Immune Mediated Necrotizing Myopathy: a Cause of Isolated Myopathy of Neck Extensor Muscle.

Immune mediated necrotizing myopathy (IMNM) is a unique form of myositis that is characterized by distinct muscle biopsy features including abundant myofiber necrosis, degeneration, and regeneration with only minimal, if any, inflammation on muscle biopsy. IMNM is clinically similar to idiopathic inflammatory myopathy (IIM); hence, muscle biopsy is essential to diagnose IMNM. Herein we describe a case of neck extensor weakness due to necrotizing myopathy. Isolated weakness of the neck extensor muscles is uncommon in IIM and IMNM. This case describes the diagnostic work-up, treatments utilized, and 2 year follow-up course without involvement of other muscle groups and without progression of neck extensor muscle weakness. Advanced imaging using magnetic resonance imaging (MRI) facilitated the diagnosis by identifying the affected muscles and site for muscle biopsy.

Spinal subdural abscess: a rare complication of decubitus ulcer.

Spinal subdural abscess (SSA) is an uncommon entity. The exact incidence is unknown, with very few cases reported in the literature. This condition may result in spinal cord compression, thus constituting a medical and neurosurgical emergency. The pathogenesis of SSA is not well-described, and the available knowledge is based on case observations only. There is only one case report that describes direct seeding from decubitus ulcers as a possible mechanism for development of SSA. We report a case of subacute onset of quadriplegia in a male patient, age 55 years, due to spinal cord compression from SSA and superimposed spinal subdural hematoma. The direct seeding from decubitus ulcers is thought to be the cause of infection in our patient. We present this case of SSA to elucidate and review the predisposing factors, pathogenesis, clinical presentation, diagnostic modalities, and treatment regarding management of this rare disorder.

Mirtazapine and mefloquine therapy for non-AIDS-related progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the human nervous system caused by the JC virus. We report what is, to the best of our knowledge, the second reported case using a combination of mefloquine and mirtazapine in a patient with non-AIDS-related PML with a good clinical outcome. Conversely, the recent trial of mefloquine in 21 patients with AIDS and 3 without AIDS failed to show a reduction of JC viral DNA levels in the cerebral spinal fluid. However, the positive clinical response seen in our patient after the initiation of this combination therapy suggests that further studies in the form of randomized controlled trials for the treatment of non-AIDS-related PML are warranted.

Gene signatures associated with prognosis and chemotherapy resistance in glioblastoma treated with temozolomide.

Background: Glioblastoma (GBM) prognosis remains extremely poor despite standard treatment that includes temozolomide (TMZ) chemotherapy. To discover new GBM drug targets and biomarkers, genes signatures associated with survival and TMZ resistance in GBM patients treated with TMZ were identified. Methods: GBM cases in The Cancer Genome Atlas who received TMZ (n = 221) were stratified into subgroups that differed by median overall survival (mOS) using network-based stratification to cluster patients whose somatic mutations affected genes in similar modules of a gene interaction network. Gene signatures formed from differentially mutated genes in the subgroup with the longest mOS were used to confirm their association with survival and TMZ resistance in independent datasets. Somatic mutations in these genes also were assessed for an association with OS in an independent group of 37 GBM cases. Results: Among the four subgroups identified, subgroup four (n = 71 subjects) exhibited the longest mOS at 18.3 months (95% confidence interval: 16.2, 34.1; p = 0.0324). Subsets of the 86 genes that were differentially mutated in this subgroup formed 20-gene and 8-gene signatures that predicted OS in two independent datasets (Spearman's rho of 0.64 and 0.58 between actual and predicted OS; p < 0.001). Patients with mutations in five of the 86 genes had longer OS in a small, independent sample of 37 GBM cases, but this association did not reach statistical significance (p = 0.07). Thirty-one of the 86 genes formed signatures that distinguished TMZ-resistant GBM samples from controls in three independent datasets (area under the curve ≥ 0.75). The prognostic and TMZ-resistance signatures had eight genes in common (ANG, BACH1, CDKN2C, HMGA1, IFI16, PADI4, SDF4, and TP53INP1). The latter three genes have not been associated with GBM previously. Conclusion: PADI4, SDF4, and TP53INP1 are novel therapy and biomarker candidates for GBM. Further investigation of their oncologic functions may provide new insight into GBM treatment resistance mechanisms.

Primary disseminated central neurocytoma: cytological and MRI evidence of tumor spread prior to surgery.

Since its description in 1982, central neurocytoma (CN) has been a relatively innocuous rare tumor of the central nervous system. Comprising of less than 0.5% of all intracranial tumors, most are reported to be slow growing, with low recurrence rates, and a favorable prognosis. Because of its rarity, its cellular biology, prognosis, and treatment strategies are difficult to ascertain. Its low-grade nature allows for continued growth before signs and symptoms of increase intracranial pressures ensue. Some authors theorize CN may derive from bipotential precursor cells of the periventricular germinal matrix, which are capable of both neuronal and glial differentiation, but maintain a low proliferative potential after birth. Several retrospective studies indicate that a MIB-1 index of greater than 2-3% will show a recurrence rate of 48-63%, respectively. Of hundreds of cases reported, the incidence of recurrence is very low, which makes aggressive forms of this tumor difficult to study. There are only 12 cases of craniospinal dissemination reported since its inception. The diagnoses of dissemination in these cases are made only after surgical intervention. We report the only case of primary disseminated CN, diagnosed on radiographic studies, and confirmed by cytology of the cerebral spinal fluid, prior to any kind of intervention. These cases may represent a subgroup of a more aggressive CN, which requires more assertive surveillance including CSF sampling and routine imaging of the neuroaxis.

Squamous cell carcinoma arising in discoid lupus erythematosus lesions of the ears infected with human papillomavirus.

We describe a 51-year-old white man with discoid lupus erythematosus (DLE) of the head, neck, trunk, and upper extremities of more than 20 years' duration who developed rapidly progressive squamous cell carcinoma (SCC) of the bilateral ear helices. Human papillomavirus (HPV) was detected from excised specimens from the ears via tissue immunohistochemistry. Human papillomavirus infection of discoid lesions may be responsible for the rapid progression of SCC of this patient's bilateral ear helices.

YKL-40, a marker of simian immunodeficiency virus encephalitis, modulates the biological activity of basic fibroblast growth factor.

Human immunodeficiency virus encephalitis causes dementia in acquired immune deficiency syndrome patients. Using proteomic analysis of postmortem cerebrospinal fluid (CSF) and brain tissue from the simian immunodeficiency virus primate model, we demonstrate here a specific increase in YKL-40 that was tightly associated with lentiviral encephalitis. Longitudinal analysis of CSF from simian immunodeficiency virus-infected pigtailed macaques showed an increase in YKL-40 concentration 2 to 8 weeks before death from encephalitis. This increase in YKL-40 correlated with an increase in CSF viral load; it may therefore represent a biomarker for the development of encephalitis. Analysis of banked human CSF from human immunodeficiency virus-infected patients also demonstrated a correlation between YKL-40 concentration and CSF viral load. In vitro studies demonstrated increased YKL-40 expression and secretion by macrophages and microglia but not by neurons or astrocytes. We found that YKL40 displaced extracellular matrix-bound basic fibroblast growth factor (bFGF) as well as inhibited the mitogenic activity of both fibroblast growth factor receptor 1-expressing BaF3 cells and bFGF-induced axonal branching in hippocampal cultures. Taken together, these findings demonstrate that during lentiviral encephalitis, YKL-40 may interfere with the biological activity of bFGF and potentially of other heparin-binding growth factors and chemokines that can affect neuronal function or survival.

Glioblastoma Treatment with Temozolomide and Bevacizumab and Overall Survival in a Rural Tertiary Healthcare Practice.

BACKGROUND: The efficacy of temozolomide (TMZ) chemotherapy for treating newly diagnosed glioblastoma (GBM), a primary brain tumor with short survival, was demonstrated in a clinical trial in 2005, and since then, the standard-of-care for newly diagnosed GBM has been maximal safe surgery followed by 60 Gray of radiation with concomitant and adjuvant TMZ (standard radiotherapy and TMZ). In 2009, clinical trials also reported on the efficacy of bevacizumab for treating recurrent GBM. We performed a retrospective cohort study to evaluate the impact of treatment regimens on overall survival for patients with GBM at a rural tertiary healthcare practice. METHODS: We retrospectively reviewed the medical records of 307 consecutive, newly diagnosed GBM patients at one institution between 1995 and 2012 and assessed treatment patterns. We also compared overall survival according to the treatment received. RESULTS: Only 0.6% (1/163) of patients diagnosed before 2005 received standard radiotherapy and TMZ versus 36.1% (52/144) of patients diagnosed since 2005 (P < 0.0001). For patients who received standard radiotherapy and TMZ, the median overall survival was 17.0 months versus 7.0 months for patients who received 60 Gray of radiation but no chemotherapy (P = 0.0000078). The median overall survival was 15.4 months in the 19 patients treated with bevacizumab monotherapy at first GBM recurrence versus 6.8 months in the 32 patients with no treatment at first GBM recurrence (P = 0.00015), but patients who received bevacizumab were younger and more likely to have had a surgical resection and 60 Gray of radiation at diagnosis. CONCLUSIONS: TMZ and bevacizumab therapies were rapidly adopted in a rural tertiary healthcare setting, and patients who received these treatments had increased overall survival. However, advantageous prognostic factors in patients who received bevacizumab at recurrence may have influenced the extent of the increase in overall survival attributed to this treatment.

Telepathology for intraoperative neuropathologic consultations at an academic medical center: a 5-year report.

Telepathology is an attractive solution for providing neuropathologic intraoperative expertise to geographically diverse hospitals from a center of excellence. To date, few reports specifically address the feasibility of such a system for intraoperative neuropathology specimens. The University of Pittsburgh Medical Center is a 20-hospital system in Southwest Pennsylvania in which the pathology department has adopted a subspecialty "centers of excellence" method of managing cases. The Division of Neuropathology is physically located at 1 hospital but provides neuropathologic expertise to the entire system. Adult neurosurgery is currently limited to 2 hospitals separated by 18 city blocks. We describe our experience in providing remote intraoperative neuropathologic consultations over a 5-year period, from 2002 to 2006. Several approaches are discussed, with emphasis on the current system and the evolution of imaging technology. Diagnostic outcomes are compared among >400 telepathology cases and >1,200 conventional intraoperative cases. Current technology is capable of facilitating teleneuropathologic intraoperative diagnoses in a timely manner, with accuracy rates comparable to those for conventional methods. However, the practice of providing these remote consultations requires a sophisticated and technologically advanced environment along with substantial planning, communication, and training of both pathologists and pathology assistants.

Leptomeningeal carcinomatosis as primary manifestation of pancreatic cancer.

Leptomeningeal carcinomatosis (LMC) is a rare complication of cancer that often presents at an advanced stage after obvious metastasis of a primary cancer or locally advanced disease. We present an uncommon case of LMC secondary to pancreatic carcinoma presenting with headache, unilateral VII nerve palsy, and lower extremity weakness. Initial cerebrospinal fluid (CSF) studies were concerning for chronic aseptic meningitis but negative for malignant cells; the diagnosis of tuberculous meningitis was erroneously evoked. Three lumbar punctures were required to capture malignant cells. The diagnosis of LMC was based on CSF examination with cytology/immunohistochemistry and leptomeningeal enhancement on MRI. Post mortem autopsy revealed advanced and diffusely metastatic pancreatic adenocarcinoma. This patient demonstrates that solid tumors can present with leptomeningeal spread that often confuses the treating physician. Fungal or tuberculous meningitis can mimic LMC in the absence of neoplastic signs and negative CSF cytology. This event is exceedingly rare in pancreatic cancer. If the index of suspicion is high, repeat CSF sampling can increase the sensitivity of detection of malignant cells and thus result in the correct diagnosis.

Infiltrative astrocytomas with granular cell features (granular cell astrocytomas): a study of histopathologic features, grading, and outcome.

Granular cell astrocytomas (GCAs) are rare, incompletely characterized infiltrative gliomas that contain a prominent component of granular cells. Such tumors can readily be mistaken for reactive conditions. We studied 22 cases to explore their morphologic spectrum, establish features useful in distinguishing GCA from nonneoplastic diseases, and to determine which parameters correlate with biologic behavior. Tumors occurred in 17 men and five women, ranging in age from 29 to 75 years, who presented mainly with seizures, headache, aphasia, or hemiparesis. Radiologically, high-grade GCAs were contrast-enhancing, cerebral hemispheric masses with prominent peritumoral edema. All contained sheets or interspersed large, round cells packed with eosinophilic, PAS-positive granules. Lymphocytic infiltrates, either perivascular or admixed with neoplastic cells, were present in 14 tumors. Transition to typical infiltrating astrocytoma was noted in 16 cases; of these, granular cells comprised 30-95% of cells. Six tumors consisted almost entirely of atypical granular cells. By WHO criteria, four GCA were grade 2, seven were grade 3, and 11 were grade 4. Glial fibrillary acidic protein staining was seen in all but one tumor, and the majority were immunoreactive for S-100 protein, KP-1, ubiquitin, and epithelial membrane antigen. Although MIB-1 proliferation indices increased with tumor grade, granular cells accounted for only a minority of immunoreactive cells. Among 18 cases with follow-up, 15 recurred after surgery and resulted in death (mean survival, 7.6 months). Two patients died postoperatively, and one was alive at 51 months. Granular cell astrocytoma is an uncommon morphologic variant that appears to be rapidly progressive and usually fatal.

Primary melanocytic tumors of the central nervous system: Report of two cases and review of literature.

BACKGROUND: Primary melanocytic tumors of the central nervous system (CNS) represent only 1% of all melanomas. We report two rare cases of primary diffuse leptomeningeal melanomatosis (PDLM; case 1) and primary melanoma of the thoraco-lumbar spine (case 2). CASE DESCRIPTION: In case 1, multiple cerebrospinal fluid (CSF) studies and a brain biopsy were non-diagnostic, with a biopsy of the cauda equina eventually demonstrating malignant melanomatosis. Diagnosis of primary spinal cord melanoma was more straightforward in case 2 with imaging and biopsy. CONCLUSION: PDLM and primary intramedullary spinal melanoma are rare variants of primary CNS melanoma. This report contrasts the diagnostic challenges between the two entities and alerts the neurosurgeon into considering the diagnosis with appropriate clinical presentation.

Diagnostic dilemma: late presentation of amelanotic BRAF-negative metastatic malignant melanoma resembling clear cell sarcoma: a case report.

Clear cell sarcoma is a rare cancer primarily of tendons, fascia, and aponeuroses that can be difficult to discern from primary cutaneous malignant melanoma. The two cancers share several histological markers, with most cases of both cancers staining positively for S-100, HMB-45, and melanin. Primary therapy of both cancers involves wide local excision, but while systemic therapy has proven benefit for malignant melanoma, it has not been established for clear cell sarcoma.We report the case of a 58 year old woman with a large, ulcerated, fungating mass on her left lower leg. Frozen section of the mass showed a malignant epithelioid and spindle cell tumor confined to the subcutaneous tissue. A provisional diagnosis of soft-tissue sarcoma was made. Through in-depth study of initial biopsy with immunohistochemistry for S-100, HMB-45, MART-1, and MITF, along with karyotyping and FISH analysis for EWS gene rearrangement, the diagnosis of amelanotic malignant melanoma was confirmed. The patient then underwent systemic treatment with ipilimumab upon recurrence with good response. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1989338475107348.

16 month-old female with intraventricular mass.

Pediatric meningiomas are rare and account for about 1.5% of all intracranial tumors. When compared to adults, intraventricular location of childhood meningiomas is four to ten times as high. Atypical pathology of these lesions is very uncommon and indicates an aggressive nature. They are usually associated with Neurofibromatosis 2 (NF2) or previous cranial irradiation. Here, we present an interesting case of an unusually large, congenital intraventricular meningioma of atypical pathology in a 16 month old child with subsequently diagnosed NF2. A brief review of literature is also presented with this case illustration.

Temporal Chondroblastoma with a Novel Chromosomal Translocation (2;5) (q33;q13).

The case of a 51-year-old man with a large temporal mass is presented. The mass eroded the floor of the middle fossa medially to the sphenoid sinus. A combined approach with neurosurgery and otolaryngology was performed to achieve maximal resection of the mass. Pathology was typical for chondroblastoma: a rare, benign but locally invasive chondroid tumor. Genetic testing revealed a translocation of (2;5) (q33;q13). This is a unique genetic mutation in all chondroid tumors to our knowledge. The diagnostic utility or role of this mutation in the pathobiology of this tumor remains to be determined.

Metastatic epithelioid trophoblastic tumor involving the spine.

STUDY DESIGN: This is a single case-based report. OBJECTIVE: We report the first case of epithelioid trophoblastic tumor (ETT) presenting as primary metastasis to the spine. SUMMARY OF BACKGROUND DATA: ETT is an extremely rare form of gestational trophoblastic neoplasm with less than 100 cases reported in the literature. A 36-year-old, postpartum woman presented with severe low back pain and was found to have a contrast-enhancing lesion in lower thoracic spine subsequently confirmed as ETT. METHODS: The patient data, history, clinical examination findings, laboratory, and histopathology data and imaging studies were retrospectively reviewed and findings reported. A literature search using Pubmed and Cochrane database was conducted. RESULT: We described the first case of an ETT to present as a primary metastasis to the spine. CONCLUSION: This first report of metastasis of ETT to the spine adds significant new information to the growing literature of this rare and newly identified tumor. It also alerts the neurosurgeon into considering the diagnosis with appropriate clinical presentation. As more number of cases of nervous system involvement with this tumor are reported, crucial information on prognostic factors and treatment regimens will emerge.

Destruction of extracellular matrix proteoglycans is pervasive in simian retroviral neuroinfection.

Disruption of the perineuronal matrix has been reported in human immunodeficiency virus (HIV) encephalitis. To better understand the extent of matrix disruption during lentiviral encephalitis, we characterized the extracellular matrix (ECM) damage in brains of 12 macaques infected with simian immunodeficiency virus (SIV). Matrix integrity was assessed by Wisteria floribunda lectin histochemistry. Confocal microscopy was used to quantify matrix loss, macrophage infiltration, and synaptic damage. Disruption of brain ECM was present shortly after retroviral infection, preceding parenchymal macrophage infiltration. In agreement with previous observations, reduced staining of presynaptic and postsynaptic proteins in SIV encephalitis occurred concurrently with matrix abnormalities. Lentiviral infection induced microglial and macrophage expression of two disintegrins and metalloproteinases with thrombospondin motifs (ADAMTS-1 and ADAMTS-4), with high substrate specificity for matrix proteoglycans. Matrix damage is pervasive during SIV neuroinfection, which suggests interventions to conserve brain matrix proteoglycans might avert or delay retroviral-induced neurodegeneration.