Leslie A. Bruch

Recurrent chromosomal imbalances and structurally abnormal breakpoints within complex karyotypes of malignant peripheral nerve sheath tumour and malignant triton tumour: a cytogenetic and molecular cytogenetic study

Background: Cytogenetic studies of malignant peripheral nerve sheath tumours (MPNSTs) and malignant triton tumours (MTTs) are rare. Aims: To undertake cytogenetic analysis of these tumours. Methods: Conventional cytogenetic analysis of 21 MPNSTs and MTTs from 17 patients (nine with peripheral neurofibromatosis (NF1)) was carried out using standard culture and harvesting procedures. For a more precise identification of composite structural rearrangements and marker chromosomes, spectral karyotypic analysis (SKY) was applied to a subset of cases. In addition, EGFR gene copy number was assessed by fluorescence in situ hybridisation (FISH) analysis in a subset of cases. Results: Cytogenetic analysis revealed predominantly complex karyotypes. SKY analysis was useful in further defining many structural anomalies. Structural aberrations most frequently involved chromosomal bands or regions 1p31–36, 4q28–35, 7p22, 11q22–23, 19q13, 20q13, and 22q11–13. Overall, loss of chromosomal material was much more common than gain. Loss of chromosomes or chromosomal regions 1p36 (48%), 3p21–pter (52%), 9p23–pter (57%), 10 (48%), 11q23–qter (48%), 16/16q24 (62%), 17(43%), and 22/22q (48%), and gains of 7/7q (29%) and 8/8q (29%) were most prominent. These gains and losses were distributed equally between MPNST and MTT, demonstrating that these entities are similar with respect to recurrent genomic imbalances. Similarly, none of the recurrent chromosomal breakpoints or imbalances was restricted to either NF1 associated or sporadic MPNSTs. FISH analysis was negative for amplification. Conclusions: These cytogenetic and molecular cytogenetic findings expand the knowledge of chromosomal alterations in MPNST and MTT, and point to possible recurring regions of interest.

Competency assessment of residents in surgical pathology using virtual microscopy

Our goal was to develop an efficient and reliable performance-based virtual slide competency examination in general surgical pathology that objectively measures pathology residents morphologic diagnostic skill. A Perl scripted MySQL database was used to develop the test editor and test interface. Virtual slides were created with the Aperio ScanScope. The examination consisted of 20 questions using 20 virtual slides. Slides were chosen to represent general surgical pathology specimens from a variety of organ systems. The examination was administered in a secure environment and was completed in 1 to 1 1/2 hours. Examination reliability, as an indicator of the tests ability to discriminate between trainee ability levels, was excellent (r = 0.84). The linear correlation coefficient of virtual slide competency examination score versus months of surgical pathology training was 0.83 (P = .0001). The learning curve was much steeper early in training. Correlation of virtual slide competency examination performance with residents performance on the 64 item Resident In-Service Examination surgical pathology subsection was 0.70. Correlation of virtual slide competency examination performance with global end of rotation ratings was 0.28. This pilot implementation demonstrates that it is possible to create a short, reliable performance-based assessment tool for measuring morphologic diagnostic skill using a virtual slide competency examination. Furthermore, the examination as implemented in our program will be a valid measure of an individual residents progress in morphologic competency. Virtual slide technology and computer accessibility have advanced to the point that the virtual slide competency examination model implemented in our program could have applicability across multiple residency programs.

Identification of a Novel, Recurrent SLC44A1-PRKCA Fusion in Papillary Glioneuronal Tumor

Mixed neuronal‐glial tumors are rare and challenging to subclassify. One recently recognized variant, papillary glioneuronal tumor (PGNT), is characterized by prominent pseudopapillary structures and glioneuronal elements. We identified a novel translocation, t(9;17)(q31;q24), as the sole karyotypic anomaly in two PGNTs. A fluorescence in situ hybridization (FISH)‐based positional cloning strategy revealed SLC44A1, a member of the choline transporter‐like protein family, and PRKCA, a protein kinase C family member of serine/threonine‐specific protein kinases, as the 9q31 and 17q24 breakpoint candidate genes, respectively. Reverse transcription‐polymerase chain reaction (RT‐PCR) analysis using a forward primer from SLC44A1 exon 5 and a reverse primer from PRKCA exon 10 confirmed the presence of a SLC44A1‐PRKCA fusion product in both tumors. Sequencing of each chimeric transcript uncovered an identical fusion cDNA junction occurring between SLC44A1 exon 15 and PRKCA exon 9. A dual‐color breakpoint‐spanning probe set custom‐designed for interphase cell recognition of the translocation event identified the fusion in a third PGNT. These results suggest that the t(9;17)(q31;q24) with the resultant novel fusion oncogene SLC44A1‐PRKCA is the defining molecular feature of PGNT that may be responsible for its pathogenesis. The FISH and RT‐PCR assays developed in this study can serve as valuable diagnostic adjuncts for this rare disease entity.

Mycoplasma pneumoniae infection, meningoencephalitis, and hemophagocytosis

Central nervous system manifestations are a common extrapulmonary complication of Mycoplasma pneumoniae infection, of which encephalitis is a well-recognized abnormality in children. In this report the first description of M. pneumoniae infection simultaneously complicated by meningoencephalitis and hemophagocytosis is presented.

An autopsy case of limbic encephalitis with voltage-gated potassium channel antibodies

Sir, Voltage-gated potassium channel (VGKC) antibodies in patients with non-paraneoplastic limbic encephalitis have recently been described [1–7]. Only one case with autopsy findings of this rare condition has been previously reported [7]. We describe postmortem findings in a case of limbic encephalitis with VGKC antibodies and normal brain MRI. The patient is a 65-year-old woman with a past medical history of diabetes mellitus and chronic obstructive pulmonary disease (COPD) who was admitted to our institution with amnesia, disorientation and seizures. The patient had been in her usual state of health, working as a manager, until approximately three and a half months prior to admission, when she began to have jerking movements in the right upper and lower extremities, intermittent twitching in the right face, and a vague history of falls. Three months prior to admission her daughter and friends began to notice memory decline with insomnia and confusion at night. By the time she was admitted to an outside institution (approximately 1-month prior to transfer), she had developed fluctuating cognitive impairment. Additionally, she experienced a witnessed complex partial seizure with secondary generalization. Following admission to the outside institution, her brain MRI was normal and CSF examination showed a white cell count of 17/cmm. Polymerase chain reaction (PCR) for herpes simplex virus was negative, and an EEG showed mild diffuse slowing. During the hospital stay, she developed hyponatremia, which was treated. On transfer to this institution, her vital signs were normal and physical examination revealed multiple bruises on her extremities, likely secondary to falls. Neurologically, she was disoriented to time and place. Following short delay, she was not able to recall any of three objects. Her language, cranial nerve, and motor examinations were normal, and she had no evidence of myoclonus, apraxia, ataxia, or general abnormal movements. Her serum sodium was 118 mmol/l (normal, 137–145 mmol/l), and her serum voltagegated potassium channel antibodies were found to be 1.73 nmol/l (normal <0.02 nmol/l). Although the patient had an elevated CSF 14-3-3 protein, the specimen submitted contained blood and was thought to be a false positive result. Paraneoplastic antibodies, anti-thyroid antibodies, and infectious serology tests were negative. PCR tests for herpes simplex virus, varicella zoster virus, cytomegalovirus and Epstein–Barr virus in the CSF were negative. A repeat brain MRI was normal, and a second EEG was non-specific. A chest CT and whole body FDG-PET ([F]fluorodeoxyglucose-PET) showed mediastinal adenopathy which was identified as a reactive hyperplasia without evidence of malignancy by lymph node biopsy. Following discharge, her mental status was stable without treatment; however, approximately a month and a half later, she was readmitted to an outside hospital after accidentally taking an excessive dose of insulin. Her subsequent hospital course was complicated with hypoglycemia, seizures, COPD exacerbation, and pneumonia. The patient was initiated on high dose methylprednisolone (250 mg i.v. q6 h) that was quickly tapered (40 mg i.v. b.i.d.) and maintained until the patient was discharged (approximately 5 weeks). Approximately 24 h following discharge for comfort care, the patient expired and a brain and chest only autopsy was performed. No occult malignancy was identified in the lungs and a patchy mixed infiltrate, suggestive of hypersensitivity myocarditis, was present in the myocardium. The brain showed mild, focal perivascular T-cell lymphocytic cuffing and parenchymal infiltration involving the leptomeninges, parenchyma of the limbic system (cingulate gyrus, hippocampus, and amygdala), and midbrain. There was also mild microglial proliferation. Spongiform change or findings of another neurodegenerative disease were not identified (Fig. 1). Limbic encephalitis with voltage-gated potassium channel (VGKC) antibodies is characterized by subacute cognitive Figure 1 Postmortem neuropathologic findings. Immunohistochemical staining for T-cell lymphocytes (CD 3) shows perivascular cuffing (arrow head) and parenchymal infiltration (arrows) in the left amygdala (a), focal leptomeningeal inflammation (arrow) in the right amygdala (b), and perivascular lymphocytic cuffing in the left hippocampus (c). A CD68 immunohistochemical stain demonstrates mild microglial proliferation (arrows) in the left hippocampus (d).

Vacuolar neuritic dystrophy in aged mouse superior cervical sympathetic ganglia is strain-specific

We have developed a model of autonomic nervous system aging using the mouse superior cervical sympathetic ganglion (SCG) which is characterized by the reproducible development of distinctive, markedly-enlarged neuritic swellings (vacuolar neuritic dystrophy, VND). These structures contained an admixture of lucent vacuoles and subcellular organelles, and involved both presynaptic and postsynaptic ganglionic elements. Quantitation of the frequency of VND was accomplished at the light microscopic level and validated by ultrastructural examination. VND lesions were 30-100-fold more frequent in the aged mouse paravertebral SCG than in the prevertebral celiac/superior mesenteric (C/SMG) sympathetic ganglia. Although VND was identified in all ages of mice examined, the number of lesions increased significantly with age. The frequency of VND was a function of the strain of mouse examined with a 40-fold difference in VND frequency between C57BL6 mice, the least involved strain, and the DBA/2J strain, which was most affected and began to develop significant numbers of lesions at an early age. As in our human studies of aging in the sympathetic nervous system, there was a prominent gender effect with males developing twofold greater numbers of VND lesions than females. Mice maintained on a significant calorie restricted diet for 30 months developed 70% fewer lesions than ad libitum-fed, age and sex matched controls. The aging mouse SCG, therefore, represents a robust animal model with reproducible, quantifiable and unambiguous neuropathology. Insights into pathogenetic mechanisms gained in the subsequent analysis of this relatively simple peripheral sympathetic nervous system model may contribute to the understanding of some of the most complex and significant problems involving higher brain function.

Hypertrophic spinal pachymeningitis with thoracic myelopathy: the initial presentation of ANCA-related systemic vasculitis.

Study Design A retrospective case review combined with a review of current literature. Objectives We describe a case of antineutrophil cytoplasmic antibodies (ANCA)-related systemic vasculitis, with nearly 4 years of clinical and radiographic follow-up, initially presenting as hypertrophic spinal pachymeningitis (HSP). The diagnosis, surgical, and medical treatment of HSP are discussed in the context of a literature review. Summary of Background Data HSP is a rare disease characterized by hypertrophic inflammation of the dura mater and clinical symptoms that progress from local pain to myelopathy. HSP has been associated with infectious, inflammatory, autoimmune, and traumatic conditions. Surgical decompression and/or corticosteroid therapy have been shown effective at managing this disorder, but identifying associated diseases can be essential to a favorable patient outcome. Methods The medical, pathologic, and radiographic records of this case were reviewed. A computer-based search of the PubMed database was used to perform a comprehensive literature review of HSP. Results We report a 66-year-old male with a history of renal cell carcinoma and bladder cancer who presented with upper abdominal pain, thoracic myelopathy (progressive weakness and numbness of the lower extremities, and gait disturbances), and weight loss. A diagnosis of HSP was subsequently shown to be the initial presentation of ANCA-related systemic vasculitis. Conclusions The possibility of an ANCA-related systemic vasculitis presenting as HSP without systemic signs is a diagnostic and therapeutic challenge for the spinal surgeon. The diagnosis of HSP should initiate a search for an associated disease process and close follow-up after initial treatment. With interdisciplinary collaboration between medicine, radiology, pathology, and orthopedics, the diagnosis was made and a treatment initiated which halted disease progression and has maintained remission for more than 4 years.

Pathology Milestones Assessing Clinical Competency by Committee

All Accreditation Council for Graduate Medical Education accredited pathology residency training programs are now required to evaluate residents using the new Pathology Milestones assessment tool. Similar to implementation of the 6 Accreditation Council for Graduate Medical Education competencies a decade ago, there have been challenges in implementation of the new milestones for many residency programs. The pathology department at the University of Iowa has implemented a process that divides the labor of the task in rating residents while also maintaining consistency in the process. The process is described in detail, and some initial trends in milestone evaluation are described and discussed. Our experience indicates that thoughtful implementation of the Pathology Milestones can provide programs with valuable information that can inform curricular changes.

Infantile cranial fasciitis: case-based review and operative technique

BackgroundCranial fasciitis (CF) is an uncommon benign primary lesion of the skull that typically affects the pediatric age group. Due to the rarity of CF, no prospective studies exist. Earliest description of this condition dates to 1980. The limited scientific and clinical literature regarding CF is dominated by case reports. For these reasons, questions pertaining to the true incidence, genetic risk factors, prognosis, and long-term outcome remain unanswered.DiscussionClinically, CF presents as a firm, painless, growing scalp mass that is typically not considered in the differential diagnosis. Preoperative pathognomonic signs and symptoms are absent, and imaging features are often nonspecific. Treatment is typically through complete surgical resection, at which time histopathological examination confirms the diagnosis of CF. Reconstruction of the skull defect in the child is critical. Autograft techniques help maintain a rigid construct that integrates with the native skull while preserving its continued ability to grow. Generally, a good outcome is observed with complete resection.Exemplary caseWe report a case of CF in an infant with emphasis on operative nuances and early follow-up results.ConclusionCF is a rare fibroproliferative disease that has a poorly defined incidence and long-term follow-up. Due to its locally invasive nature and nonspecific presentation, CF is often difficult to differentiate from malignancies and infections. Complete surgical resection is the best approach for diagnosis and cure. Its occult clinical presentation often allows it to achieve considerable growth, leaving a sizeable skull defect following resection. Since CF presents in the pediatric population, allograft reconstruction is preferred over titanium mesh or other synthetic materials to allow osseous integration and continued uninterrupted skull growth.

Using Focused Laboratory Management and Quality Improvement Projects to Enhance Resident Training and Foster Scholarship

Training in patient safety, quality, and management is widely recognized as an important element of graduate medical education. These concepts have been intertwined in pathology graduate medical education for many years, although training programs face challenges in creating explicit learning opportunities in these fields. Tangibly involving pathology residents in management and quality improvement projects has the potential to teach and reinforce key concepts and further fulfill Accreditation Council for Graduate Medical Education goals for pursuing projects related to patient safety and quality improvement. In this report, we present our experience at a pathology residency program (University of Iowa) in engaging pathology residents in projects related to practical issues of laboratory management, process improvement, and informatics. In this program, at least 1 management/quality improvement project, typically performed during a clinical chemistry/management rotation, was required and ideally resulted in a journal publication. The residency program also initiated a monthly management/informatics series for pathology externs, residents, and fellows that covers a wide range of topics. Since 2010, all pathology residents at the University of Iowa have completed at least 1 management/quality improvement project. Many of the projects involved aspects of laboratory test utilization, with some projects focused on other areas such as human resources, informatics, or process improvement. Since 2012, 31 peer-reviewed journal articles involving effort from 26 residents have been published. Multiple projects resulted in changes in ongoing practice, particularly within the hospital electronic health record. Focused management/quality improvement projects involving pathology residents can result in both meaningful quality improvement and scholarly output.