Cytogenetic signatures of recurrent pregnancy losses.

OBJECTIVES: To investigate the incidence of chromosomal abnormalities in the products of conception (POC) of patients with spontaneous miscarriages (SM) and with recurrent pregnancy losses (RPL) and to determine biological mechanisms contributing to RPL. METHODS: During a 20-year period, 12 096 POC samples underwent classical chromosome analysis. Cytogenetic findings were compared between the SM and RPL cohorts. RESULTS: Analysis of RPL cohort has identified an increased incidence of inherited and de novo structural chromosome abnormalities, recurrent polyploid conceptions, and complex mosaic alterations. These abnormalities are the signature of genomic instability, posing a high risk of genetic abnormalities to offspring independent of maternal age. Predominance of male conceptions in the RPL cohort points toward an X-linked etiology and gender-specific intolerance for certain genetic abnormalities. CONCLUSIONS: Our study showed several possible genetic etiologies of RPL, including parental structural chromosome rearrangements, predisposition to meiotic nondisjunction, and genomic instability. Loss of karyotypically normal fetuses might be attributed to defects in genes essential for fetal development, as well as aberrations affecting the X chromosome. Molecular studies of parental and POC genomes will help to identify inherited defects in genes involved in meiotic divisions and DNA repair to confirm our hypotheses, and to discover novel fetal-essential genes.

Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease.

Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature.

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions.

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.

Langerhans cell histiocytosis and Erdheim-Chester disease, both with cutaneous presentations, and papillary thyroid carcinoma all harboring the BRAF(V600E) mutation.

Langerhans cell histocytosis (LCH) and Erdheim-Chester disease are two rare histiocytic disorders. Their occurrence in the same patient is more infrequent, but has been described. We report a case of a 38-year-old woman who presented with a diagnosis of single system cutaneous LCH. Subsequently, she developed multiple papules on her extremities consistent with a non-LCH xanthogranuloma type lesion. BRAF(V600E) mutation immunostain, VE1 was positive in the skin lesion, which was confirmed by molecular polymerase chain reaction (PCR) studies, initiating a complete systemic workup for Erdheim-Chester disease. Systemic involvement was confirmed with bilateral sclerotic bone lesions and retroperitoneal and pelvic fibrosing disease. She was also found to have a BRAF(V600E) mutation positive papillary thyroid carcinoma. New suspicious cutaneous lesions presenting in patients with a history of LCH need to be biopsied. A BRAF(V600E) mutation in a non-LCH histiocytic lesion with a xanthogranuloma phenotype (CD163/CD68/CD14/fascin/Factor 13a) should prompt an Erdheim-Chester disease workup. This is a unique case of a woman with BRAF(V600E) mutation positive Erdheim-Chester disease and cutaneous LCH, while also being, to our knowledge, the first reported case in the English literature of it occurring in a patient with a BRAF(V600E) mutation positive papillary thyroid carcinoma.

Clinical considerations and key issues in the management of patients with Erdheim-Chester Disease: a seven case series.

BACKGROUND: Erdheim-Chester Disease (ECD), a non Langerhans' cell histiocytosis of orphan nature and propensity for multi-systemic presentations, comprises an intricate medical challenge in terms of diagnosis, treatment and complication management. OBJECTIVES: The objectives are to report the clinical, radiological and pathological characteristics, as well as cardinal therapeutic approaches to ECD patients and to provide clinical analyses of the medical chronicles of these complex patients. METHODS: Patients with biopsy proven ECD were audited by a multi-disciplinary team of specialists who formed a coherent timeline of all the substantial clinical events in the evolution of their patients' illness. RESULTS: Seven patients (five men, two women) were recruited to the study. The median age at presentation was 53 years (range: 39 to 62 years). The median follow-up time was 36 months (range: 1 to 72 months). Notable ECD involvement sites included the skeleton (seven), pituitary gland (seven), retroperitoneum (five), central nervous system (four), skin (four), lungs and pleura (four), orbits (three), heart and great vessels (three) and retinae (one). Prominent signs and symptoms were fever (seven), polyuria and polydipsia (six), ataxia and dysarthria (four), bone pain (four), exophthalmos (three), renovascular hypertension (one) and dyspnea (one). The V600E BRAF mutation was verified in three of six patients tested. Interferon-α treatment was beneficial in three of six patients treated. Vemurafenib yielded dramatic neurological improvement in a BRAF mutated patient. Infliximab facilitated pericardial effusion volume reduction. Cladribine improved cerebral blood flow originally compromised by perivenous lesions. CONCLUSIONS: ECD is a complex, multi-systemic, clonal entity coalescing both neoplastic and inflammatory elements and strongly dependent on impaired RAS/RAF/MEK/ERK signaling.

Successful treatment of pediatric histiocytic sarcoma using abbreviated high-risk leukemia chemotherapy.

Histiocytic sarcoma (HS) is a malignant tumor composed of proliferating cells of histiocytic origin. True HS is exceedingly rare, particularly in pediatric patients. These tumors are frequently aggressive, and outcome for patients with HS has traditionally been poor. There is currently no consensus on the optimal management of these tumors, with the literature consisting largely of case reports and small case series utilizing a wide variety of therapies. We describe a case of HS in an 8-year-old female who was successfully treated with an abbreviated leukemia chemotherapy regimen.

Langerhans cell sarcoma: case report and review of world literature.

Langerhans cell sarcoma is a rare malignancy with only 1 pediatric case (less than 15 y of age) reported. Here, we report the second case of Langerhans cell sarcoma in a child who presented with cord compression. This patient was treated with extensive surgical resection, postoperative chemotherapy, and involved-field radiation therapy. She completed therapy and remains in remission for 27 months. A review and analysis of all 53 cases published in the world literature is provided to help guide physicians treating this disease. Recently discovered genetic mutation involving BRAF is also discussed.

Bullous Sweet's syndrome after granulocyte colony-stimulating factor therapy in a child with congenital neutropenia.

We present the case of a 20-month-old boy with congenital neutropenia for which he was being treated with granulocyte colony-stimulating factor (G-CSF) who developed bullous Sweet's syndrome. Because of the challenging and extensive differential diagnosis of an acute bullous eruption in an immunocompromised child, we highlight the importance of a prompt and precise diagnosis before initiation of any systemic therapy in children with Sweet's syndrome.

Optic pathway glioma as part of a constitutional mismatch-repair deficiency syndrome in a patient meeting the criteria for neurofibromatosis type 1.

Patients with constitutional mismatch repair-deficiency (CMMR-D) caused by the biallelic deletions of mismatch repair (MMR) genes have a high likelihood of developing malignancies of the bone marrow, bowel, and brain. Affected individuals often have phenotypic features of neurofibromatosis type 1 (NF-1), including café-au-lait spots. Optic pathway gliomas (OPGs), a common manifestation of NF-1, have not been reported. We report the case of a 3-year-old male with an extensive OPG who met the diagnostic criteria for NF-1. He was subsequently found to have multiple colonic polyps and bi-allelic loss of PMS2. Testing for NF-1 was negative.

Increased expression of peripheral blood leukocyte genes implicate CD14+ tissue macrophages in cellular intestine allograft rejection.

Recurrent rejection shortens graft survival after intestinal transplantation (ITx) in children, most of whom also experience early acute cellular rejection (rejectors). To elucidate mechanisms common to early and recurrent rejection, we used a test cohort of 20 recipients to test the hypothesis that candidate peripheral blood leukocyte genes that trigger rejection episodes would be evident late after ITx during quiescent periods in genome-wide gene expression analysis and would achieve quantitative real-time PCR replication pre-ITx (another quiescent period) and in the early post-ITx period during first rejection episodes. Eight genes were significantly up-regulated among rejectors in the late post-ITx and pre-ITx periods, compared with nonrejectors: TBX21, CCL5, GNLY, SLAMF7, TGFBR3, NKG7, SYNE1, and GK5. Only CCL5 was also up-regulated in the early post-ITx period. Among resting peripheral blood leukocyte subsets in randomly sampled nonrejectors, CD14(+) monocytes expressed the CCL5 protein maximally. Compared with nonrejectors, rejectors demonstrated higher counts of both circulating CCL5(+)CD14(+) monocytes and intragraft CD14(+) monocyte-derived macrophages in immunohistochemistry of postperfusion and early post-ITx biopsies from the test and an independent replication cohort. Donor-specific alloreactivity measured with CD154(+) T-cytotoxic memory cells correlated with the CCL5 gene and intragraft CD14(+) monocyte-derived macrophages at graft reperfusion and early post-ITx. CCL5 gene up-regulation and CD14(+) macrophages likely prime cellular ITx rejection. Infiltration of reperfused intestine allografts with CD14(+) macrophages may predict rejection events.

Post-transplant Burkitt lymphoma is a more aggressive and distinct form of post-transplant lymphoproliferative disorder.

BACKGROUND: Although the literature reports a low incidence of Burkitt lymphoma (BL) as a post-transplant lymphoproliferative disorder (PTLD), this entity appears to be different from other monomorphic PTLDs (M-PTLDs), both in its aggressive clinical presentation and its distinct pathologic profile. METHODS: Patients with BL, diagnosed in the post-transplant setting, (patients aged ≤ 18 years) were retrieved from the pathology archives at Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center from 1982 to 2010. Clinical outcomes were obtained along with pathologic review. RESULTS: Twelve patients with pediatric BL in the post-transplant setting (9 boys, 3 girls) were retrieved. The patients displayed a monomorphic population of small to intermediate-sized, noncleaved, lymphoid elements with a "starry-sky" pattern. The immunophenotype for patients available to the study was CD20+ (n = 9/10), CD10+ (n = 8/8), bcl-6+ (n = 11/11), with a near 100% Ki-67/MIB-1 proliferation index (n = 7/7), and negative for TdT (n = 7/7). Most pretransplant Epstein-Barr virus titers were negative (n = 8/10), with post-transplant titers positive in all tested patients (n = 11), and with positive Epstein-Barr-encoded RNA in situ hybridization in most cases (n = 9/11). The median time from transplantation to diagnosis was 52 months (range, 6-107 months). Nine patients were currently alive after immediate antineoplastic chemotherapy, with median disease-free time of 93 months from diagnosis (range, 2-199 months). CONCLUSIONS: BL-PTLD had a higher Epstein-Barr virus incidence compared with sporadic and immunodeficiency-associated BL and represented a distinct monomorphic PTLD. Although some M-PTLDs can be managed less aggressively with decreased immunosuppression alone, immediate lymphoma-specific chemotherapy was associated with a favorable outcome and was strongly recommended.

Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy.

BACKGROUND & AIMS: Pathologists participating in the National Institutes of Health-sponsored Biliary Atresia Research Consortium (BARC) developed and then evaluated a standardized system for histologic reporting of liver biopsies from infants with cholestasis. METHODS: A set of 97 anonymous liver biopsy samples was sent to 10 pathologists at BARC centers. A semiquantitative scoring system that had 16 histologic features was developed and then used by the pathologists, who had no knowledge of clinical history, imaging results, or laboratory data. Interobserver agreement was evaluated statistically. Agreement on scoring of each feature and on the pathologists' diagnosis, compared with the final clinical diagnosis, was evaluated by using weighted kappa statistics. RESULTS: There was moderate to substantial interobserver agreement in identification of bile plugs in ducts, giant-cell transformation, extramedullary hematopoiesis, and bile duct proliferation. The pathologists' diagnosis of obstruction in clinically proven cases of biliary atresia (BA) ranged from 79%-98%, with a positive predictive value of 90.7%. Histologic features that best predicted BA, on the basis of logistic regression, included bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis (each P<.0001). CONCLUSIONS: The BARC histologic assessment system identified features of liver biopsies from cholestatic infants, with good interobserver agreement, that might be used in diagnosis and determination of prognosis. The system diagnosed BA with a high level of sensitivity and identified infants with biliary obstruction with reasonable interobserver agreement. However, distinguishing between BA and disorders such as total parenteral nutrition-associated liver disease and alpha(1)-antitrypsin deficiency is not possible without adequate clinical information.

Prognostic scoring indices in Wilson disease: a case series and cautionary tale.

OBJECTIVES: In children with acute presentations of Wilson disease (WD), liver transplantation may be the only effective therapy. The Wilson Index is a prognostic index used to determine the risk of death without transplant in WD. We sought to determine the accuracy of this system in our own patient population. PATIENTS AND METHODS: The clinical course of patients diagnosed as having acute WD seen at the Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center between 2003 and 2008 was reviewed. RESULTS: Six patients were identified; their index scores ranged from 7 to 13, with 3 patients receiving a score predictive of death without transplantation (≥ 10). Of those 3, 1 underwent transplantation and 2 survived without transplant. The latter 2 have been removed from the transplant waitlist. In all, 5 patients were listed for transplantation, and 2 of the 5 received prioritized status 1A listing. Only 2 of the 5 patients went to transplantation, and neither was status 1A at the time of transplant. CONCLUSIONS: Prognostic scoring systems, although useful, may not be entirely accurate. Likewise, aggressive utilization of status 1 prioritization may result in unnecessary transplants and misallocation of a rare resource. However, deferring status 1 prioritization may yield an incomplete response to therapy and preclude lifesaving transplantation. Continued investigation of predictors of outcome in WD is necessary.

Cytomorphology of Erdheim-Chester disease presenting as a retroperitoneal soft tissue lesion.

Erdheim-Chester disease (ECD) is a rare, multisystem disorder of macrophages. Patients manifest with histiocytic infiltrates that lead to xanthogranulomatous lesions in multiple organ systems. The cytologic features of this disorder are not well characterized. As a result, the cytologic diagnosis of ECD can be very challenging. The aim of this report is to describe the cytomorphology of ECD in a patient presenting with a retroperitoneal soft tissue lesion. A 54-year-old woman with proptosis and diabetes insipidus was found on imaging studies to have multiple intracranial lesions, sclerosis of both femurs and a retroperitoneal soft tissue mass. Fine needle aspiration (FNA) and a concomitant core biopsy of this abnormal retroperitoneal soft tissue revealed foamy, epithelioid and multinucleated histiocytes associated with fibrosis. The histiocytes were immunoreactive for CD68, CD163, Factor XIIIa and fascin, and negative for S100, confirming the diagnosis of ECD. ECD requires a morphologic diagnosis that fits with the appropriate clinical context. This case describes the cytomorphologic features of ECD and highlights the role of cytology in helping reach a diagnosis of this rare disorder.

Epithelioid hemangioendothelioma of the middle ear in a child.

The differential diagnosis of middle ear masses encompasses a wide variety of pathologic conditions. In this report, we describe the case of a 6-year-old girl who presented with facial nerve weakness and was found to have a middle ear mass. The mass was excised, and final pathology revealed hemangioendothelioma. This report describes the youngest patient with this diagnosis presenting as a middle ear mass in the Western literature. This article provides this patient's presentation, imaging and histopathologic findings, and clinical course and reviews the current literature on this unique pathologic diagnosis.

Co-occurrence of Langerhans cell histiocytosis and Rosai-Dorfman disease: possible relationship of two histiocytic disorders in rare cases.

Rosai-Dorfman disease and Langerhans cell histiocytosis are both disorders of accessory immune cells. Two cases have been previously reported of concurrent Langerhans cell histiocytosis and Rosai-Dorfman disease. In this report, we characterize the findings and selected molecular studies in nine additional cases. Histology was reviewed. Immunohistochemical stains were performed on all cases in which slides or blocks were available. A combination of CD1a, S-100, CD3, CD20, langerin, CD68, CD163, CD21, CD35 and CD123 immunohistochemical stains were performed. High-resolution array comparative genomic hybridization was performed on six samples from five cases. In these cases, seven were female and two male, with an average age of 25 years (15 months-59 years). A majority of the cases were identified in lymph node. Areas of Langerhans cell histiocytosis had a typical appearance with the existence of bland 'coffee-bean' nuclei, clear cytoplasm and associated eosinophils. The immunophenotype was typical, including expression of CD1a, S100, CD68 and langerin. In areas of Rosai-Dorfman disease, there was emperipolesis seen in all cases. Cells were intermediate-large in size with large round nuclei and ample clear or pale cytoplasm. The lesional cells were positive for S100, CD68, CD163, without expression of langerin or CD1a. Array comparative genomic hybridization showed gains and/or losses in four of the six samples. One case showed no gains or losses and one additional case showed gains and losses in the Langerhans cell histiocytosis, while no abnormalities were discovered in the Rosai-Dorfman disease component. These findings are comparable to those seen in previous studies of Langerhans cell histiocytosis. We report the clinical and pathologic findings of the combination of Langerhans cell histiocytosis and Rosai-Dorfman disease. Furthermore, we suggest on the basis of evidence from our cases that, when simultaneous, the two entities may be pathophysiologically related.

Recurrent low gamma-glutamyl transpeptidase cholestasis following liver transplantation for bile salt export pump (BSEP) disease (posttransplant recurrent BSEP disease).

Bile salt export pump (BSEP) deficiency is a hereditary cholestatic syndrome that results from mutations in the ABCB11 (ATP-binding cassette B11) gene. Severely affected patients develop end-stage liver disease in the first decade of life. Liver transplantation has traditionally been thought of as curative for BSEP disease. We describe the clinical course of 6 patients who developed recurrent low gamma-glutamyl transpeptidase cholestasis, that mimicks BSEP disease, following transplantation. All had documented genetic defects in ABCB11 that were predicted to lead to a congenital absence of BSEP protein. The time to development of recurrence was variable; 4 underwent repeat liver transplantation for complications of recurrent disease and all 4 again developed recurrent disease after retransplantation. Siblings of these patients who also underwent liver transplantation for BSEP disease have not developed "recurrent" disease. Three of the patients with "recurrent" disease ultimately died, 2 as a direct result of complications of their liver disease.

Genetic variants in major histocompatibility complex-linked genes associate with pediatric liver transplant rejection.

BACKGROUND & AIMS: Limited access to large samples precludes genome-wide association studies of rare but complex traits. To localize candidate genes with family-based genome-wide association, a novel exploratory analysis was first tested on 1774 major histocompatibility complex single nucleotide polymorphisms (SNPs) in 240 DNA samples from 80 children with primary liver transplantation and their biologic parents. METHODS: Initially, 57 SNPs with large differences (P < .05) in minor allele frequencies were selected when parents of children with early rejection (rejectors) were compared with parents of nonrejectors. RESULTS: In hypothesis testing of selected SNPs, the gamete competition statistic identified the minor allele G of the SNP rs9296068, near HLA-DOA, as being significantly different (P = .018) between outcome groups in parent-to-child transmission. Subsequent simple association testing confirmed over- and undertransmission of rs9296068 based on the most significant differences between outcome groups, of 1774 SNPs tested (P = .002), and allele (G) frequencies that were greater among rejectors (51.4% vs 36.8%, respectively, P = .015) and lower among nonrejectors (26.8% vs 36.8%, respectively, P = .074) compared with 400 normal control Caucasian children. In early functional validation, rejectors demonstrated significant repression of the first HLA-DOA exon closest to rs9296068. Also, intragraft B lymphocytes, whose antigen-presenting function is selectively inhibited by HLA-DOA were 3-fold more numerous during rejection among rejectors with the risk allele, than those without. CONCLUSIONS: The minor allele of the SNP rs9296068 is significantly associated with liver transplantation rejection and with enhanced B-lymphocyte participation in rejection, likely because of a dysfunctional HLA-DOA gene product.

Proteinaceous Lymphadenopathy in a Young Patient With History of Classical Hodgkin Lymphoma: A Case Report With Literature Review.

Proteinaceous lymphadenopathy (PLD) is a poorly defined, underreported pathological entity of uncertain etiology characterized by massive deposition of amorphous, eosinophilic, and periodic acid-Schiff-positive material involving lymph nodes, which is distinct from amyloid and clonal immunoglobulin deposition. PLD can resemble collagen sclerosis and needs to be differentiated from lymphomas with sclerosis, particularly classical Hodgkin lymphoma, nodular sclerosis type, and therefore is an important pitfall in the diagnosis of lymphoma with sclerosis. We are reporting a young patient with history of classical Hodgkin lymphoma who eventually developed PLD and review the literature on this subject.

Telomere length shortening in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a clonal, proliferative disorder of phenotypically immature CD1a(+) Langerhans cells (LC). The aetiology of LCH is unknown and data supporting an immune dysregulatory disorder as well as a clonal neoplasm have been reported. Telomere shortening has been associated with cancers and premalignant lesions as well as promoting chromosomal instability. To determine whether LCH LC have altered telomere lengths, we used dual detection of CD1a expression by immunofluorescence and telomere length by fluorescence in situ hybridization of LCH LC and lymphocytes in local, multisystem and systemic LCH and compared these with telomere lengths of LC and lymphocytes in reactive lymph nodes. LCH LC showed significantly shorter telomere lengths than LC from reactive lymph nodes or unaffected skin. Lymphocyte telomere lengths showed similar profiles among the different samples. These data show a significant telomere shortening in LCH LC in all stages of disease involvement compared with LC from reactive lymph nodes, suggesting that LCH may share mechanisms of telomere shortening and survival with clonal preneoplastic disorders and cancer, although an initiating infectious or immune event is still possible.