Histone H3 trimethylation on lysine 27 immunostaining pattern in DICER1-associated tumors.

Background: DICER1-associated tumors are heterogeneous and affect several organs. DICER1-associated primary intracranial sarcoma is associated with histone H3 trimethylation on lysine 27 (H3K27me3) loss in nucleus by immunohistochemistry. Methods: We explored the H3K27me3 immunostaining pattern in other DICER1-associated tumors. Twelve tumors from eleven patients with confirmed DICER1 mutations (sporadic and germline) data from a pancancer next-generation sequencing panel, and four tumors of pleuropulmonary blastoma (PPB) were retrieved from our database and stained with anti-H3K27me3 antibody. Results: The H3K27me3 expression in the nucleus showed heterogeneous mosaic loss in neoplastic Sertoli cell components in three of the five cases of moderately to poorly differentiated Sertoli-Leydig cell tumors. Among two tumors of DICER1-associated primary intracranial sarcoma, one showed complete loss of H3K27me3 in all neoplastic cells, whereas the other showed mosaic loss in the sarcomatous spindle cells. One DICER1-associated tumor with epithelial and mesenchymal differentiation, including pulmonary blastoma and PPB, showed mosaic loss of glandular epithelial and mesenchymal components. Four cases of type II PPB and a single case of type III PPB showed a similar mosaic loss of H3K27me3 staining restricted to large spindle cell components. All other components in all tumors-including Leydig cells; the areas of epithelial, cartilaginous, and rhabdomyomatous differentiation; and all cells of the remaining three cases (one papillary thyroid carcinoma and two cases of PPB type I)-demonstrated retained H3K27me3 staining. Conclusions: H3K27me3 expression is not universally lost in DICER1-associated tumors and thus is not predictive of DICER1 mutation status. The mosaic regional loss of H3K27me3 immunostaining is consistent in PPB type II and III, which can be a helpful diagnostic marker for these tumors and suggests a similarity to DICER1-associated intracranial sarcoma.

Intracranial Infantile Hemangioma: Highlighting a Rare Presentation With a Case Report and Literature Review.

Infantile hemangioma is a common benign vascular tumor in children, but it is very unusual to be found intracranially. Our literature review identified 44 reported cases. Presentation can vary from asymptomatic to a life-threatening presentation that necessitates urgent surgical removal. There is no general consensus on management of these rare lesions and until recently, treatment was limited to surgery or pharmacological management with steroids, propranolol or interferon. We present a case of a four-week-old male infant with history of vomiting and increase in head circumference since birth. MRI of the brain revealed a large complex cyst occupying the right frontoparietal region, with round soft tissue component that is isointense on T1 and hyperintense on T2 weighted images. Complete surgical resection with evacuation of the cyst was achieved. Histopathology of the mass showed infantile hemangioma with positive CD31 on immunohistochemistry. The patient achieved an excellent outcome following surgical resection.

Diagnostic Insights into Pediatric Pleomorphic Xanthoastrocytoma through DNA Methylation Class and Pathological Diagnosis Analysis.

This study adopts an innovative approach to utilize the DNA methylation class (MC) by prioritizing the understanding of discrepancies over traditional direct comparisons with the pathological diagnosis (PD). The aim is to clarify the morphological criteria for pleomorphic xanthoastrocytoma (PXA). Using the Children's Brain Tumor Network online database, PXA-diagnosed cases were sourced. MCs and CDKN2A/B statuses were ascertained using the Heidelberg methylation brain tumor classifier v12.5 (v12.8 for selected cases). Three distinct groups emerged: Group 1 confirmed PXA through both PD and MC (7 cases); Group 2 identified PXA via PD alone (7 cases); and Group 3 diagnosed PXA using MC (5 cases). Key insights from the study include the frequent local infiltration of PXA into gray matter structures, mirroring infiltrative astrocytoma. The MC for PXA stands out for its sensitivity. Cases with a PXA morphological diagnosis diverging from the DNA class warrant attention to newer differential diagnoses such as high-grade astrocytoma with piloid features, pilocytic astrocytoma NF1-associated, and NET-PATZ1. Tumors with a MC indicative of PXA but lacking its typical features may, if high-grade, behave as grade 4 gliomas. In contrast, their low-grade counterparts could belong to the PXA morphological continuum. Further research is pivotal for cementing these findings.

An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.

The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene ( LMNB1 ) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry LMNB1 gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR modified cell lines and mouse models, we have identified a novel silencer element that is lost in ADLD patients and that specifically targets overexpression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving the LMNB1 and the recruitment of the PRC2 repressor complex. Loss of the silencer element in ADLD identifies a previously unknown role for silencer elements in tissue specificity and disease causation.

A Case of Wilms Tumor in a Primary Adrenal Mature Teratoma.

We report the first known case of an adrenal teratoma containing a Wilms tumor component, in a 12-month-old girl with Trisomy 21. Despite adrenal teratomas being relatively uncommon, this particular instance raises interesting questions regarding the tumor origin, given the coexistence of both a teratoma and a Wilms tumor. Two main theories of development have been hypothesized, one of which suggests that the Wilms tumor may develop from a primary teratoma and the other proposing that the teratoma could originate from a primary Wilms tumor. Our case study leans toward the former, as the majority of the tumor displayed characteristics of a typical mature teratoma, with the Wilms component discovered as an incidental finding. Successful surgical intervention led to the gross total resection of the tumor. Twelve months post-resection, the patient remains free of recurrence. This report contributes to our understanding of these rare tumor types and underlines the importance of identifying the primary tumor to ensure appropriate management and treatment.

Brain pathology in patients with congenital heart disease.

INTRODUCTION: Brain pathology in patients with congenital heart disease (CHD) is associated with neuro-developmental delay. Imaging studies support vascular etiology for both white and gray matter lesions. In this retrospective study, we described the pathological changes in the brains of patients with CHD. MATERIAL AND METHODS: Last twenty autopsy cases in pediatric patients with CHD at our institution were retrieved and autopsy reports were reviewed. Available hematoxylin-eosin, special, and immunostains were evaluated, and at least one section from each case was stained with anti-glial fibrillary acidic protein (GFAP), anti-amyloid precursor protein (APP), and anti-HLA-DR antibody. Staining pattern of these immunostains was compared to staining pattern in five control cases. Control cases comprised of 2 cases with no significant pathological changes, and 3 cases with telencephalic leukoencephalopathy. The following histological features were assessed: necrotic cells in cortex, hippocampus, and cerebellum, APP and GFAP staining pattern, and the presence of focal lesions and amphophilic globules. Twenty patients (10 males, 10 females) were identified, with age range between 2 weeks and 19 years. RESULTS: The pathological findings were as follows: 10 cases had changes consistent with acute global hypoperfusion, 8 cases showed features consistent with chronic global hypoperfusion, 4 cases presented focal white matter necrosis (2 with intra-vascular emboli), and 16 cases showed diffuse moderate to severe gliosis, including 7 cases with amphophilic globules. Subarachnoid hemorrhages were present in 5 cases, subdural hemorrhage in 4 cases, intra-ventricular hemorrhage in 2 cases, and germinal matrix hemorrhage in 1 case. CONCLUSIONS: In conclusion, diffuse gliosis is the prominent pathological feature in CHD cases. Most of the pathological changes are known to occur in cerebral hypoperfusion regardless of primary cause. Better techniques to improve cerebral perfusion are warranted in the management of these patients.

Classification of Pediatric Gangliogliomas Based on the Histological Infiltration.

Ganglioglioma is a well-circumscribed low-grade glioneuronal tumor with a broad morphological spectrum. Diffuse glioneuronal tumors are used to describe cases with infiltrative growth. Molecular studies of some of these cases are consistent with ganglioglioma. This work aimed to clarify the growth patterns in ganglioglioma. The available slides and clinical and molecular information for 46 patients (50 samples) with a diagnosis of ganglioglioma under the open pediatric brain tumor atlas from the children's brain tumor network database were reviewed to confirm the integrated diagnosis and to evaluate the growth patterns in these cases. Ten samples from nine patients were excluded as no slides were available, the integrated diagnoses were changed in seven cases (nine samples), ten cases (ten samples) were diagnosed as low-grade glial/glioneuronal tumors, and the diagnosis of ganglioglioma was confirmed in seventeen samples from sixteen patients (nine females and seven males; age ranges from eight months-19 years with a mean of 9.9 years). Infiltration is defined as the presence of neoplastic cells among the nonneoplastic parenchyma. The growth pattern was predominantly circumscribed in six cases, predominantly infiltrative in five cases, and combined growth patterns in five cases. This work confirmed the presence of an infiltrative/diffuse variant of ganglioglioma as a significant pattern. The differential diagnosis in these cases was mainly infiltrative glioma, usually IDH-wild type in this population, which may introduce a high-grade glioma in the differential. Awareness of infiltrative ganglioglioma variants should be helpful in this scenario.

White matter cellular changes in ischemic injuries.

OBJECTIVES: The white matter ischemic changes described in the literature are not specific and include white matter rarefaction, axonal damage, myelin degeneration, astrocytic fragmentation and beading of its processes (clasmatodendrosis), oligodendrocyte loss, and microglial activation. This morphological spectrum overlaps with morphological features of many other conditions. This retrospective study aims to describe the cellular changes (using immunohistochemical studies) in a spectrum of ischemic leukoencephalopathy. METHODS: We studied 24 white matter ischemic injury cases with a well-documented interval from the ischemic event of interest. The autopsy reports were reviewed for the clinical information and pathological features to select the most representative areas for other stains and immunostains: luxol fast blue with hematoxylin and eosin (LFB-HE), anti-amyloid precursor protein (APP), anti-glial fibrillary acidic protein (GFAP), and anti-human leukocyte antigen (HLA-DR) antibodies. RESULTS: The early changes detected in mild injury were axonal staining highlighted by APP immunostain and astrocytic and microglial reaction with no significant cellular loss. The most severe injury may lead to losing almost all cellular elements (complete infarct) and replacement by macrophages with time. Injuries in between resulted in a morphological spectrum of selective cellular injury (incomplete infarct), including apoptotic nuclei, axonal staining and swellings, clasmatodendrosis, and loss of ramified microglia. CONCLUSIONS: The pathological findings suggested that widespread axonal staining and swellings are early features followed or accompanied by loss of HLA-DR positive ramified microglia and then by astrocytes in ischemic leukoencephalopathy. The awareness of this morphological spectrum would prevent misdiagnosis, provide a better understanding of this condition and can guide future studies on this important and common subject.

Infiltration in Pilocytic Astrocytoma: A Diagnostic Pitfall.

Glioma can be classified according to its infiltrative capacity into circumscribed and "diffuse"/infiltrative glioma. Pilocytic astrocytoma is typically grouped under the circumscribed astrocytic glioma in the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors. The distinction of pilocytic astrocytoma from diffuse glioma is fundamental as it could be the difference between CNS WHO grade 1 and grade 4 glioma. This study aims to determine the infiltrative nature of pilocytic astrocytoma in different brain locations. All cases diagnosed as "pilocytic astrocytoma" were retrieved from 2008 to 2021. The clinical information (age, sex, location of the tumor), pathological description, and performed immunostaining were obtained from the pathological reports. The available pathological slides were retrieved and examined for the following features: diagnosis, infiltrative vs. circumscribed tumor, and immunostaining characteristics. There were 20 males and 19 females aged 17 months to 31 years. The diagnosis of pilocytic astrocytoma was confirmed in 38/39 cases, and in one case, the diagnosis changed to a dysembryoplastic neuroepithelial tumor. Histological infiltration is defined as the presence of neoplastic cells among the nonneoplastic brain parenchyma. Twenty cases were well-circumscribed with no evidence of infiltration histologically, while 18/38 cases showed apparent infiltration into adjacent brain tissue. The infiltration was not restricted to cerebellar pilocytic astrocytoma (12/24, 50%) but was also present in 3/7 supratentorial, single brainstem, and single spinal cord cases. In conclusion, cases with typical morphological features of pilocytic astrocytoma could show areas of brain infiltration, which should not affect the certainty of the diagnosis.

Gliosarcoma With Glioneuronal and Rhabdomyosarcoma Components.

Gliosarcoma is a rare subtype of glioblastoma, isocitrate dehydrogenase (IDH) wildtype. This biphasic tumor has two components. The first one is glial and usually represented by glioblastoma. The second is a sarcomatous component usually represented by nonspecific spindle cell sarcoma. Rarely, different glial tumors could represent the non-sarcomatous component, including oligodendroglioma and ependymoma. There were only two reported cases in the literature with glioneuronal components (both were anaplastic ganglioglioma) as the non-sarcomatous component. This work reports a gliosarcoma in the right frontal lobe of a 13-year-old female with a glioneuronal tumor representing the non-sarcomatous component and a rhabdomyosarcoma representing the sarcomatous component. The child lived for only six months after the resection of the tumor. The short survival attests to the dismal prognosis of gliosarcoma regardless of the nature of the non-sarcomatous component.

Diffuse GFAP Immunopositivity in the Oligodendrocyte-like Component of Pilocytic Astrocytoma Distinguishes It from Mimickers.

Pilocytic astrocytoma with a predominant oligodendrocyte-like component can be difficult to distinguish from oligodendroglioma, dysembryoplastic neuroepithelial tumors (DNTs), central neurocytoma, and ependymoma (clear cell phenotype). The utility of GFAP immunostaining in this context is not well discussed. All cases with a diagnosis of pilocytic astrocytoma were retrieved from the pathological archives along with the following information: age, sex, and pathological description. The GFAP immunostaining was scored as score 1 (<25%), score 2 (25−50%), score 3 (50−75%), and score 4 (>75%). The comparison group included oligodendrogliomas, DNTs, ependymomas, and central neurocytomas. All 26 cases (16 males and 10 females) of pilocytic astrocytoma showed strong and diffuse (score 4) GFAP immunostaining in the neoplastic cells of both the solid fibrillary and oligodendrocyte-like components. The staining pattern in the neoplastic round cells in the oligodendrocyte-like areas was perinuclear cytoplasmic with no processes. In the comparison group, GFAP immunostaining was mostly restricted to the reactive astrocytes in the background. Focal areas of the neoplastic cells showed scores of 1−3 in the neoplastic cells, but the staining pattern was different from those in pilocytic astrocytoma. In the setting of tumors with predominant oligodendrocyte-like areas, the GFAP immunostaining score and pattern help distinguish pilocytic astrocytoma from its mimickers.

Spectrum of paired-like homeobox 2b immunoexpression in pediatric brain tumors with embryonal morphology.

Paired-like homeobox 2b (PHOX2B) is an established immunomarker for peripheral neuroblastoma and autonomic nervous system cells. We aimed to evaluate the utility of PHOX2B immunostaining in central nervous system (CNS) tumors with embryonal morphology. Fifty-one tumors were stained with PHOX2B and submitted for whole slide image analysis: 35 CNS tumors with embryonal morphology (31 CNS embryonal tumors and four gliomas); and 16 peripheral neuroblastomas were included for comparison. Diffuse nuclear immunopositivity was observed in all (16/16) neuroblastomas (primary and metastatic). Among CNS embryonal tumors, focal immunoreactivity for PHOX2B was observed in most (5/7) embryonal tumors with multilayered rosettes (ETMR) and a single high-grade neuroepithelial tumor (HGNET) with PLAGL2 amplification; the remaining 27 CNS tumors were essentially immunonegative (<0.05% positive). Among ETMR, PHOX2B expression was observed in a small overall proportion (0.04%-4.94%) of neoplastic cells but focally reached up to 39% in 1 mm 'hot spot' areas. In the PLAGL2-amplified case, 0.09% of the total neoplastic population was immunoreactive, with 0.53% in the 'hot spot' area. Care should be taken in interpreting PHOX2B immunopositivity in a differential diagnosis that includes metastatic neuroblastoma and CNS tumors; focal or patchy expression should not be considered definitively diagnostic of metastatic peripheral neuroblastoma.

Primary Adrenal Malignant Rhabdoid Tumor in a 14-Year-Old Female: A Case Report and Literature Review.

Malignant rhabdoid tumor (MRT) is a rare, SWItch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1)-deficient, aggressive tumor, occurring predominantly in children below 3 years of age. Primary adrenal MRT is extremely rare, with only 3 cases reported in the literature. A previously healthy 14-year-old female presented with left upper quadrant/epigastric abdominal pain. Imaging studies revealed an 8.0 × 8.0 × 6.5 cm, heterogeneous, partially enhancing mass along the superior margin of the left kidney encasing the adrenal gland. Surgical resection of the tumor revealed a hypercellular heterogeneous neoplasm arising from the adrenal gland. It was composed predominantly of primitive small round blue cells with focal true rosettes and areas of vague glandular epithelial differentiation and chondroid differentiation. Classic rhabdoid-type cytoplasmic inclusions were focally present. Mitoses, tumor necrosis, and hemorrhage were readily seen. Tumor cells showed complete loss of SMARCB1 (INI1) nuclear staining, demonstrated strong, and diffuse positivity for glypican 3, patchy positivity for CD99, cytokeratin, Sal-like protein 4, Lin-28 homolog A, epithelial membrane antigen, and S100. Molecular studies revealed biallelic frameshift mutations in the SMARCB1 gene (c.673delG and c.683dupT) without pathogenic copy number aberrations. The histologic, immunohistochemical, and molecular findings support a diagnosis of MRT. The unusual age, location, and mutations of this case expand the clinicopathologic and molecular spectrum of MRT.

Pediatric Metastatic Hepatoblastoma With an ARID1A Mutation and Rhabdoid Cells.

The small cell undifferentiated component of hepatoblastoma is an uncommon histologic component and is distinguished from small cell undifferentiated like pattern (originally called hepatoblastoma and now recognized to be malignant rhabdoid tumor) by the bi-allelic SMARCB1 mutations or copy number alterations in the latter. AT-rich interactive domain-containing protein 1A (ARID1A) is a part of the ATP-dependent switch/sucrose non-fermentable complex assembly, but mutations have not been reported as drivers of malignant rhabdoid tumor. ARID1A mutations in hepatocellular carcinoma are associated with poor prognosis but its significance in hepatoblastoma is unknown. We report a unique case of hepatoblastoma in a 19-month-old female with an unusual/atypical small cell undifferentiated component with ARID1A and beta-catenin mutations. It had an aggressive clinical course despite treatment, with metastases to the left psoas muscle, perihepatic and paratracheal lymph nodes, spinal cord, and leptomeninges. Leptomeningeal metastases resulted in diffuse cerebral edema and death. The initial diagnostic biopsy did not reveal rhabdoid cells while all metastatic foci showed cells with rhabdoid morphology in the autopsy specimens. Although this rhabdoid component resembled malignant rhabdoid tumor morphologically, molecular analyses failed to show mutations or deletions of SMARCB1.

Histopathologic features of alveolar capillary dysplasia with misalignment of pulmonary veins with atypical clinical presentation.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare neonatal lung disease with fatal outcome. Typically, respiratory symptoms present in the first 24 hours of life and patients die within the neonatal period. Atypical, delayed clinical presentations and/or longer survival have also been reported. Here, we studied the clinicopathologic relationship of ACD/MPV by examining 16 cases of ACD/MPV, focusing on atypical features. Based on the presence of diffuse vs. focal/patchy ACD/MPV histopathologic changes, we divided the cases into classic and nonclassic pathology groups. MPV was found in all ACD/MPV. Ten of 16 cases exhibited classic diffuse abnormalities, while 6 of 16 had a nonclassic focal/patchy distribution. However, among 7 patients with atypical clinical features, only 2 had nonclassic pathology, while 4 out of 9 clinically typical cases had nonclassic ACD/MPV pathology. Marked intrapulmonary aberrant arteriovenous vessels were present in all atypical cases. In conclusion, clinical presentation is not always correlated with histopathology in ACD/MPV. Atypical ACD/MPV should be suspected in any infants with fulminant pulmonary hypertension. Abnormal pulmonary veins and aberrant intraseptal vessels are the most important clues for diagnosis. Additional studies are needed for further elucidation of diagnostic histological criteria of atypical ACD/MPV and to explore its pathogenesis.

Phox2b Immunohistochemical Staining in Detecting Enteric Neural Crest Cells in Hirschsprung Disease.

BACKGROUND: It can be challenging to recognize undifferentiated/immature ganglion cells, especially single forms. Ganglion cells and glia are derived from enteric neural crest cells (ENCCs), a group of autonomic nervous system (ANS)-lineage neural crest progenitors that PHOX2B regulates. Phox2b is an excellent marker for neoplastic and non-neoplastic ANS cells (eg, peripheral neuroblastic tumors [pNTs]). We hypothesized that Phox2b immunohistochemical staining (IHC) would also be useful for detecting ENCCs. METHODS: Hematoxylin and eosin, calretinin IHC, and Phox2b IHC were reviewed on 21 pull-through specimens and on a cohort of 12 rectal biopsies. RESULTS: Phox2b IHC demonstrated nuclear positivity in all of the ganglion cells across the different phases of differentiation without background staining. The Phox2b result correlated with the morphological findings, calretinin IHC results, and diagnoses based on the routine diagnostic method. The intensity was uniformly strong in the undifferentiated/immature forms and became variable in the mature forms; this pattern was similar to that seen in pNTs. CONCLUSION: Phox2b IHC was highly sensitive and specific for detecting ganglion cells. It worked especially well for immature ganglion cells, seen in premature neonates, and scattered single forms in transition zones. In basic research settings, Phox2b can be a useful marker for early differentiation of ENCCs.

Loss of Ramified Microglia Precedes Axonal Spheroid Formation in Adult-Onset Leukoencephalopathy with Axonal Spheroids.

Two different pathological mechanisms have been suggested to underlie adult-onset leukoencephalopathy with axonal spheroids (ALAS). Pathological studies have suggested that ALAS involves primary axonopathy with secondary demyelination. However, the identification of mutations in Colony Stimulating Factor 1 Receptor (CSF1R), important for microglial survival, has suggested that ALAS is a microgliopathy. This study examines the correlation between microglial changes and axonopathy in ALAS. A total of 6 ALAS cases were studied. White matter lesions were classified into three evolving stages: 1) numerous axonal spheroids among well-myelinated fibers; 2) moderate loss of myelinated fibers with or without axonal spheroids; and 3) a leukodystrophy-like pattern of severe confluent axonal and myelin loss. Axonal spheroids and ramified microglia were semi-quantified and the lesions were assigned a score of 0-3. We found a strong correlation between the preponderance of axonal spheroids and ramified microglial loss. All areas with a predominance of axonal spheroids showed a near-complete absence of ramified microglia, which was also apparent in small cortical and white matter lesions. In contrast, some areas with no ramified microglia showed no axonal pathology. Our findings support the suggestion that ramified microglia loss precedes axonal spheroids formation. This observation will help to better understand the pathogenesis of ALAS and suggests a protective role of microglia.

Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.

OBJECTIVE: Clinical, radiologic, and molecular analysis of patients with genomic deletions upstream of the LMNB1 gene. METHODS: Detailed neurologic, MRI examinations, custom array comparative genomic hybridization (aCGH) analysis, and expression analysis were performed in patients at different clinical centers. All procedures were approved by institutional review boards of the respective institutions. RESULTS: Five patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations. Patients had unique nonrecurrent deletions upstream of the LMNB1, varying in size from 250 kb to 670 kb. Deletion junctions were embedded in repetitive elements. Expression analysis revealed increased LMNB1 expression in patient cells. CONCLUSIONS: Our findings confirmed the association between LMNB1 upstream deletions and leukodystrophy previously reported in a single family, expanding the phenotypic and molecular description of this condition. Although clinical and radiologic features overlapped with those of autosomal dominant leukodystrophy because of LMNB1 duplications, patients with deletions upstream of LMNB1 had an earlier age at symptom onset, lacked early dysautonomia, and appeared to have lesser involvement of the cerebellum and sparing of the spinal cord diameter on MRI. aCGH analysis defined a smaller minimal critical region required for disease causation and revealed that deletions occur at repetitive DNA genomic elements. Search for LMNB1 structural variants (duplications and upstream deletions) should be an integral part of the investigation of patients with autosomal dominant adult-onset leukodystrophy.

The effects of delayed formalin fixation on endometrial pathology in hysterectomy specimens.

Opening hysterectomy specimens for pathological assessment can be performed before or after formalin fixation. The former method, preferred by most pathologists, limits the autolytic changes of the endometrium, but it may result in a distortion of the uterine wall as a result of the contraction of the myometrium. This may interfere with the assessment of the degree of tumor extension to the uterine wall. The latter method, which is less common, preserves the uterine wall but may limit the assessment of the endometrial glands due to autolytic changes, and the effect of nuclear features is unknown. In this study, we assessed 78 hysterectomy specimens opened by the second method for these changes. The autolytic changes were present in all cases, but they didn't limit the pathologist's assessment to reach the final diagnosis in both the benign and malignant cases. Although, it was difficult to determine which of the nuclear changes was caused by delayed fixation, we found nuclear rounding and prominence of the nucleoli were not features of autolytic changes. Conditions with nuclear features that may mimic mild nuclear atypia were common in these specimens, but not severe atypia. We concluded that a delayed opening of the uterus is an acceptable procedure in dealing with these specimens.