PD-L1 and PD-1 expression in pediatric post-transplant Burkitt lymphoma and other monomorphic post-transplant lymphoproliferative disorders.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of immune suppression. Programmed death protein 1 (PD-1), a regulator of host immune activation, binds to programmed death-ligand 1 (PD-L1) to suppress the T-cell immune response. PD-1/PD-L1 pathway may play a role in PTLD. The objective was to describe intratumoral expression of PD-L1 and PD-1 in pediatric monomorphic PTLD, and assess if density of these cells is associated with progression-free survival (PFS) and overall survival (OS). PROCEDURE: Clinical variables and outcome data were collected on B-cell monomorphic PTLD treated in Toronto, Canada between 2000 and 2017. Diagnostic area from tumor tissue was identified to count CD3-positive or PD-1-positive cells and CD3-negative lymphoma B cells or PD-L1-positive cells. CD3+ , PD-1+ , and PD-L1+ cell densities were compared between cases of PTLD. OS and PFS were analyzed. RESULTS: We identified 25 cases of B-cell monomorphic PTLD; majority Burkitt lymphoma (32%) and diffuse large B-cell lymphoma (56%). All cases had CD3+ cells infiltrating the tumor, and median percentage of CD3+ cells was 14% (interquartile range: 6.2%-25%). Twelve cases (48%) had PD-1+ cell infiltrating (range: 1%-83%) and 13 cases (52%) had no PD-1+ cells infiltrating. Sixteen cases (64%) had PD-L1+ cells present; however, there was no PD-L1 expression on any Burkitt lymphoma tissue. When comparing PD-1 and PD-L1 expression, there was no difference in OS or PFS. CONCLUSION: Intratumoral presence of PD-1+ and PD-L1+ cells varied in pediatric patients with monomorphic PTLD; however, no relationship to OS and PFS was identified.

A Malignant Hepatoblastoma Mimicking a Benign Mesenchymal Hamartoma: Lessons Learned.

Differentiating hepatoblastomas from other congenital benign hepatic tumors is key to surgical management. We, herein, present an unusual case of an antenatally diagnosed liver lesion assessed in the neonatal period. Because of its predominantly cystic ultrasound/MRI appearance and borderline alpha-fetoprotein serum levels the diagnosis of mesenchymal hamartoma was favored and protocol-based tumor resection was performed. Due to the intraoperative diagnosis of a fetal subtype of hepatoblastoma with positive resection margins the child had to undergo a second laparotomy. This report raises awareness to an unusual appearance of hepatoblastoma and discusses noninvasive imaging clues to consider atypical appearances of hepatoblastoma preoperatively as they can have profound implications in patient management.

Pseudodiverticulum of the Cervical Esophagus With Remnant of Branchial Tissues in a Newborn: A Case Report.

Congenital pseudodiverticula of the esophagus are very rare. This case report describes the presentation, management and histopathology of a peudodiverticulum of the cervical esophagus in a neonate. The infant presented with respiratory distress and a right neck mass that required surgical excision. Pathology revealed a pseudodiverticulum that contained ectopic thymic, thyroid, and parathyroid tissue within the wall of the lesion. The presence of ectopic tissues of branchial origin and an aberrant right subclavian artery suggest an error in branchial development and neural crest cell migration.

A Novel Secondary Neoplasm Following Allogeneic Hematopoietic Stem Cell Transplant: Mixed Donor-Recipient Primitive Mesenchymal Proliferation of the Liver.

Post-hematopoietic stem cell transplant secondary solid neoplasms are uncommon and usually host-derived. We describe a 6-year-old female who developed a mixed donor-recipient origin mesenchymal stromal tumor-like lesion in the liver following an unrelated hematopoietic stem cell transplant complicated by severe graft-versus-host disease. This lesion arose early post-transplant in association with hepatic graft-versus-host disease. At 12 years post-transplant, the neoplasm has progressively shrunken in size and the patient remains well with no neoplasm-associated sequelae. This report characterizes a novel lesion of mixed origin post-transplant and offers unique insights into the contribution of bone marrow-derived cells to extra-medullary tissues.

Patterns and Predictors of Metastatic Spread to the Neck in Pediatric Thyroid Carcinoma.

OBJECTIVE: Evaluate patterns and predictors of spread to the neck in pediatric metastatic differentiated thyroid carcinoma (DTC). METHODS: Patients <18 years old undergoing thyroidectomy by a single surgeon from January 2015 to December 2019 were included. Neck sublevels were removed separately according to AJCC boundaries. Clinical outcomes included nerve injury, hypocalcemia, hematoma, and residual tumor. RESULTS: Forty-eight children underwent thyroid surgery. Thirty (63%) were for malignancy, 27 (90%) of which were DTC. Nineteen (70%) patients with DTC underwent 24 neck dissections; 19 central plus lateral and 5 central alone. The female to male ratio increased from 1:1 to 3:1 with age. Two children with lateral neck involvement had sub-centimeter primaries. Patients requiring neck dissection were more likely to have 1) diffuse sclerosing or tall cell variant, 2) T3 or T4 disease, 3) genetic mutation, 4) lymphatic invasion, 5) extracapsular extension, 6) positive resection margin. Levels IIA (79%), III (89%), IV (84%), VI (100%) were most commonly involved. Levels IB (16%), IIB (16%), VB (16%) were also involved, often without involvement of adjacent levels. Permanent injuries included one unilateral recurrent laryngeal nerve, one mild marginal mandibular nerve and one mild accessory nerve. Hypocalcemia was highest following neck dissection for malignant disease. One patient was re-operated for a mediastinal node. Most patients with N1 disease received radioactive iodine. Most patients have no evidence or indeterminate disease on long-term follow-up. CONCLUSION: Children with lateral nodal spread from DTC should be considered for neck dissection including Levels IB, IIA, IIB, III, IV, VB, bilateral VI. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1002-E1009, 2021.

Utility of sonography for identifying metastatic cervical adenopathy in children with differentiated thyroid carcinoma at presentation.

BACKGROUND: No study has evaluated the diagnostic accuracy of sonography for the depiction of metastatic cervical adenopathy in children with differentiated thyroid carcinoma at presentation or determined which sonographic features are most useful. OBJECTIVE: To evaluate the diagnostic accuracy of sonography for identifying metastatic cervical adenopathy in children with differentiated thyroid carcinoma at presentation and to determine the most useful sonographic features. MATERIALS AND METHODS: We evaluated cervical lymph node sonography and histology in children with proven thyroid carcinoma in a 10-year period. We excluded children in whom a preoperative sonogram was not available and those who did not have surgical resection of lymph nodes. We used histology as the gold standard. On sonography, we analyzed the size, shape, echotexture and vascularity of the lymph nodes and correlated these findings with the histology. RESULTS: We reviewed sonograms and histology of resected lymph nodes in 52 children and adolescents with proven differentiated thyroid carcinoma (33 females; ages 5-18 years, mean 13.2 years). Metastatic cervical lymph node disease was proved on histology in 33/52 (64%) of our patients at presentation. Sonographic findings correctly predicted whether the nodes were histologically involved with metastatic disease in 42/52 (81%). Sensitivity of sonography was 79%, specificity 84%, positive predictive value (PPV) 90%, negative predictive value (NPV) 70% and accuracy 81%. A significant association was seen between round shape (P=0.0002), abnormal echotexture (P≤0.0001) and vascularity (P≤0.0001), and abnormal lymph node histology. Importantly, in 11/26 (47%) patients with sonographic and histologically proven abnormal nodes, the nodes were normal in size and shape and the presence of metastatic involvement was recognized sonographically only on the basis of abnormal echogenicity and vascularity. CONCLUSION: Sonography has a high accuracy, specificity and PPV for identifying metastatic cervical lymph node involvement in children with differentiated thyroid carcinoma at presentation. Most of the abnormal lymph nodes were round in shape and had abnormal echogenicity and vascularity. Importantly, this paper emphasizes that in children, nodes with histologically proven metastases from differentiated thyroid carcinoma can be normal in size and shape. In these patients the presence of metastatic involvement might be recognized sonographically only on the basis of abnormal echogenicity and vascularity.

Posttransplant Lymphoproliferative Disorder in Pediatric Patients: Characteristics of Disease in EBV-seropositive Recipients.

BACKGROUND: Patients at greatest risk of posttransplant lymphoproliferative disorder (PTLD) are those who acquire primary Epstein-Barr virus (EBV) infection after solid organ transplantation. The incidence of PTLD among patients who are EBV-seropositive before transplant is lower, and little is known about the differences in presentation and outcome of this population. We describe the characteristics of EBV-seropositive transplant recipients (R+) who developed PTLD and compare survival outcomes with EBV-seronegative recipients (R-). METHODS: A hospital-based registry was used to identify all patients with biopsy-proven PTLD for the period 2000-2014. Characteristics and outcomes were compared between R+ and R- patients with PTLD. RESULTS: Sixty-nine patients were included, among which 20 (29.0%) were R+ and 49 (71.0%) were R-. Multiorgan transplant patients accounted for 25% of PTLD cases in R+ patients, while accounting for only 2.1% of all transplants during the study period. There was no difference in PTLD site between R+ and R- patients. PTLD among R+ individuals occurred during the second year after transplant (median: 1.92; range: 0.35-3.09 y) compared with during the first year for R- individuals (median: 0.95; range: 0.48-2.92 y; P = 0.380). There was a trend for a higher overall mortality among R+ individuals (log rank: 0.09). PTLD-related mortality did not differ between R+ and R- individuals (log rank: 0.17). CONCLUSIONS: PTLD among R+ individuals was more likely to occur among multiorgan recipients, and there was a tendency for poorer outcomes at 1 and 5 years after the diagnosis of PTLD.

Posttransplant lymphoproliferative disorder in pediatric patients: Survival rates according to primary sites of occurrence and a proposed clinical categorization.

Posttransplant lymphoproliferative disorder (PTLD) is a devastating complication of organ transplant. In a hospital-based registry, we identified biopsy-proven cases of PTLD among children during a 15-year period and reviewed trends in PTLD rates, the sites of involvement, and the associated survival rates. Cases that were included had at least 1 year of follow-up after the diagnosis of PTLD. We studied 82 patients with first-episode PTLD. Median age at diagnosis was 6.4 years (IQR 3.2-12.3 years). The most frequent PTLD sites were tonsillar/adenoidal (T/A [34%]) and gastrointestinal (32%), followed by miscellaneous (defined as less common sites including central nervous system, kidney, lung, and soft tissue [12%]), lymph node (11%), and multisite (11%). Kaplan-Meier survival curves showed that T/A PTLD was associated with decreased all-cause mortality compared with PTLD at other sites (log-rank 0.004), even after adjustment for histological subtype (P = .047). PTLD-related mortality was also decreased among T/A PTLD (log-rank 0.012) but showed a trend toward significance only after adjustment for histological subtype (P = .09). Among first episodes of PTLD, T/A PTLD was associated with a survival advantage compared with PTLD at other sites, even after adjustment for potential confounders. Based on our observations, we propose a clinical categorization of PTLD according to anatomical site of occurrence.

Epididymal melanotic neuroectodermal tumor of infancy: A rare cause of scrotal mass in an infant.

Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, benign neoplasm of neural crest origin more commonly seen in the craniofacial region. We report a case of MNTI of the epididymis in a 6-month-old male child with emphasis on the sonographic appearance which has not been previously described. In this case, the mass was inseparable from the testicle and therefore the differential diagnosis considered both extratesticular and intratesticular masses. MNTI should be added to the differential diagnosis of scrotal masses, particularly if they present in a child younger than 12 months of age.

Thyroglossal duct cysts in children: Sonographic features every radiologist should know and their histopathological correlation.

Distinguishing between thyroglossal duct cysts (TGDC) and dermoid cysts (DC) sonographically can be challenging. We illustrate the three sonographic features in neck masses in children recently identified as being most suggestive of TGDC (septa, irregular wall and solid elements) and their corresponding histopathology. These three variables form a proposed predictive model for TGDC as a guide to surgical intervention. Pediatric radiologists should be familiar with these key imaging features, as compared with other imaging features described in TGDC also illustrated here, which are less discriminating.

NUT midline carcinoma of the larynx: an international series and review of the literature.

AIMS: NUT midline carcinoma (NMC) is a rare undifferentiated and aggressive carcinoma that locates characteristically to the midline of the head and neck, and mediastinum. NMC is characterized by chromosomal rearrangements of the gene NUT, at 15q14. The BRD4 gene on 19q13 is the most common translocation partner forming a fusion oncogene, BRD4-NUT. By the end of 2014, the International NUT Midline Carcinoma Registry had 48 patients treated for NMC. Laryngeal NMC are exceedingly rare, and we report a case series of seven cases. METHODS AND RESULTS: We searched for cases in files of different hospitals as well as a thorough search of the English language literature. The diagnosis of NMC is made by demonstration of NUT rearrangement either by immunohistochemistry, fluorescence in-situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR). We found three previously published cases, and in this series add four cases of our own. CONCLUSIONS: NMC consists of monomorphic, often discohesive, cells with an epithelioid appearance and distinct nucleoli. The tumours typically show abrupt squamous differentiation. The mean age of the patients was 34 years, hence significantly lower than that for conventional laryngeal carcinoma. All tumours were located in the supraglottis and five patients died of the disease after 3, 7, 8, 9 and 11 months. Laryngeal NMC may be underdiagnosed, and an increased awareness among pathologists is warranted. NMC has characteristic morphological features, and positive immunostaining with the NUT antibody is diagnostic. Its aggressive behaviour demands a very intense treatment strategy and the need for its recognition is emphasized further by new promising treatment strategies.

Imaging of childhood angiomatoid fibrous histiocytoma with pathological correlation.

BACKGROUND: Angiomatoid fibrous histiocytoma is a rare soft-tissue tumor that more often affects children and young adults. There is little information available regarding the imaging appearance of angiomatoid fibrous histiocytoma in children. OBJECTIVE: To describe the ultrasonographic (US) and magnetic resonance (MR) imaging findings of angiomatoid fibrous histiocytoma in children. MATERIALS AND METHODS: A retrospective analysis was done of US and MR imaging findings in children with angiomatoid fibrous histiocytoma. Clinical findings and histopathology with molecular analysis results were also collected. RESULTS: There were 7 children with angiomatoid fibrous histiocytoma with a median age of 6 years (age range: 16 months-14 years). Patients presented clinically with a soft-tissue mass in the extremities or in the trunk. Four children had anemia, and three of them had additional systemic symptoms. Two patients had US and three had MR imaging while the remaining two had both. Lesion size ranged from 1.3 cm to 7.2 cm. In four patients, angiomatoid fibrous histiocytoma presented as a nonspecific predominantly solid mass. The other three patients had a combination of the following imaging findings: intralesional blood-filled cystic spaces with fluid-fluid levels, enhancing fibrous pseudocapsule and hemosiderin deposition. These findings correlated well with histopathology. CONCLUSION: The imaging detection of intralesional blood-filled cystic spaces with fluid-fluid levels, enhancing fibrous pseudocapsule and hemosiderin deposition in a soft-tissue tumor in a child may suggest the diagnosis of angiomatoid fibrous histiocytoma. A history of systemic symptoms and anemia in the presence of a soft-tissue mass may also be a clue for the diagnosis of angiomatoid fibrous histiocytoma.

A case of pancreatitis, panniculitis and polyarthritis syndrome: Elucidating the pathophysiologic mechanisms of a rare condition.

Pancreatitis-Panniculitis-Polyarthritis (PPP) syndrome is rare and its physiopathology unclear. A 6-year old boy suffered of traumatic pancreatitis complicated by PPP syndrome. Extensive investigations demonstrated high levels of pancreatic lipase and fatty acids in the affected peripheral tissues. These findings support the sequence of peripheral lipolysis and fatty acid accumulation inducing tissue inflammation.

Primary conjunctival anaplastic large cell lymphoma in a child.

Conjunctival tumors in children are uncommon and behave differently from those in adults. The vast majority of tumors are benign. Of the malignant lesions in this age group, lymphoma and melanoma are most commonly reported. Most lymphoid tumors in children represent lymphoid hyperplasia, not lymphoma. Clinical differentiation of these two entities is not possible and biopsy is required to establish the diagnosis. We present an unusual case of primary anaplastic large cell lymphoma of the conjunctiva in a young boy.

Glatiramer acetate-induced acute hepatotoxicity in an adolescent with MS.

Glatiramer acetate (GA), a synthetic copolymer, is a frequently used first-line treatment for relapsing-remitting multiple sclerosis (RRMS). Probable autoimmune hepatotoxicity during GA treatment has been reported,(1-4) but GA hepatotoxicity in the absence of positive autoimmune markers has not previously been described. Here, we report GA-induced hepatotoxicity in a pediatric patient with multiple sclerosis (MS).

A solitary tonsil can cause severe obstructive sleep apnea.

Hypertrophy of the tonsils and adenoids is the most common cause of pediatric obstructive sleep apnea. Bilateral tonsillectomy, most commonly performed with adenoidectomy, is the accepted treatment for obstructive sleep apnea. We report the unusual case of a child who underwent unilateral tonsillectomy and adenoidectomy at another institution and subsequently presented to us with persistent severe obstructive sleep apnea and a diagnosis of attention deficit hyperactivity disorder. The adenoids were not obstructing the choanae. The remaining tonsil was removed and the patient's sleep apnea resolved. This is the first objectively documented report of a solitary tonsil causing severe obstructive sleep apnea (using polysomnography) that resolved after removal of the remaining tonsil.

Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection.

Recent genetic-based studies have implicated a number of immune-related genes in the pathogenesis of inflammatory bowel disease (IBD). Our recent genetic studies showed that RAC2 is associated with human IBD; however, its role in disease pathogenesis is unclear. Given Rac2's importance in various fundamental immune cell processes, we investigated whether a defect in Rac2 may impair host immune responses in the intestine and promote disease in the context of an infection-based (Citrobacter rodentium) model of colitis. In response to infection, Rac2(-/-) mice showed i) worsened clinical symptoms (days 13-18), ii) increased crypt hyperplasia at days 11 and 22 (a time when crypt hyperplasia was largely resolved in wild-type mice; WT), and iii) marked mononuclear cell infiltration characterized by higher numbers of T (CD3(+)) cells (day 22), compared to WT-infected mice. Moreover, splenocytes harvested from infected Rac2(-/-) mice and stimulated in vitro with C. rodentium lysate produced considerably higher levels of interferon-γ and interleukin-17A. The augmented responses observed in Rac2(-/-) mice did not appear to stem from Rac2's role in NADPH oxidase-driven reactive oxygen species production as no differences in crypt hyperplasia, nor inflammation, were observed in infected NOX2(-/-) mice compared to WT. Collectively, our findings demonstrate that Rac2(-/-) mice develop more severe disease when subjected to a C. rodentium-induced model of infectious colitis, and suggest that impaired Rac2 function may promote the development of IBD in humans.

Nested stromal epithelial tumor of the liver in Beckwith-Wiedemann syndrome.

ABSTRACT Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by overgrowth, congenital malformation, and tumor predisposition. Children with BWS have a higher incidence of tumors, commonly intra-abdominal tumors such as Wilms tumor, hepatoblastoma, and adrenal cortical carcinoma. Here, we describe the first case of a rare hepatic malignancy of nested stromal epithelial tumor (NSET) of the liver in a child with BWS. A 22-month old girl with BWS had a new incidental liver mass. Her alpha-fetoprotein levels were normal. She underwent a liver segmentectomy. Histopathologic features combined with immunohistochemistry results (positivity for pankeratin [AE1/3], CD56, CK19, CD117, CD99 [weak membranous pattern], ß-catenin, and WT1-COOH [focal]), were diagnostic of NSET of the liver. This is the first case of NSET of the liver associated with BWS. Its occurrence at such an early age is consistent with the tumor predisposition of BWS.

Progressive transformation of germinal centers in children and adolescents: an intriguing cause of lymphadenopathy.

BACKGROUND: The clinical implications of a diagnosis of progressive transformation of germinal centers (PTGC) in children are not well known. METHODS: To better understand this entity, we conducted a retrospective review of all patients aged 0-18 years diagnosed with PTGC at our center between 1998 and 2010. RESULTS: Twenty-nine patients were identified. Median age at diagnosis was 11.5 years, and median duration of follow-up was 2.8 years. Thirteen patients (45%) had a single episode of PTGC with no other associated features. Five patients (17%) had recurrent PTGC. Four patients (14%) had PTGC associated with Hodgkin lymphoma (HL): one preceding, two concurrent, and one subsequently developed HL. The most commonly associated HL was nodular lymphocyte-predominant HL. Seven patients (24%) had PTGC associated with immune disorders, including lupus, Castleman disease, and probable autoimmune lymphoproliferative syndrome. Overall, 15 patients (52%) had more than one lymph node biopsy. The cumulative incidence of a second biopsy after a diagnosis of PTGC was 42.3% ± 12.2% at 4 years. PTGC was PET-avid in all four patients tested. CONCLUSIONS: PTGC is a nonspecific manifestation of a variety of associated conditions. There is a small risk of subsequent HL, and a larger risk of requiring multiple biopsies for recurrent PTGC. The presence of an immune disorder should be considered in patients who present with generalized lymphadenopathy, splenomegaly, immune cytopenias, and/or progression to HL. Routine surveillance imaging may not be required. Future research should determine the optimal surveillance strategy for patients with PTGC and the indications for repeat biopsies.

Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis.

BACKGROUND & AIMS: RAC1 is a guanosine triphosphatase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases are associated with dysregulation of immune defenses. We studied the role of RAC1 in inflammatory bowel diseases using human genetic and functional studies and animal models of colitis. METHODS: We used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 messenger RNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulfate sodium. RESULTS: We observed a genetic association between RAC1 with ulcerative colitis in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the single nucleotide polymorphisms rs10951982 (P(combined UC) = 3.3 × 10(-8), odds ratio = 1.43 [95% confidence interval: 1.26-1.63]) and rs4720672 (P(combined UC) = 4.7 × 10(-6), odds ratio = 1.36 [95% confidence interval: 1.19-1.58]). Patients with inflammatory bowel disease who had the rs10951982 risk allele had increased expression of RAC1 compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected against dextran sulfate sodium-induced colitis. CONCLUSIONS: Human studies and knockout mice demonstrated a role for the guanosine triphosphatase RAC1 in the development of ulcerative colitis; increased expression of RAC1 was associated with susceptibility to colitis.