidase in lysosome and glycophagy deficiency. While the initial pathology of Pompe disease is glycogen accumulation in lysosomes, the special role of the lysosomal pathway in glycogen degradation is not fully understood. Hence, we investigated the characteristics of accumulated glycogen and the mechanism underlying glycophagy disturbance in Pompe disease. Skeletal muscle specimens were obtained from the affected sites of patients and mouse models with Pompe disease. Histological analysis, immunoblot analysis, immunofluorescence assay, and lysosome isolation were utilized to analyze the characteristics of accumulated glycogen. Cell culture, lentiviral infection, and the CRISPR/Cas9 approach were utilized to investigate the regulation of glycophagy accumulation. We demonstrated residual glycogen, which was distinguishable from mature glycogen by exposed glycogenin and more α-amylase resistance, accumulated in the skeletal muscle of Pompe disease. Lysosome isolation revealed glycogen-free glycogenin in wild type mouse lysosomes and variously sized glycogenin in Gaa-/- mouse lysosomes. Our study identified that a defect in the degradation of glycogenin-exposed residual glycogen in lysosomes was the fundamental pathological mechanism of Pompe disease. Meanwhile, glycogenin-exposed residual glycogen was absent in other glycogen storage diseases caused by cytoplasmic glycogenolysis deficiencies. In vitro, the generation of residual glycogen resulted from cytoplasmic glycogenolysis. Notably, the inhibition of glycogen phosphorylase led to a reduction in glycogenin-exposed residual glycogen and glycophagy accumulations in cellular models of Pompe disease. Therefore, the lysosomal hydrolysis pathway played a crucial role in the degradation of residual glycogen into glycogenin, which took place in tandem with cytoplasmic glycogenolysis. These findings may offer a novel substrate reduction therapeutic strategy for Pompe disease. © 2024 The Pathological Society of Great Britain and Ireland.

Spinal calcifying pseudoneoplasm of the neuraxis (CAPNON) associated with facet joint pathologies: CAPNON diagnostic and pathogenic insights.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like fibro-osseous lesion that can develop anywhere in the neuraxis. Approximately a half of reported CAPNONs developed in the spinal region, mostly close to the facet joint (FJ). The diagnosis of spinal CAPNONs is challenging given the existence of mimics and associated pathologies including calcific degeneration of the FJ ligaments (DFJL) and synovial cysts (SCs). The pathogenesis of CAPNON remains elusive, although there have been a few hypotheses including degenerative, reactive, proliferative and immune-mediated processes. Our present study examined clinical, radiological and pathological features of 12 spinal CAPNONs in comparison to 9 DFJL foci, and diagnostic and pathogenic relationship between CAPNONs and FJ pathologies. On imaging, CAPNONs were all tumor-like and typically bigger than DFJL foci. All CAPNONs showed pathologically diagnostic features including characteristic cores, consistently identifiable core-surrounding/peripheral palisading of macrophages and other cells including multinucleated giant cells, variable infiltration of CD8+ T-cells, and multifocal immunopositivity of neurofilament light chain (NF-L). These features were absent or limited in the DFJL foci with statistically significant differences from CAPNONs, except calcifications. Spinal CAPNONs co-existed with DFJL foci in all cases; some had transitional foci with overlapping focal CAPNON and DFJL-like features. These findings, along with our previously reported relationship between CAPNONs and SCs, suggest that spinal CAPNONs may occur in association with or in transition from calcifying/calcified degenerative lesions of FJ ligaments and/or SCs when a reactive proliferative process is complemented by other pathogenic changes such as immune-mediated pathology and NF-L deposition/expression.

Clinicopathologic characteristics of Nocardia brain abscesses: Necrotic and non-necrotic foci of various stages.

Nocardia brain abscesses are rare bacterial infections associated with a high mortality rate, and their preoperative diagnosis can be difficult for various reasons including a nonspecific clinical presentation. While late-stage nocardial brain abscesses may be radiologically characteristic, early-stage lesions are nonspecific and indistinguishable from another inflammatory/infectious process and other mimics. Despite the paucity of previous histopathological descriptions, histopathological examination is critical for the identification of the pathogen, lesion stage(s), and possible coexisting pathology. In this study, we examined the clinical, radiological and histopathological features of 10 patients with brain nocardiosis. Microscopic findings were analysed in correlation with clinical and radiological features in 9 patients, which revealed that brain nocardiosis was characterized by numerous necrotic and non-necrotic foci of various stages (I-IV) along with Nocardia identification, as well as the leptomeningeal involvement in most cases, and co-infection of brain nocardiosis with toxoplasmosis in 2 patients. The imaging features were characteristic with a multilobulated/bilobed ring-enhancing appearance in 8 patients including 2 patients with multiple lobulated and non-lobulated lesions and 1 patient showing the progression from a non-lobulated to lobulated lesion. These findings suggest that nocardial brain abscesses particularly at late-stages share common characteristics. Nevertheless, given the complex pathologic features, including possible co-infection by other pathogens, nocardial brain abscesses remain a therapeutic challenge.

Neuroanatomical location of brain metastases from solid tumours based on pathology: An analysis of 511 patients with a comparison to the provided clinical history.

Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011-2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization.

Cylindrical spirals and other concentric structures of skeletal muscle in patients with neurological diseases.

Cylindrical spirals (CSs) are ultrastructurally distinct, intracytoplasmic inclusions characterized by concentrically wrapped lamellae, which are rarely found in skeletal muscle biopsies on electron microscopy (EM). CSs are often confused with other EM concentric structures including concentric laminated bodies and mitochondrial concentric cristae (MCC), due to similarities in these ultrastructures. In this study, we found CSs in 9 muscle biopsies from 9 patients, accounting for 0.5% of the biopsies examined routinely by EM. The frequency of CSs in these muscles varied from sparse and segregated to focally frequent and aggregated. CS-associated features included muscle fiber denervation atrophy in all 9 cases, fiber type grouping in 7/8 cases, tubular aggregates in 3/9 cases, and MCC in 2/9 cases. We also compared the concentric structures and highlighted their differences to distinguish CSs from other similar structures. Clinically, 8 out of 9 patients were adults aged 41-74 years and only one patient was 17 month-old. CSs were associated with several neurological diseases including Huntington's disease, amyotrophic lateral sclerosis, Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes, and other complex neurological disorders with neuropathy/encephalopathy, as well as anti-MDA5+ dermatomyositis. Eight of nine patients had genetic findings such as trinucleotide repeat expansion of huntingtin gene, ALS2 variant, MT-TL1 m.3243A > G mutation, and PMP 22 gene deletion. These results suggest that CSs may be highly variable in frequency and likely are under-reported/under-detected; they may be associated with neurogenic myopathy or central/peripheral nervous system disorders including some genetic neurological/neuromuscular diseases. Our findings of more CS-associated neurological diseases and an association of CSs with muscle neurogenic features may contribute to a better understanding of the clinico-pathological significance of CSs.

Rheumatoid nodules: a narrative review of histopathological progression and diagnostic consideration.

Rheumatoid nodules (RNs) are the most common extra-articular manifestation of rheumatoid arthritis and are also seen in patients with other autoimmune and inflammatory diseases. The development of RNs includes histopathological stages of acute unspecified inflammation, granulomatous inflammation with no or minimal necrosis, necrobiotic granulomas typically with central fibrinoid necrosis surrounded by palisading epithelioid macrophages and other cells, and likely an advanced stage of "ghost" lesions containing cystic or calcifying/calcified areas. In this article, we review RN pathogenesis, histopathological features in different stages, diagnostically related clinical manifestations, as well as diagnosis and differential diagnosis of RNs with an in-depth discussion about challenges in distinguishing RNs from their mimics. While the pathogenesis of RN formation remains elusive, it is hypothesized that some RNs with dystrophic calcification may be in transition and may be in coexistence or collision with another lesion in patients with RA or other soft tissue diseases and comorbidities. The diagnosis of typical or mature RNs in usual locations can be readily made by clinical findings often with classic RN histopathology, but in many cases, particularly with atypical or immature RNs and/or unusual locations, the clinical and histopathological diagnosis can be challenging requiring extensive examination of the lesional tissue with histological and immunohistochemical markers to identify unusual RNs in the clinical context or other lesions that may be coexisting with classic RNs. Proper diagnosis of RNs is critical for appropriate treatment of patients with RA or other autoimmune and inflammatory diseases.

Lymphomas in patients with neurofibromatosis type 1 (NF1): another malignancy in the NF1 syndrome?

Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem syndrome caused by mutations in the neurofibromin 1 (NF1) gene that encodes for the protein neurofibromin acting as a tumour suppressor. Neurofibromin functions primarily as a GTPase-activating protein for the Ras family of oncogenes, which activates many signalling pathways for cell proliferation and differentiation; without neurofibromin, Ras is constitutively activated, thereby turning on many downstream signalling pathways related to oncogenesis. Patients with NF1 have a well known predisposition for certain types of malignancies including malignant peripheral nerve sheath tumours, gliomas, and breast cancers, as well as a potential association of NF1 with lymphoproliferative disorders such as lymphomas. In this article, we review the pathophysiology and tumourigenesis of NF1, previously reported cases of cutaneous lymphomas in NF1 patients along with our case demonstration of a NF1-associated scalp B-cell lymphoma, and NF1-associated extra cutaneous lymphomas. The diagnosis of lymphomas particularly cutaneous lymphomas may be difficult in NF1 patients as they often have skin lesions and/or cutaneous/subcutaneous nodules or tumours like neurofibromas, which raises the possibility of underdiagnosed cutaneous lymphomas in NF1 patients. We also comprehensively discuss the association between NF1 and lymphomas. In summary, most studies support a potential association between NF1 and lymphomas. Further investigation is needed to clarify the association between NF1 and lymphomas in order to bring clinical awareness of possibly underdiagnosed NF1-associated lymphomas and individualised management of NF1 patients to practice.

Diagnosis and management of intraparenchymal rhabdomyosarcoma.

BACKGROUND: Intracranial rhabdomyosarcomas represent a rare condition, posing a diagnostic challenge to physicians. Brain intraparenchymal rhabdomyosarcomas are exceptionally rare with poorly understood pathogenesis. METHODS: Here we report the first adult case of intraparenchymal rhabdomyosarcoma (RMS) with brainstem and cranial nerve involvement. We conducted a literature search using Embase, MEDLINE, and PubMed for published cases of patients with rhabdomyosarcoma of the brain. The keywords used were 'rhabdomyosarcoma' combined with 'intraparenchymal', 'parenchymal', 'cerebral' or 'brain' for title/abstract. Included cases were adult patients (>18 years of age). RESULTS: A 59-year-old man presents with multiple cranial nerve palsies. MRI revealed a solitary pontine lesion that was not responsive to steroids. No systemic lesions were identified with an extensive imaging workup. A wide range of serum and cerebrospinal fluid tests were non-diagnostic during a ten-month workup until, ultimately, the patient died as a result of aspiration pneumonia. At autopsy, pathological examination on whole-brain autopsy revealed RMS, centred in the left side of pons with extension to the left side of the midbrain and the right side of pons with multiple cranial nerve involvement. There are only 20 adult cases of primary intraparenchymal RMS reported in the literature. Our present case is the first reported adult RMS in this location, with novel molecular information, providing some insight into the pathogenesis of this rare diagnosis. CONCLUSIONS: Intraparenchymal rhabdomyosarcoma without evidence of systemic primary disease is extremely rare, resulting in delayed diagnosis in some cases, particularly those not amenable to biopsy. The diagnostic challenge posed by this complementary case highlights the importance of maintaining a differential of neoplasm in the face of non-diagnostic investigations to the contrary.

Incidental multifocal calcifying pseudoneoplasm of the neuraxis: case report and literature review.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is thought to be a rare tumefactive lesion with unknown pathogenesis. Its prevalence is questionable with few previously reported cases of incidental CAPNON, and likely underdiagnosis. We report a unique case of incidental multifocal CAPNON. A 64-year-old female was admitted with loss of consciousness due to a ruptured right middle cerebral artery aneurysm with subarachnoid and intraventricular hemorrhage. She has a craniotomy and clipping. At time of operation, numerous small dural-based nodules were found, and one was excised for biopsy and was diagnosed as CAPNON. Retrospective review of her CT images identified nodules that were all ipsilateral to the ruptured aneurysm. A literature review revealed that incidental and/or multifocal CAPNONs are rare but likely underreported. Our case suggests a reactive process in the pathogenesis of CAPNON.

ALK-negative CNS anaplastic large cell lymphoma: case report and review of literature.

BACKGROUND: Central nervous system (CNS) lymphomas frequently pose a diagnostic challenge to physicians. CNS anaplastic large cell lymphoma (ALCL) is a rare condition. A majority (80%) of ALCLs harbour anaplastic lymphoma kinase 1 (ALK-1) mutation with only a minority testing negative for this mutation. METHODS: Here we report a rare case of ALK-negative CNS ALCL with dural involvement. We conducted a literature search using PubMed for published studies in English on cases of patients with ALCL of the brain. The keywords used were 'anaplastic large cell lymphoma', 'ALK' and 'primary central nervous system lymphoma'. RESULTS: A 63-year-old man presents with waxing and waning cranial nerve and spinal cord symptoms. MRI revealed multiple intracranial and intra-spinal lesions that were highly steroid responsive. A wide range of serum and CSF tests were non-diagnostic during three months of workup before a lesion appeared in the cervical spine that required decompression and allowed us to obtain a tissue sample. Final pathology revealed ALK-negative ALCL. There are only 24 reported adult cases to date of CNS ALCL in the English literature. To our knowledge, this is the first case of ALK-negative ALCL with primarily CNS and meningeal involvement. CONCLUSIONS: ALK-negative ALCL with CNS involvement is extremely rare, which frequently results in delayed diagnosis (average 40.5 days). The diagnostic challenge posed by this case highlights the importance of a team approach to workup and diligent patient follow-up for such a rare disease.

The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.

Neurofilaments in neurologic disorders and beyond.

Many neurologic diseases can initially present as a diagnostic challenge and even when a diagnosis is made, monitoring of disease activity, progression and response to therapy may be limited with existing clinical and paraclinical assessments. As such, the identification of disease specific biomarkers provides a promising avenue by which diseases can be effectively diagnosed, monitored and used as a prognostic indicator for long-term outcomes. Neurofilaments are an integral component of the neuronal cytoskeleton, where assessment of neurofilaments in the blood, cerebrospinal fluid (CSF) and diseased tissue has been shown to have value in providing diagnostic clarity, monitoring disease activity, tracking progression and treatment efficacy, as well as lending prognostic insight into long-term outcomes. As such, this review attempts to provide a glimpse into the structure and function of neurofilaments, their role in various neurologic and non-neurologic disorders, including uncommon conditions with recent knowledge of neurofilament-related pathology, as well as their applicability in future clinical practice.

Clinicopathologic Profiles of Sporadic Late-Onset Nemaline Myopathy: Practical Importance of Anti-α-Actinin Immunostaining.

BACKGROUND AND OBJECTIVES: Sporadic late-onset nemaline myopathy (SLONM) is a treatable or otherwise fatal myopathy. Diagnosis of SLONM is still challenging, and no therapeutic consensus has been achieved. Here, we reported the clinicopathologic features and long-term follow-up data of SLONM in a Chinese cohort. METHODS: We performed a retrospective evaluation of clinical, pathologic, and treatment outcomes of 17 patients with SLONM diagnosed between March 1986 and April 2021 at our neuromuscular center. Immunohistochemistry (IHC) with antibodies against 5 Z-disc-associated proteins was performed in the muscle biopsies of SLONM to identify a potential pathologic marker in aid of diagnosis. In comparison, we also performed muscle IHC in patients with selective type II fiber atrophy (n = 22), neurogenic atrophy (n = 22), mitochondrial myopathy (n = 5), immune-mediated necrotizing myopathy (n = 5), and normal controls (n = 5). RESULTS: Most of the patients exhibited asymmetric limb muscles weakness (71%, 12/17) and neck extensor weakness (53%, 9/17). Immunofixation electrophoresis was performed in 11 patients, and 4 of them were identified with monoclonal gammopathy of undetermined significance (MGUS). EMG from 16 patients demonstrated a myopathic pattern with spontaneous activities in 69% (11/16) of them. Muscle MRI showed preferential involvement of paraspinal, gluteus minimus and medius, semimembranosus, and soleus muscles. Suspected nemaline bodies on modified Gomori trichrome were confirmed by IHC using anti-α-actinin antibody (100%, 17/17), anti-myotilin antibody (94%, 16/17), anti-desmin antibody (94%, 16/17), anti-α-B crystallin antibody (65%, 11/17), and anti-telethonin antibody (18%, 3/17) with various positive rates. Notably, anti-α-actinin IHC showed the highest percentage of strongly positive staining (77%, 13/17), being the only one without negative results. Moderate improvement following autologous stem cell transplantation (ASCT) was noted in 3/4 patients with MGUS; favorable outcomes were also achieved in 6/7 patients without MGUS, including 3 patients with complete recovery who were given a combined treatment of prednisone and another immunosuppressant. DISCUSSION: SLONM is a treatable myopathy with ASCT or traditional immunotherapy, especially when combined with steroids and immunosuppressants. Anti-α-actinin immunostaining is the most reliable pathologic marker to identify rod-bearing fibers, and it should be performed routinely in adult patients with undiagnosed nonnecrotic myopathies.

Spinal calcifying pseudoneoplasm of the neuraxis (CAPNON) and CAPNON-like lesions: CAPNON overlapping with calcified synovial cysts.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumour-like fibro-osseous lesion in the neuraxis including the spine. It is diagnosed by the presence of the following histological features: granular amorphous to chondromyxoid fibrillary cores with calcification/ossification, peripheral palisading of spindle to epithelioid cells, variable fibrous stroma, and foreign body reaction with multinucleated giant cells, as well as positive NF-L immunostaining. Spinal CAPNON is sometimes named as tumoural calcinosis that is tumour-like dystrophic calcification usually in the periarticular tissue and also described in calcified synovial cyst (CSC). We examined clinical, radiological and pathological features of five spinal CAPNONs and 21 spinal CSCs including three recurrent lesions. The results demonstrated some radiological and pathological overlaps between these two entities, as well as distinct features of each entity to be diagnosed. All CAPNONs showed the diagnostic histological features with NF-L positivity mainly in lesion cores and variable CD8+ T-cells. In contrast, CSCs exhibited the synovial lining and variable degenerative/reactive changes with some CAPNON-like features, but mostly no to occasionally limited NF-L positivity and less CD8+ T-cells with statistically significant differences between groups of CAPNONs and CSCs. Four CSCs contained CAPNON-like foci with the CAPNON diagnostic features including prominent NF-L positivity, and some transitional features from CSC to CAPNON. As the pathogenesis of CAPNON is likely reactive/degenerative in association with an inflammatory/immunological process involving NF-L protein deposition, our findings suggest the link between spinal CAPNON and CSC, with possible transition from CSC to CAPNON or CAPNON developing in reaction to CSC.