Faculty Bibliography

Inflammatory orbital lesions include a broad list of diagnoses, many of them with overlapping clinical and radiographic features. They often present a diagnostic conundrum, even to the most experienced orbital specialist, thus placing considerable weight on surgical biopsy and histopathological analysis. However, histopathological diagnosis is also inherently challenging due to the rarity of these lesions and the overlaps in histologic appearance among distinct disease entities. We herein present the case of an adolescent male with a subacutely progressive orbital mass that generated a significant diagnostic dilemma. Early orbital biopsy was consistent with a benign fibro-inflammatory lesion, but corticosteroid therapy was ineffective in halting disease progression. After an initial substantial surgical debulking, histopathological analysis revealed several key features consistent with IgG4-related disease (IgG4-RD), a systemic fibro-inflammatory process typically accompanied by multifocal tumor-like lesions. Surprisingly, within months, there was clear evidence of clinical and radiographic disease progression despite second-line rituximab treatment, prompting a second surgical debulking. This final specimen displayed distinctive features of Rosai-Dorfman disease (RDD), a systemic inflammatory disease characterized by uncontrolled histiocytic proliferation. Interestingly, certain features of this re-excision specimen were still reminiscent of IgG4-RD, which not only reflects the difficulty in differentiating RDD from IgG4-RD in select cases, but also illustrates that these diagnoses may exist along a spectrum that likely reflects a common underlying pathogenetic mechanism. This case emphasizes the importance of surgical biopsy or resection and histopathological analysis in diagnosing-and, ultimately, treating-rare, systemic inflammatory diseases involving the orbit, and, furthermore, highlights the shared histopathological features between RDD and IgG4-RD.

BACKGROUND:Ecchordosis physaliphora (EP) is a congenital, uniformly asymptomatic, hamartomatous lesion of the primitive notochord. Herein we report, to our knowledge, the first credible case report of unprovoked intra-sphenoidal rupture resulting in recurrent pneumocephalus and cerebrospinal fluid (CSF) leak, definitively captured over serial imaging during clinical and radiologic surveillance. CASE DESCRIPTION/METHODS:A 68-year old woman with Marfan syndrome presented to the Emergency Department with the worst headache of life. Imaging demonstrated extensive pneumocephalus and revealed a small, dorsal midline clival lesion consistent with EP and a trans-sphenoidal defect. Remote imaging encounters confirmed typical EP without pneumocephalus or cortical defect, and an uneventful clinical course years preceding presentation. Over the ensuing months during neurosurgical follow-up, the patient reported recurrent headaches, imbalance, and unprovoked clear rhinorrhea. Further imaging demonstrates an apparently enlarging trans-sphenoidal defect which was managed by endoscopic trans-nasal resection and nasoseptal flap. Pathologic evaluation confirmed the diagnosis of EP and chronic dural defect. CONCLUSIONS:This represents, to our knowledge, the first unambiguous example of spontaneous EP rupture and recurrent pneumocephalus captured over serial imaging. The case further underscores rare, but potentially significant complications of EP and highlights management options. BACKGROUND:. Herein we report, to our knowledge, the first documented spontaneous rupture of EP resulting in recurrent pneumocephalus, credibly captured over serial radiologic surveillance. CLINICAL PRESENTATION/METHODS:A 68 year-old woman with history of hypertension, hyperlipidemia, and Marfan syndrome presented to the Emergency Department reporting the "worst headache of her life" after engaging in an interpersonal dispute the evening preceding presentation.

Sudden unexplained death in childhood (SUDC) affects children >1-year-old whose cause of death remains unexplained following comprehensive case investigation and is often associated with hippocampal abnormalities. We prospectively performed systematic neuropathologic investigation in 20 SUDC cases, including (i) autopsy data and comprehensive ancillary testing, including molecular studies, (ii) ex vivo 3T MRI and extensive histologic brain samples, and (iii) blinded neuropathology review by 2 board-certified neuropathologists. There were 12 girls and 8 boys; median age at death was 33.3 months. Twelve had a history of febrile seizures, 85% died during apparent sleep and 80% in prone position. Molecular testing possibly explained 3 deaths and identified genetic mutations in TNNI3, RYR2, and multiple chromosomal aberrations. Hippocampal abnormalities most often affected the dentate gyrus (altered thickness, irregular configuration, and focal lack of granule cells), and had highest concordance between reviewers. Findings were identified with similar frequencies in cases with and without molecular findings. Number of seizures did not correlate with hippocampal findings. Hippocampal alterations were the most common finding on histological review but were also found in possibly explained deaths. The significance and specificity of hippocampal findings is unclear as they may result from seizures, contribute to seizure pathogenesis, or be an unrelated phenomenon.

BACKGROUND:Spinal epidural lipomatosis (SEL) is a rare condition defined as pathological overgrowth of the normally present epidural fat within the spinal canal. SEL is associated with Cushing disease, obesity and chronic corticosteroid therapy. Diabetes mellitus type 1 (DM1) has not known to be a risk factor for SEL. The neurological symptoms of SEL are attributed mainly to mechanical compression on the spinal cord and the cauda equina. METHODS:A retrospective chart review of patients evaluated at NYU Multiple Sclerosis Care Center identified three diabetic patients with progressive myelopathy associated with SEL. We report the clinical course, diagnostic workup and outcomes in these three patients with SEL-associated myelopathy. RESULTS:Three patients (2 females and 1 male) had long-standing DM1 and developed progressive myelopathy in their early 40's. All were found to have thoracic SEL (extensive extradural T1, T2 hyperintense signal; biopsy confirmed in one case) with associated extensive abnormal cord signal in lower cervical/upper thoracic spinal cord. A comprehensive evaluation for metabolic, infectious, autoimmune and vascular causes of myelopathy that included serologies, cerebrospinal fluid analyses, and spinal angiography did not reveal an alternative cause for myelopathy. One of the patients underwent a surgical decompression of SEL with subsequent clinical and radiologic improvement. CONCLUSIONS:Our case series suggest that patients with DM1 and myelopathy of unknown cause should be evaluated for SEL. Timely diagnosis and appropriate intervention may forestall progression of neurological disability and even result in neurologic improvement. SEL should be considered on the short list of diagnoses that cause potentially reversible progressive myelopathy.

The following fictional cases are intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.¹.

ROS1 is a transmembrane receptor tyrosine kinase proto-oncogene that has been shown to have rearrangements with several genes in glioblastoma and other neoplasms, including intrachromosomal fusion with GOPC due to microdeletions at 6q22.1. ROS1 fusion events are important findings in these tumors, as they are potentially targetable alterations with newer tyrosine kinase inhibitors; however, whether these tumors represent a distinct entity remains unknown. In this report, we identify 3 cases of unusual pediatric glioma with GOPC-ROS1 fusion. We reviewed the clinical history, radiologic and histologic features, performed methylation analysis, whole genome copy number profiling, and next generation sequencing analysis for the detection of oncogenic mutation and fusion events to fully characterize the genetic and epigenetic alterations present in these tumors. Two of 3 tumors showed pilocytic features with focal expression of synaptophysin staining and variable high-grade histologic features; the third tumor aligned best with glioblastoma and showed no evidence of neuronal differentiation. Copy number profiling revealed chromosome 6q22 microdeletions corresponding to the GOPC-ROS1 fusion in all 3 cases and methylation profiling showed that the tumors did not cluster together as a single entity or within known methylation classes by t-Distributed Stochastic Neighbor Embedding.

CONTEXT/BACKGROUND:X-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GH, IGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs. CASE DESCRIPTION/METHODS:The patient's mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For over 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During pre-conception planning, X-LAG was diagnosed: single-nucleotide polymorphism (SNP) microarray showed chromosome Xq26.3 microduplication. After conception, SNP microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother's pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and PIT1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and OCT4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index-5.6% (mother) and 8.5% (infant)-the highest reported in X-LAG. CONCLUSIONS:This is the first prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential.