Hyaline protoplasmic astrocytopathy in epilepsy.

Hyaline protoplasmic astrocytopathy (HPA) describes a rare histologic finding of eosinophilic, hyaline cytoplasmic inclusions in astrocytes, predominantly in the cerebral cortex. It has mainly been observed in children and adults with a history of developmental delay and epilepsy, frequently with focal cortical dysplasia (FCD), but the nature and significance of these inclusions are unclear. In this study, we review the clinical and pathologic features of HPA and characterize the inclusions and brain tissue in which they are seen in surgical resection specimens from five patients with intractable epilepsy and HPA compared to five patients with intractable epilepsy without HPA using immunohistochemistry for filamin A, previously shown to label these inclusions, and a variety of astrocytic markers including aldehyde dehydrogenase 1 family member L1 (ALDH1L1), SRY-Box Transcription Factor 9 (SOX9), and glutamate transporter 1/excitatory amino acid transporter 2 (GLT-1/EAAT2) proteins. The inclusions were positive for ALDH1L1 with increased ALDH1L1 expression in areas of gliosis. SOX9 was also positive in the inclusions, although to a lesser intensity than the astrocyte nuclei. Filamin A labeled the inclusions but also labeled reactive astrocytes in a subset of patients. The immunoreactivity of the inclusions for various astrocytic markers and filamin A as well as the positivity of filamin A in reactive astrocytes raise the possibility that these astrocytic inclusions may be the result of an uncommon reactive or degenerative phenomenon.

Neuropathology Evaluation of in Utero Correction of Myelomeningocele and Complications of Late-Onset GBS Infection.

Background: Myelomeningocele (MMC) causes significant morbidity and mortality. Efforts have been directed to correct this defect in utero. The neuropathology literature on antenatally repaired MMC and associated complications in humans is limited. Case report: A 12-day-old female, who underwent prenatal MMC repair via a two-layer closure (dural replacement patch, primary skin closure), was born at 34 weeks' gestation. Her group B streptococcus positive mother received appropriate antepartum prophylactic antibiotics. She remained stable until day 11 of life when she underwent rapid clinical deterioration. Despite aggressive intervention, she expired on day 12. Review of placental pathology showed maternal and fetal inflammatory response. Autopsy revealed Gram-positive cocci and inflammation within the basilar leptomeninges and lumbosacral region. Neural and dermal elements were present within the MMC repair. Conclusion: This case documents integration of the dermal matrix patch to neural elements, adhering the spinal cord to scar tissue, the clinical implications of which remain unclear.

Intraoperative Diagnosis for Pediatric Brain Tumors.

Central nervous system (CNS) tumors are now the most common type of solid tumor in individuals aged 0-19 years, with an incidence rate in the United States around 5 per 100,000, accounting for about 1 out of 4 childhood cancers. Pediatric pathologists encounter brain tumor cases with varying frequency, but many of these encounters begin in the context of intraoperative consultation or "frozen section." This review provides an overview of the technical aspects of intraoperative consultation specific to, or more helpful in, CNS tumors, emphasizing helpful cytologic and histologic features of the more commonly encountered pediatric CNS tumors, and illustrating some common diagnostic pitfalls and how these may be avoided.

Characterization of knee dysfunction and related risk factors during pregnancy.

BACKGROUND: Knee pain can be a common complaint during pregnancy; however, the severity of symptoms and their associated risk factors have not been described. QUESTIONS/PURPOSES: The aim of this study was to characterize knee-related dysfunction and describe risk factors in a general obstetric population. PATIENTS AND METHODS: Patients in obstetric clinics completed the International Knee Documentation Committee (IKDC) questionnaire to assess their knee function, as well as the Pregnancy Physical Activity Questionnaire (PPAQ), a validated tool to assess physical activity. Age, weeks gestation, height, weight, and history of knee problems prior to pregnancy were analyzed to identify independent associations with IKDC score and determine predictors of knee dysfunction. RESULTS: 310 patients were included in this study, of which 68, 111 and 131 were in their first, second and trimesters, respectively. Mean age of the total study group was 30.3 ± 5.5 years. Knee function decreased with each trimester, from a mean IKDC score of 88.9 ± 13.0 in the first trimester, 84.5 ± 16.8 in the second, and 82.0 ± 20.0 in the third, with corresponding decreases in activity levels of 258.5 ± 141.7, 254.0 ± 141.5, and 246.1 ± 156.6 MET-h/wk. Of the total study group, 26.1% had IKDC scores <75, including 13.2%, 25.2%, and 33.6% in the first, second and third trimesters. Risk factors for knee dysfunction included high activity levels of PPAQ ≥ 500 MET-h/wk (OR 2.8), history of knee problems (OR 2.7), age <25 years (OR 2.6), and BMI ≥ 30 kg/m2 (OR 1.9). CONCLUSION: In our cohort, 26.1% of pregnant women reported severe knee dysfunction, and this was associated with high levels of activity, younger age, greater BMI, and history of knee problems. These findings may have implications for women who wish to maintain training and fitness during pregnancy. Future studies are recommended to assess the need for intervention, as well as to identify optimal methods to prevent and address symptoms in this population. LEVEL OF EVIDENCE: IV, Case Series.

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.

Catastrophic congenital hemangioma with severe coagulopathy leading to fatal cardiac failure: Case report and review.

We present a complex case of a neonate, delivered urgently for hydrops fetalis, with a large vascular mass of the extremity, diagnosed postnatally as a congenital hemangioma. The patient suffered immediate cardiac compromise and severe coagulopathy atypical for the diagnosis and subsequently died from these complications. Treatment was imperative but challenging due to a lack of a standardized treatment approach and few historical reports of equally critically ill patients. In this report, we review potential medical and surgical interventions and discuss treatment considerations in similar, life-threatening cases of congenital hemangiomas.

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.

Cartilaginous Metaplasia Involving the Atrioventricular Node and Bundle of His Contributing to Sudden Early Neonatal Death.

Cartilaginous metaplasia involving the atrioventricular (AV) node is an uncommon entity that may cause sudden cardiac death secondary to dysrhythmias. We report 2 autopsy cases of full-term male newborns: 1 stillborn and 1 live-born, with antemortem bradycardia who died in the peripartum period. An examination of the cardiac conduction system in both cases demonstrated extensive cartilaginous metaplasia of the central fibrous body and involvement of the AV node and bundle of His. The cases highlight the recognition of cardiac conduction system anomalies as a cause of sudden perinatal death. In cases of perinatal death with preceding arrhythmia, postmortem sections of the cardiac conduction system are recommended to examine for cardiac conduction system anomaly.

Proliferative Index in Pediatric Pilocytic Astrocytoma by Region of Origin and Prediction of Clinical Behavior.

BACKGROUND/AIMS: Pilocytic astrocytomas are common pediatric tumors. Molecular profiles vary with location of origin. Comparisons of proliferation have not been reported. We sought to identify differences in growth by region and whether these predict clinical behavior. METHODS: A retrospective review of all patients undergoing surgery for a pilocytic astrocytoma at Children's Hospital LA from 2003 to 2015 was completed. Tumor location, determined by imaging, was stratified into infratentorial, supratentorial, or optic pathway. Proliferation was measured by Ki-67 immunostaining. A p value of 0.05 was deemed significant. RESULTS: 77 patients were identified. 51 had posterior fossa tumors, 12 had supratentorial tumors, and 14 had optic pathway tumors. Mean Ki-67 score was 3.67, 4.09, and 3.83%, respectively (p = 0.82). Ki-67 of ≥4% trended towards recurrence (p = 0.11), incomplete resection (p = 0.15), and younger age at presentation (p = 0.04). Ki-67 was weakly correlated with shorter survival after surgery (r = -0.103, p = 0.41). Partial resection strongest predicted recurrence (p < 0.001; OR = 13.0). CONCLUSION: Proliferative index does not change by location. Higher cell proliferation was seen in younger patients and associated with shorter time to and a higher risk of recurrence. Further study is needed to identify predictors for clinical behavior. Importance of Study: This study provides a detailed analysis of the proliferative indices of tumors arising from characteristic locations within the brain. With recent advances in our understanding of the differences in molecular and genetic profiles despite similar histologic diagnoses, we felt that it was important to review whether there were unique components of tumor behavior that could be identified. In turn, we sought to determine whether tumor behavior could be used to predict the clinical course. This knowledge is important, given that not every tumor may undergo complete surgical resection, and that some lesions may require more aggressive upfront adjuvant therapy or be closely monitored for recurrence.

Transmission of a TP53 germline mutation from unaffected male carrier associated with pediatric glioblastoma in his child and gestational choriocarcinoma in his female partner.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline alterations in the tumor suppressor gene TP53 LFS is associated with numerous malignancies including astrocytoma. Sanger sequencing and chromosomal microarray studies of blood and tumor tissue from a 4-yr-old boy with glioblastoma demonstrated a germline TP53 mutation with loss of heterozygosity for the short arm of Chromosome 17 as the second inactivating event in the tumor. There was no family history of LFS, but the child's mother had recently died from metastatic choriocarcinoma after antecedent normal term delivery of a then 6-mo-old daughter. The choriocarcinoma contained the same TP53 mutation detected in the proband and the 6-mo-old daughter was confirmed to be a carrier. Unexpectedly, the germline TP53 mutation was found to be inherited from the unaffected father. We report here the second genetically confirmed case of TP53-mutated choriocarcinoma in the partner of an LFS patient. Based on this case and recent literature, female partners of LFS patients may have increased risk of choriocarcinoma due to transmission of germline TP53 mutation from male carriers. Although the Toronto protocol has established an effective approach to detect tumors and improve survival in children and adults with LFS, there is a need to expand the current criteria to include surveillance of female partners of LFS patients for choriocarcinoma and other gestational trophoblastic disease. Recognition of this unique mode of transmission of TP53 mutations should be considered in genetic counseling for cancer risk assessment and family planning.

Bronchial Mucoepidermoid Carcinoma With the Classic MAML2 Gene Rearrangement in a 2-year-old Boy.

Pulmonary mucoepidermoid carcinoma (PMEC) is rare. To date, primary PMEC has not been reported in a child younger than 3 years of age. We report a case of a 2-year-old boy who presented with 3 episodes of wheezing, cough, and fever over a period of 1 month. Radiologic findings were consistent with foreign body aspiration with consequent bronchial obstruction. Bronchoscopy was performed and attempts to retrieve the foreign body resulted in a biopsy of a fleshy lesion. By histology, the lesion was an epithelial neoplasm comprising cells arranged in a nested pattern. The neoplastic cells were round with round nuclei and amphophilic, vacuolated cytoplasm. Our diagnosis was low-grade salivary gland-type carcinoma of the bronchus. The pneumonectomy specimen showed a well-circumscribed, polypoid intrabronchial mass measuring 2.1 cm in greatest dimension. Histologic examination of the tumor showed an admixture of intermediate cells which were predominant, a small number of mucus cells and rare foci of squamous cells. The final diagnosis rendered was a low-grade mucoepidermoid carcinoma of the bronchus. Accurate diagnosis of PMEC can be challenging on limited biopsy material as seen in the case reported here. The use of molecular studies such as MAML2 gene rearrangement may facilitate diagnosis in difficult cases. Increased awareness of this entity and further molecular studies are needed for a better understanding of the pathogenesis of PMEC. To date, the reported age range for primary bronchial mucoepidermoid carcinoma is between 3 years and 78 years. This case represents the youngest patient reported in the English literature.

Solitary Fibrous Tumors in Pediatric Patients: A Rare and Potentially Overdiagnosed Neoplasm, Confirmed by STAT6 Immunohistochemistry.

Pathological diagnosis of solitary fibrous tumor (SFT) in the pediatric population is challenging, as it occurs uncommonly in this age-group and resembles other spindle cell neoplasms. SFT contains a NAB2-STAT6 fusion gene, which can be reliably detected using STAT6 immunohistochemistry. Positive staining is highly sensitive and specific. We sought to investigate the utility of STAT6 immunohistochemistry, to show how commonly SFT was historically recognized at 3 academic pediatric institutions, to reclassify them when appropriate, and to demonstrate features of major mimics of SFT. Our series included cases with a previous diagnosis of SFT or for which SFT was among key considerations, from 3 major academic pediatric hospitals seen over the past 30 years. Of 18 tumors identified, only 3 tumors from 2 patients demonstrated positive STAT6 staining as well as the typical histology and immunophenotype seen in SFT. The remaining 15 tumors were reclassified based on morphology, additional immunohistochemistry and fluorescence in situ hybridization as desmoid-type fibromatosis (3 tumors), nerve sheath/neural tumors (3 tumors), low-grade fibromyxoid sarcoma, medallion-like dermal fibroma, poorly differentiated Sertoli cell tumor, nodular/proliferative fasciitis, calcifying fibrous tumor, aneurysmal bone cyst of soft tissue, STAT6-negative SFT with adipocytic differentiation, undifferentiated small round blue cell tumor, and scar (1 tumor each). Our study confirms that SFT is rare in the pediatric population and that it is potentially overdiagnosed. STAT6 immunohistochemistry is recommended to confirm the diagnosis of SFT in the pediatric population.

Quadruple Neoplasms following Radiation Therapy for Congenital Bilateral Retinoblastoma.

PURPOSE: The aim of this study was to describe a 34-year-old male with hereditary bilateral retinoblastoma treated with radiotherapy as a child who developed 4 distinct tumors within the radiation field. METHODS: A 34-year-old male with bilateral retinoblastoma status postradiation therapy and recurrence requiring enucleation presented with left-eye visual acuity changes. Magnetic resonance imaging demonstrated a left orbital mass and a right parasellar complex lobulated mass (right sphenoid and right cavernous sinus). Two weeks later, the patient underwent excision of the orbital mass and biopsy of an upper-lid nodule. This was followed by craniotomy for removal of the complex mass. RESULTS: Histology revealed 4 distinct tumors, including an undifferentiated pleomorphic sarcoma (left orbit), a radiation-induced meningioma (right sphenoid), a schwannoma (right cavernous sinus), and a basal-cell carcinoma (left lid). CONCLUSION: Although occurrence of a second neoplasm is a well-known outcome following radiation treatment in patients with hereditary retinoblastoma, the diagnosis of 4 additional neoplasms is rare. Pleomorphic sarcoma, radiation-induced meningioma, and schwannoma are uncommon tumors and not well represented in the literature describing irradiated retinoblastoma patients. Secondary malignancies are a leading cause of early death in retinoblastoma survivors, and long-term follow-up is crucial for patient care.

Iatrogenic Uterine Diverticulum in Pregnancy After Robotic-assisted Myomectomy.

Uterine diverticula are rare outpouchings of the uterus associated with abnormal uterine bleeding, pelvic pain, dysmenorrhea, and adverse obstetric events. At the time of cesarean delivery at 36 5/7 weeks' gestation during the patient's first pregnancy and 36 6/7 weeks during the second pregnancy, a fundal iatrogenic uterine diverticulum at the site of a prior robotic-assisted myomectomy was noted. The outpouching communicated with the endometrial cavity and was extremely attenuated, palpably 2 to 3 mm thick. Further research is needed to determine the incidence of iatrogenic uterine diverticulum after robotic myomectomy and whether these malformations increase the risk of adverse obstetric outcomes.

The relationship between previous treatment for cervical dysplasia and preterm delivery in twin gestations.

OBJECTIVE: To describe the impact of previous cervical surgery on preterm birth prior to 34 weeks in twins. METHODS: A retrospective review of twin pregnancies delivered between January 1998 and December 2005 at two institutions was performed. Women with a prior cold knife cone (CKC), loop electrosurgical excision procedure (LEEP), or ablative procedure were compared to a control group of women who had not undergone a previous treatment for cervical dysplasia. The primary outcome was delivery before 34 weeks of gestation. RESULTS: A total of 876 women met inclusion criteria. Of these, 110 (12.6%) had previous surgical procedures for cervical dysplasia, including CKC (n = 10), LEEP (n = 36), cryotherapy (n = 59) and CO2 laser treatment (n = 5). Delivery prior to 34 weeks was more common in women with a previous CKC compared to women with no prior treatment (40% versus 11.3%; odds ratio [OR], 3.6; 95% confidence interval [CI], 1.7-8.0). Delivery prior to 34 weeks was not more common in women with a previous LEEP (8.3%; OR, 0.8; 95% CI, 0.3-2.3) or ablative procedure (9.4%; OR, 0.9; 95% CI, 0.4-1.9) in comparison to the untreated group. Adjusting for the potential confounders of age, tobacco use, infertility treatments and previous preterm birth did not change the results. CONCLUSIONS: Previous CKC is associated with delivery prior to 34 weeks while LEEP and ablative procedures are not. CKC should be carefully considered and avoided when possible in reproductive age women.

Post-loop electrosurgical excision procedure sepsis in a human immunodeficiency virus-infected woman.

BACKGROUND: Squamous intraepithelial lesions are more prevalent in women infected with the human immunodeficiency virus (HIV) compared with immunocompetent women. Loop electrosurgical excision procedure (LEEP) is commonly used to treat squamous intraepithelial lesions because it may be performed as an outpatient procedure with minimal blood loss and a low complication rate. CASE: We report a major infectious post-LEEP complication in an HIV-infected female who had an uneventful LEEP in which a cellulose hemostatic agent was used. Despite the severity of the infection, she was successfully treated with a minor surgical procedure along with broad antibiotic coverage. CONCLUSION: Although a cellulose hemostatic agent contaminated with perineal secretions may have served as a nidus for infection, use of perioperative antibiotics or cervical cleansing should be considered to prevent sepsis in immunocompromised hosts.