Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Lipofibromatosis-like neural tumors: Report of a case and review of 73 reported cases.

Lipofibromatosis-like neural tumors (LPF-NTs) are a recently discovered group of spindle cell tumors defined by the presence of a lipofibromatosis-like pattern, CD34 and/or S100 reactivity, and frequent neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangements. As new cases emerge, the spectrum of features observed in LPF-NTs continues to evolve. Here we describe the case of an 11-year-old with LPF-NT with a dermatofibrosarcoma protuberans-like honeycomb pattern, CD34 and S100 co-expression, and an NTRK1 rearrangement. We also review the clinical and molecular features of the 73 cases of LPF-NT previously described in the literature.

Histopathologic Spectrum of Morphea.

ABSTRACT: Morphea is an autoimmune skin disease with protean clinical manifestations. Histologic features are similarly variable, and skin biopsies may be nondiagnostic. A single-institution retrospective cohort study was conducted. Morphea patients who had a biopsy in 2005-2015 were included, and a histopathological review was conducted by 2 pathologists. There were 51 biopsy specimens from 40 subjects. The most common histologic features were dermal sclerosis (90%), dermal thickening (78%), collagen homogenization (86%), a superficial and deep infiltrate (76%), a moderate-abundant inflammatory infiltrate (73%), and periadnexal fat loss/decreased skin appendages (71%). Twenty-four specimens were not diagnostic of morphea. In these specimens, the main clues to diagnosis included the presence of dermal sclerosis (79%), subtle collagen homogenization (75%), dermal thickening (58%), moderate-to-abundant plasma cells (50%), and perineural inflammation (50%). There were no statistically significant differences between active and inactive lesions, nor untreated and treated lesions. The histopathologic features of morphea are variable and a high proportion of biopsies are not diagnostic. Clinicians and pathologists should have a high degree of suspicion to correctly make the diagnosis of morphea.

A sixteen-year single-center retrospective chart review of Spitz nevi and spitzoid neoplasms in pediatric patients.

BACKGROUND: Spitzoid neoplasms in pediatric patients pose an interesting challenge for clinicians. More data on the clinical, histologic, and molecular characteristics of these lesions are necessary to distinguish features that may portend recurrence or malignant behavior to help determine future treatment guidelines in pediatric patients. METHODS: Institutional Review Board approval was obtained from Children's Hospital of Wisconsin to conduct a retrospective analysis of spitzoid neoplasms. Patients with biopsied or excised spitzoid neoplasms between 01/01/2000 and 08/01/2016 were included. Pertinent clinical and histologic data were collected. Atypical, unusual, or diagnostically uncertain lesions were selected for re-review. RESULTS: 266 lesions from 264 patients were included. 243 were classified as benign (91.35%), 22 as atypical (8.27%), and 1 as spitzoid melanoma (0.38%). No clinical or histologic variables were found to be statistically significant between the benign Spitz, atypical Spitz, and spitzoid melanoma cohorts. No known deaths occurred. CONCLUSION: Our findings highlight the extreme variability of spitzoid neoplasms clinically and histologically. Importantly, this study demonstrates that the vast majority of spitzoid neoplasms in pediatric populations are benign and supports conservative management of spitzoid lesions in children.

Desmoplastic fibroma associated with tuberous sclerosis: case report and literature review.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that affects the skin, brain, kidneys, and other organ systems. It may exhibit a wide spectrum of clinical manifestations. Desmoplastic fibroma (DF) of the jaw is a rare benign myofibroblastic neoplasm. Less than 10 cases of DF associated with TSC have been published previously. We report a new case of a maxillary DF in a 12-year-old girl with TSC. The presentation, diagnostic process, and management of this case are discussed, and the literature is reviewed for the additional cases of DF associated with TSC; 7 previously reported cases are summarized. Small sample size limits conclusions, but there may be differences in the presentations of DF of the jaws in patients with TSC vs those in the general population. DF of the jaws may be a manifestation of TSC, and the authors propose surveillance panoramic radiographs every 2 to 3 years in patients with TSC.

Traumatic rupture of a giant congenital splenic cyst presenting as peritonitis.

Splenic cysts are uncommon, with large cysts and complications being rare. We describe a 6-year-old patient who initially presented 1 day after falling onto her abdomen at the playground with worsening abdominal pain and distention. An ultrasound of the abdomen demonstrated free abdominal fluid in all four quadrants. A subsequent contrast-enhanced computed tomography scan of the abdomen and pelvis was performed which showed a large splenic cyst with open communication to the peritoneal cavity. A congenital primary cyst was confirmed on pathology after partial splenectomy was performed. Although the majority of splenic cysts are asymptomatic, rupture can lead to acute peritoneal signs and mimic other significant causes of abdominal pain such as viscous injury or acute appendicitis.

Modified Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy for Hepatoblastoma in a Small Infant: How Far Can We Push the Envelope?

: For patients with hepatoblastoma, a timely and complete resection of the tumor is critical to the patient's tumor recurrence-free survival. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), a 2-stage hepatectomy procedure, has revolutionized the surgical management of large hepatic tumors with insufficient future liver remnant (FLR) at presentation. Although existing data support the utility of ALPPS in adults with primary and metastatic hepatobiliary malignancy, the literature in children is scarce. To our knowledge, this is the first report showing clinical applicability and safety of the modified ALPPS procedure in a small infant (54 days old) with hepatoblastoma who presented with insufficient FLR. Our report suggests the modified ALPPS could potentially expand the surgical treatment alternative for small infants with large hepatoblastoma.

T-cell/histiocyte-rich large B-cell lymphoma in pediatric patients: an under-recognized entity?

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) under-recognized in the pediatric population. A meticulous workup is necessary to avoid a misdiagnosis of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) or classical Hodgkin lymphoma (HL). A strong degree of suspicion and an emphasis on immunohistochemical staining are required to reach the diagnosis. Few children with advanced stage disease have been described to date. We report two pediatric patients with high stage THRLBCL and highlight their clinical and pathological features.

Significant response to oral Etoposide in the treatment of an unresectable cardiac sarcoma.

Primary cardiac sarcomas are rare and carry a poor prognosis. The standard of care is complete resection. Outcomes for patients without complete resection are dismal, and the benefit of adjuvant therapy is uncertain. A 9-year-old girl presented with a large right-sided cardiac mass. After biopsy, the tumor was classified as an undifferentiated sarcoma. Resection was not feasible due to apparent invasion of the right ventricle and atrioventricular groove. Treatment with oral etoposide resulted in a 97% reduction in tumor volume and allowed for complete resection of residual tumor. She is alive with no evidence of disease 25 months from diagnosis.

Microcystic adnexal carcinoma: the first reported congenital case.

Microcystic adenexal carcinoma is a rare, locally aggressive, malignant appendage tumor also known as sclerosing sweat duct carcinoma. Since widespread recognition of microcystic adenexal carcinoma as a distinct clinicopathologic entity, approximately 300 total cases have been reported in the literature, with only eight previous cases reported in children under the age of 18, with no reported cases in patients younger than 6 years old. Our patient is unique in that the lesion was present at birth, making this the youngest case of microcystic adenexal carcinoma reported.

Marfan syndrome type II: there is more to Marfan syndrome than fibrillin 1.

Marfan syndrome is a well-described autosomal dominant syndrome with widely variable clinical manifestations. Cardiovascular complications include mitral valve prolapse with or without associated mitral valve insufficiency, aortic root dilatation, and most importantly the occasional development of aortic aneurysms or rupture. Given the inconsistent phenotype along with the potentially life-threatening implications, clinicians are increasingly turning to genetic testing for definitive diagnostic confirmation. It has been well established that mutations in the FBN1 gene encoding the structural protein Fibrillin 1 is the molecular etiology of Marfan syndrome. However, there are numerous patients who meet the Ghent clinical diagnostic criteria for Marfan syndrome who do not have identifiable FBN1 mutations. Recently, mutations in TGFBR1 and TGFBR2 (transforming growth factor beta receptors 1 and 2, respectively) have been shown to result in Loeys-Dietz syndrome, a connective tissue disorder with significant phenotypic overlap with Marfan syndrome. Individuals with this Marfanoid disorder lack the ocular findings of Marfan syndrome and often have dysmorphic features such as unusual facies, cleft palate, and contractures. In addition, Loeys-Dietz syndrome patients often present in childhood with significant cardiovascular problems. This article serves to report an illustrative case of Loeys-Dietz syndrome and reviews the phenotypic consequences of FBN1 and TGFBR1 and TGFBR2 gene mutations.

Bilateral lung transplant in Gauchers type-1 disease.

We report a case of a patient who received a bilateral lung transplant for end-stage lung disease secondary to Gauchers type-1 disease with no evidence of recurrence of the disease in the transplanted lung.

Sudden and unexpected fetal death associated with agenesis of the arcuate nucleus in the medulla oblongata.

Abnormalities have been reported in the medullary arcuate nucleus (ARCN) in unexpected late fetal death. They speculated that this developmental anomaly may underlie cardioventilatory abnormalities intrapartum and postpartum. This article describes a case of an unexpected late fetal death associated with absence of the ARCN.