Jennifer Picarsic

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

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

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.

Molecular Characterization of Sporadic Pediatric Thyroid Carcinoma with the DNA/RNA ThyroSeq v2 Next-Generation Sequencing Assay

The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n = 18) were studied. We previously tested 15 cases by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not tested previously. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n = 3) and TPR/NTRK1 (n = 1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could identify only molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n = 13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype, but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules to aid future classification, treatment, and clinical management recommendations.

Nosology and Pathology of Langerhans Cell Histiocytosis

The classification of the histiocytoses has evolved based on new understanding of the cell of origin as a bone marrow precursor. Although the pathologic features of the histiocytoses have not changed per se, molecular genetic information now needs to be integrated into the diagnosis. The basic lesions of the most common histiocytoses, their patterns in different sites, and ancillary diagnostics are now just one part of the classification. As more is understood about the cell of origin and molecular biology of the histiocytoses, future classifications will be refined.

Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites

Autoinflammatory diseases are caused by pathologic activation of the innate immune system. Primary hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation caused by monogenic mutations resulting in cytotoxic cell defects and subsequent failure to eliminate activated macrophages. Secondary HLH is often diagnosed in cases without a known Mendelian inheritance. However, some cases of “secondary” HLH have been shown to harbor mutations with partial dysfunction of the cytotoxic system. Recently, macrophage intrinsic abnormalities caused by NLRC4 inflammasome mutations have been linked to autoinflammation and recurrent macrophage activation syndromes resembling a primary HLH. We report a case of a former 28-week preterm infant with congenital anemia, ascites, and a heavy edematous placenta with fetal thrombotic vasculopathy, who developed hepatosplenomegaly and unexplained systemic inflammation with laboratory features of HLH in the early postnatal course and died at 2 months of age. Postmortem examination confirmed the hepatosplenomegaly with marked sinusoidal hemophagocytosis, along with striking hemophagocytosis in the bone marrow and lymph nodes. There was extensive acute and chronic ischemic bowel disease with matted bowel loops, fibrous adhesions, and patchy necrotizing enterocolitis features. Whole exome sequencing analysis demonstrated a novel mosaic heterozygous NLRC4 512 C> T (p.Ser171Phe) de novo mutation predicated to cause a dominant, gain-of-function mutation resulting in a constitutively active protein. The assembly of NLRC4-containing inflammasomes via an induced self-propagation mechanism likely enables a perpetuating process of systemic macrophage activation, presumed to be initiated in utero in this patient.

Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ-induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.

United States Medical Licensing Examination step 1 two-digit score: a correlation with the American Board of Pathology first-time test taker pass/fail rate at the University of Pittsburgh Medical Center.

CONTEXT Factors that correlate with success or failure on the American Board of Pathology (ABP) examination are not known. Other medical residency programs have shown that standardized test scores correlate with specialty board examination scores; however, data from pathology programs are lacking. OBJECTIVE To investigate whether the 2-digit score on step 1 of the United States Medical Licensing Examination (USMLE) was correlated with ABP examination performance at a large university pathology program. DESIGN Nine years of data (2001-2009) from pathology residents (n  =  72) at the University of Pittsburgh Medical Center (UPMC, Pittsburgh, Pennsylvania) was collected from existing files and deidentified. Step 1 USMLE 2-digit scores and ABP failure rates for first-time test takers were compared. Results are reported as the percentage of residents who failed either the anatomic pathology or clinical pathology part of the ABP examination in cohorts by their USMLE 2-digit score (≤80, 81-85, 86-89, ≥90). RESULTS The rolling 5-year (2005-2009) ABP average failure rate for first-time test takers of the anatomic pathology examination was 3.1% (UPMC) and 14.1% (nationally); in clinical pathology, it was 13.8% (UPMC) and 23.6% (nationally). At UPMC, no resident failed the anatomic pathology or clinical pathology parts of the ABP examination if his or her 2-digit USMLE step 1 score was 90 or more across 9 years of training (2001-2009). CONCLUSIONS In the UPMC pathology program, 2-digit scores on USMLE step 1 of 90 or more and 80 or less were strong measures of ABP first-time pass/failure rates, whereas scores of 81 to 89 were less-accurate measures. The USMLE step 1 score is one of many criteria that can be used for screening applicants for a pathology residency program.

Bartonella henselae Endocarditis and Glomerulonephritis with Dominant C3 Deposition in a 21-Year-Old Male with a Melody Transcatheter Pulmonary Valve: Case Report and Review of the Literature

We report a case of a 21-year-old young man with underlying congenital heart disease who developed Bartonella henselae endocarditis of the right ventricular outflow tract (RVOT) conduit of his Melody transcatheter (percutaneous) pulmonary valve (TPV), with an initial presentation of glomerulonephritis with a dominant C3 pattern, with renal failure and circulating cryoglobulins. There are few reports of a glomerulonephritis with a dominant C3 pattern presenting as a manifestation of B. henselae endocarditis. While most cases of B. henselae endocarditis affect the aortic valve, in this case the valve damage was to the RVOT of the Melody TPV, a percutaneous transcatheter valve delivery system that had previously replaced his pulmonary homograft, which had become dysfunctional as a result of prior Streptococcus viridans endocarditis. The pulmonary homograft had been in place since childhood as a result of a Ross procedure to repair his congenital aortic stenosis. The patients renal failure significantly improved after surgical resection of the infected RVOT and institution of appropriate antibiotic therapy.

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.