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Hirschsprung disease (HD) is characterized by circumferential aganglionosis of the rectum with variable proximal bowel involvement. The underlying pathogenesis is due to failure of caudal migration of neural crest cells during pre-natal development, causing functional bowel obstruction. Definitive therapy is surgical resection; however, a subset of patients will require reoperation. An important cause of reoperation is the rare but distinct entity described as the ganglion cell "vanishing" phenomenon. In this phenomenon, affected patients have normal circumferential ganglion cells present at the proximal margin during primary resection. They undergo a variable asymptomatic period post-primary resection but ultimately develop recurrent symptoms. Upon reoperation, ganglion cells seemingly vanish and are no longer present in the previously functioning and ganglionated bowel proximal to the initial anastomotic site. To further characterize and investigate this poorly understood pathology, here we present 2 cases of HD patients who required reoperation. Our small series implicates that an immune component may contribute as patient 2 had a brisk neurotrophic eosinophilic infiltrate only present in the reoperation specimen. However, this was not observed in patient 1. Other possible etiologies include post-operative ischemia/hypoxia, visceral neuropathy, or signaling abnormalities within the residual ganglion cells themselves.

We have identified 9 pregnant patients who were diagnosed with malignancy and initiated chemotherapy during their second trimester (cervical cancer [n = 3], leukemia [n = 3], breast cancer [n = 2], and Hodgkin's lymphoma [n = 1]). Five of the patients' placentas were small for gestational age (SGA). Pathologic examination revealed inflammatory changes in 4 of the placentas: 2 from the SGA placentas and 2 from non-SGA placentas. Examination revealed 3 placentas with villitis of unknown etiology (VUE) and 1 with intervillositis; all were negative for bacterial and viral cultures and by immunohistochemical (IHC) stains. In the VUE cases, IHC stains showed positivity of CD25+/FOXP3+ with focal positivity and CD3 and CD4 IHC were focally to strongly positive. Literature suggests that the use of chemotherapy during pregnancy can be detrimental to both the mother and the fetus; however, there has been limited focus on the effects of chemotherapy on the placenta. We suggest that the inflammatory process noted in the placentas is due to chemotherapy-induced toxic effects.

Two cases of devastating fetal malformations associated with vanished monochorionic twins were identified upon review of pathology files. A 35-year-old G1P0 woman and 36-year-old G3P1 woman were both diagnosed with an intrauterine twin gestation via transvaginal ultrasound at 10 weeks. The spectrum of fetal anomalies ranged from omphalocele, bilateral upper extremity, and unilateral lower extremity hypoplasia, to craniofacial malformation with diaphragmatic hernia. On histopathologic examination, the placentas demonstrated vascular anastomoses between the surviving co-twin and the "vanished" fetal sac. We propose anastomotic placental vasculature as a contributing factor to the observed fetal malformations. Additionally, genetic or teratogenic factors may have been attributed to the demise of the first twin and the anomalies seen in the other twin. While such instances are rare, they are important to consider when counseling patients regarding outcomes associated with a monochorionic vanished twin.

Bile duct paucity is the absence or marked reduction in the number of interlobular bile ducts (ILBD) within portal tracts. Its syndromic variant, Alagille syndrome (ALGS), is a multisystem disorder with effects on the liver, cardiovascular system, skeleton, face, and eyes. It is inherited as an autosomal dominant trait due to defects in NOTCH signaling pathway. ALGS is characterized by vanishing ILBD with subsequent chronic obstructive cholestasis in approximately 89% of cases. Cholestasis stimulates formation of new bile ductules through a process of neoductular reaction, making it difficult to evaluate the presence or absence of ILBD. Therefore, finding a method to differentiate clearly between ILBD and the ductular proliferation is essential for accurate diagnosis. A database search identified 28 patients with confirmed diagnosis of ALGS between 1992 and 2014. Additionally, 7 controls were used. A panel of two immunostains, cytokeratin 7 (CK7) and epithelial membrane antigen (EMA), was performed. CK7 highlighted the bile duct epithelium of ILBD and ductular proliferation, while EMA stained only the brush border of ILBD. In our ALGS group, the ratio of EMA-positive ILBD to identified portal tracts was 12.6% (range, 0%-41%). However, this same ratio was 95.0% (range, 90%-100%) among control cases (P < 0.001). We propose a panel of two immunostains, CK7 and EMA, to differentiate ILBD from ductular proliferation in patients with cholestasis. With this panel, identification of bile duct paucity can be achieved. Additional studies, including molecular confirmation and clinical correlation, would provide a definitive diagnosis of ALGS.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a potentially fatal neurologic syndrome in which patients present with a spectrum of central nervous system deficits. Sixty percent of the cases can be attributed to the presence of tumors, most often ovarian teratomas. This report examines 6 pediatric patients who presented with neurologic deficits associated with the presence of such tumors. These cases illustrate a perplexing phenomenon, where benign teratomas could have a possible association with anti-NMDAR encephalitis. The purpose of this study was to compare the histology and immunohistochemistry of tumors associated with this syndrome to ovarian teratomas found in patients presenting with no neurologic symptoms. After obtaining institutional review board approval, 57 cases of ovarian teratomas were identified at our institution over 12 years. Six patients were identified with anti-NMDAR encephalitis. A panel of immunostains, including S100, GFAP, MAP2, and NeuN was applied to patients' tumor sections as well as the 6 controls from age-matched patients. No qualitative histologic or immunohistochemical differences were seen between the study cases and control group. Because no qualitative differences were identified between the study cases and the control group, testing of paired serum and cerebrospinal fluid remains the best method for diagnosis of anti-NMDAR encephalitis. Tumor banking with molecular analysis of ovarian teratomas, including whole-genome sequencing and comparative genomic hybridization between ovarian tissue saved from patients with and without anti-NMDAR encephalitis, is necessary to fully understand the etiopathogenesis of anti-NMDAR encephalitis.

Nontuberculous mycobacterial (NTM) infections are serious, though rare, in patients with severe combined immunodeficiency who have received bone marrow transplants. A 5-year-old female patient underwent stem cell/bone marrow transplant with disseminated NTM. Real-time polymerase chain reaction (PCR) using a fluorescence resonance energy transfer (FRET) probe for detection and identification of NTM was performed. The FRET-based real-time PCR assay amplified mycobacterial DNA, and the postamplification melt curve analysis classified the organism as a NTM. The pyrosequence of the hypervariable region A definitively identified the infecting organism as Mycobacterium avium. Real-time PCR along with melt curve analysis and pyrosequencing provides faster, definitive identification of mycobacteria, as compared to bacterial culture. In this case report, we emphasize the importance of utilizing molecular means for fast and accurate diagnosis.

Colorectal adenocarcinoma (CRAC) is exceedingly rare in the pediatric population (fewer than 2 cases per 1 million children). There are 2 major categories of pediatric colorectal adenocarcinoma syndromes: polyposis-related and hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome. Germ line mutations in DNA mismatch repair (MMR) genes (eg, MLH1, MSH2, PMS2, MSH6) have been established as the molecular genetic basis of Lynch syndrome. Another prognostic factor in adult CRAC is the reduced expression of epithelial cadherin (E-cadherin), which has been associated with poor outcome in some adult CRAC cases; however, its role in predicting prognoses in pediatric cases remains unclear. Seven pediatric patients with primary CRAC were reviewed. Available molecular genetic test results were evaluated, and immunohistochemical labeling for MMR proteins and E-cadherin were performed on 5 patients. Four of the 5 patients in our study with available paraffin blocks showed loss of MMR protein expression, consistent with Lynch syndrome. In cases stained for E-cadherin, 3 were strongly positive and 2 were weakly positive; however, with the small sample size and the relatively short follow-up period, an accurate correlation between E-cadherin and prognosis cannot be reached with any degree of certainty. Our findings highlight the importance of genetic testing for MMR gene mutations in children with colorectal cancer and suggest further investigation into the prognostic role of E-cadherin in pediatric CRAC.

Ciliated hepatic foregut cysts (CHFCs) are rare congenital legions that arise from the embryonic foregut. The cysts are formed during fetal development by evagination from their respective portions of the foregut, and are characterized by a ciliated epithelial lining. Approximately 100 cases of CHFC have been reported, of which only 13 were in children. Although CHFC is typically benign, malignant transformation to squamous cell carcinoma (SCC) has been reported in 3 cases. Survival rate after progression to malignancy is poor, as SCC in this setting is biologically aggressive. We present 4 new cases of CHFC in children between 5 months and 17 years old. Our cases are unusual, as some of the cysts exhibit multilocularity and biliary communication, and 2 of our patients were diagnosed under the age of 1. Additionally, 1 of the cysts was 19.3 cm in diameter, making it the largest reported CHFC to our knowledge. Ciliated hepatic foregut cysts should be included in the differential diagnosis of hepatic lesions.

Histiocytoid cardiomyopathy (HC) is a rare but distinctive arrhythmogenic disorder characterized by incessant ventricular tachycardia, cardiomegaly, and often sudden death by age 2 years. The underlying genetic mechanism of HC has eluded researchers for decades. To further identify the potential molecular-genetic bases of HC, molecular analyses of HC hearts and hearts of age-matched controls were performed. Total RNA and genomic DNA were prepared from formalin-fixed, paraffin-embedded cardiac tissue from 12 cases of HC and 12 age-matched controls. To identify genes differentially expressed in HC, whole genome cDNA-mediated annealing, selection, extension, and ligation profiling was performed. TaqMan quantitative polymerase chain reaction confirmed changes in RNA expression. DNA copy number changes were measured by TaqMan copy number variant analysis. Analysis of differential gene expression in HC cases identified 2 significantly downregulated gene sets aligned sequentially along the genome. The 1st gene cluster consisted of genes S100A8 , S100A9 , and S100A12 at 1q21.3c, and the 2nd cluster consisted of genes IL1RL1 ( ST2 ), IL18R1 , and IL18RAP at 2q12.1a. Strong decreases in interleukin 33 expression were also observed. Decreases in copy number of the S100A genes were confirmed by TaqMan copy number variant assays. S100A genes are downstream of the p38-MAPK pathway that can be activated by interleukin 33 signaling. These data suggest a model in which the interleukin 33-IL1RL1/p38-MAPK/ S100A8-S100A9 axis is downregulated in HC cardiac tissue and provide several candidate genes on 1q21.3c and 2q12.1a for inherited mutations that may predispose individuals to HC.

Studies comparing placental pathology between human immunodeficiency virus (HIV)-positive and HIV-negative patients have shown conflicting results. In addition, few studies have evaluated the infectious etiology of placental inflammation in HIV-positive patients. We examined a cohort of placentas from 73 HIV-positive and 41 HIV-negative patients to gain a better understanding of the spectrum of placental inflammatory lesions. Bacterial and viral immunohistochemistry (IHC) was run on a subset of placentas (12 HIV-positive and 7 HIV-negative) with the greatest amount of inflammation. Although few histologic differences were seen between the HIV-positive and HIV-negative groups, chorioamnionitis was of a higher stage in the HIV-positive placentas. An infectious agent was found by IHC in 3 of 7 HIV-negative patients (2 Neisseria spp. and 1 group B Streptococcus ). One HIV-positive placenta showed gram-positive cocci on fetal membranes; organisms were not detected by IHC. In 2 patients, the etiologic agent was not suspected prior to IHC. This study identified that acute inflammation is less common in placentas from HIV-positive patients, compared with HIV-negative patients. However, when severe inflammation is present, infectious organisms may be identified by IHC, providing a more specific diagnosis and offering a beneficial impact in maternal and fetal management.

The pathogenesis of right ventricular fibrofatty changes can be broadly divided into genetic or acquired. The genetic cause is termed arrhythmogenic right ventricular dysplasia, an inherited cardiomyopathy characterized by fibrofatty replacement of the right ventricular myocardium, and represents an underdiagnosed cardiac entity leading to syncope, recurrent ventricular tachycardias, heart failure, and sudden death. Our study demonstrates that fibrofatty changes can also be seen in pediatric cardiac allografts. Conversely, fat replacement without fibrosis may be seen secondary to infectious myocarditis, chronic inflammation, and ischemia and as part of the aging process. We examined 29 failed cardiac allografts to identify the etiology of graft failure. In this study, 4 patients (13%) had severe right ventricular fibrofatty changes, and when compared with control patients, those with fibrofatty changes had a shorter interval from transplant to graft failure, 2.75 years vs 5.45 years (P  =  0.029). Neither body mass index nor other physiologic parameters found on electrocardiography, echocardiography, or cardiac catherization were different between groups. Furthermore, arrhythmias indicative of arrhythmogenic right ventricular dysplasia were not observed in the study group. This study suggests the fibrofatty infiltration in cardiac allografts is a clinically different entity from arrhythmogenic right ventricular dysplasia and has an unknown etiology. Our study findings suggest that identifying fibrofatty infiltrates in cardiac transplant patients during routine right ventricular biopsy can be a predictive factor for shortened life of the pediatric cardiac allograft.

Undifferentiated embryonal sarcoma (UES) of the liver is a primitive mesenchymal, malignant neoplasm occurring in children. The link between UES and mesenchymal hamartoma (MH) is controversial. Whether they share the same histiogenesis, representing 2 ends of a spectrum, or are distinct entities is unclear. The genetic aberrations of these neoplasms are not well understood, although a common breakpoint (19q13.4) was recently identified. The purpose of this study was to elucidate immunohistochemical markers that may establish a link between the 2 tumors by reviewing cases of UES and MH. Cases of UES from 1990 to 2008 were identified. Clinical demographics were reviewed. Hematoxylin and eosin staining and immunohistochemical staining for vimentin, alpha-1 antitrypsin, and alpha-fetoprotein were performed. Eleven children were diagnosed with UES. Five cases were seen arising in association with MH, and transitional zones were evident. The mean age at presentation was 10 years. To our knowledge, the 11-month-old patient is the youngest reported case of UES in concurrence with MH. All UES tumor cells were positive for vimentin, diastase-resistant periodic acid-Schiff stain, and alpha-1 antitrypsin. Chromosomal analysis of 3 UES cases, 2 arising with MH, showed complex karyotypes with no involvement of 19q13.4. We suggest a continuum between UES and MH. Although a chromosomal anomaly of 19q13.4 was not identified, a submicroscopic involvement of this locus cannot be excluded. Additionally, our analyses suggest that multiple chromosomal aberrations may be associated with the MH/UES spectrum.

NUT midline carcinoma (NMC) is a rare and aggressive malignant epithelial tumor defined by rearrangement of the NUT gene on chromosome 15. In two thirds of cases, NUT is involved in a balanced translocation with BDR4 on chromosome 19, while in the remaining cases, NUT is rearranged with variant fusion partners such as BRD3. These undifferentiated tumors primarily affect midline structures, usually in the upper aerodigestive tract and mediastinum. Most reported cases have followed a rapidly lethal clinical course. We report the clinical and pathological findings of NMC in the youngest patients identified so far. The 1st case involves a newborn who presented with a supraorbital mass and extensive multiorgan involvement, including the spine, lungs, liver, pancreas, adrenal glands, and subcutaneous tissue. The 2nd patient was a 2-year-old male with an abdominal mass involving the liver and pancreas with pulmonary metastasis. Histopathological analysis of both tumors showed undifferentiated malignant neoplasms, and immunohistochemistry showed positivity for epithelial markers. Both tumors demonstrated t(15;19), and immunohistochemistry with NUT monoclonal antibodies and fluorescent in situ hybridization confirmed NUT rearrangement. The patients died from disease at 1 and 2 months postpresentation. Thus far, 25 cases have been reported, including our 2 current cases. Presentation ages range from 0 to 78 years (mean, 23 years). Herein, we report the 2 youngest reported cases of NMC, including the 1st congenital case and the 1st case arising within the liver/pancreas. Increased awareness and further molecular studies are required for a better understanding of NMC pathobiology and improved therapeutic outcomes.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign lesion consisting of mammary stromal proliferation with anastomosing slits mimicking vascular spaces. Grossly, it most often resembles fibroadenoma, but may commonly be confused with angiosarcoma and other types of benign vascular proliferations. While PASH has been described in female and male adults since the mid-1980s, there have been only a few accounts in the pediatric population. We present a series of 12 pediatric patients with PASH, including a 3-year-old male, who we believe to be the youngest patient to present with this entity. In our study, PASH was found in 12% of tumors diagnosed preoperatively as fibroadenomas and in 12% of cases diagnosed preoperatively as gynecomastia. Our series documents that PASH is not uncommon in pediatric breast pathology and delineates important differences between adult and pediatric presentations of this entity.

Detection of Epstein-Barr virus (EBV) may be achieved by various methods, including EBV-encoded RNA (EBER) in-situ hybridization (ISH) and immunohistochemistry (IHC) for latent membrane protein (LMP-1). We compared novel automated ISH and IHC techniques in pediatric lymphoproliferative disorders with results obtained by manual ISH. Thirty-seven pediatric cases previously studied by manual EBER ISH (including 18 EBER-positive, 15 EBER-negative, and 4 EBER-equivocal cases) were used for the study. Automated EBER ISH and automated LMP-1 IHC were performed using the BondMax autostainer and prediluted EBER probe and EBV cell surface 1 to 4 at 1:50 dilution, respectively. Results of each of the automated techniques for EBV detection were compared with results by manual EBER ISH. Compared with manual EBER ISH as the gold standard, automated ISH had a sensitivity and specificity of 94% and 69%, respectively, accuracy of 83%, positive predictive value (PPV) of 79%, and negative predictive value (NPV) of 90%. Automated IHC had a sensitivity of 44%, specificity of 93%, accuracy of 67%, PPV of 88%, and NPV of 59%. Automated ISH and IHC correlated significantly (P < 0.045). Automated ISH is useful for diagnosis of EBV-related pediatric neoplasms, being easy to perform and interpret and requiring only the technologist's time to set up and having a high sensitivity and NPV The automated IHC protocol is of too low sensitivity for routine use, although results show high specificity and PPV.

Anaplastic large cell neuroblastomas (ALCNB) are a subset of undifferentiated neuroblastomas with marked pleomorphic and anaplastic features that render them diagnostically challenging. We reviewed the records of all patients diagnosed with ALCNB at Children's Healthcare of Atlanta (Egleston Children's Hospital) for their clinical, biologic, and pathologic characteristics and their treatment outcomes. From 1998 to 2006, 7 patients were diagnosed with ALCNB. All patients presented with abdominal-pelvic masses, 3 of them of adrenal origin and 2 with thoracic extension, with clinical stages 3 or 4, and were considered to have high-risk disease. The N-MYC oncogene was amplified in 3 cases and catecholamines were elevated in 5 of 6 patients tested. All pretreatment tumors demonstrate pleomorphic, anaplastic morphology with bizarre mitoses admixed with undifferentiated but monomorphic cells with minimal if any neuropil or neuro-ganglionic differentiation. Immunohistochemical markers for neuron specific enolase (NSE) and synaptophysin were strongly positive in all specimens and chromogranin in 4 of 5. Interestingly, all tumors showed strong Fli-1 nuclear positivity despite a negative CD-99 stain. However, reverse transcription polymerase chain reaction or fluorescent in-situ hybridization testing for Ewing sarcoma transcripts was negative in 4 available specimens. This same Fli-1 antibody had tested negative on 30 conventional neuroblastomas, indicating a peculiar cross reactivity with this subset of ALCNB. Posttreatment biopsies showed maturation changes to more conventional neuroblastoma histology in 5 of the 7 cases. Follow-up ranged from 9 months to 4 years from diagnosis (median: 25 months). Five patients are still alive after treatment, 1 died 9 months after diagnosis, and another patient refused high-risk therapy and progressed and died 9 months from diagnosis. Anaplastic large cell neuroblastomas are a subset of undifferentiated neuroblastomas characterized by the absence or marked paucity of histologic clues for the diagnosis of neuroblastoma. Although all these tumors are strongly positive for NSE and synaptophysin, they also show Fli-1 positivity. However, they are negative by molecular testing for EWS transcripts, and they are immunohistochemically negative for CD99. The true neuroblastic nature of these tumors is supported by the N-MYC oncogene amplification in some of them, catecholamine production, immunohistological reactivity, and their posttherapy maturation to a more recognizable neuroblastic morphology. Although follow-up is still somewhat limited, the response and survival of the patients in our institution is better than a previous European study that indicated an aggressive clinical behavior of these tumors, although treatment modalities were not described in that report. Further study of this variant of neuroblastoma with more patients is required to determine optimal therapy, more accurately predict outcome, and to ascertain if ALCNB are a distinct biologic group of neuroblastomas.

Agnathia (otocephaly) is a sporadic malformation characterized by agenesis of the mandible with characteristic dysmorphologic sequelae. We compare the prenatal presentations and dysmorphologic abnormalities of 2 female fetuses with agnathia. Fetus 1 was delivered at 33 weeks' gestational age and showed agnathia with characteristic sequelae of microstomia; microglossia; persistent buccopharyngeal membrane; and ventrally placed, malformed external ears. Fetus 2 was delivered at 32 weeks' gestational age and exhibited agnathia, astomia, and microglossia; in contrast to fetus 1, however, the external ears were laterally placed, low set, and malformed. For both fetuses, tridimensional computed tomographic scan showed the unique complete absence of the mandible. Additional malformations were documented and differed between the fetuses. We discuss the current molecular mechanisms implicated in 1st branchial arch patterning, particularly the impact of bone morphogenetic protein and fibroblast growth factor 8, and how these findings have the potential to explain the spectrum of abnormalities present in these 2 fetuses with agnathia without associated holoprosencephaly.

Recurrent laryngeal papillomatosis (RLP), a chronic disease associated with human papilloma virus (HPV), requires serial surgical procedures for debulking, resulting in debilitating long-term dysphonia, laryngeal scarring, and rarely malignant degeneration. Human papilloma virus 11 tumors have been widely accepted as more aggressive than HPV 6 tumors; however, the clinical course has been difficult to predict at disease onset, and the biologic mediators of proliferation have not been well characterized. A retrospective case review of 43 patients (4 months to 10 years at diagnosis) was performed on children treated for recurrent laryngeal papillomatosis. Patient charts were reviewed for demographic information, age at RLP diagnosis, approximate frequency of surgical intervention, and absolute number of surgical procedures performed. Human papilloma virus subtyping was performed. Expression analysis of the HPV-encoded E6 and E7 oncogenes was performed by reverse-transcriptase polymerase chain reaction. Fourteen patients had subtype 11 (33%) and 29 patients had subtype 6 (67%). As expected, HPV 11 patients showed a more aggressive clinical course than HPV 6 patients. However, 38% of patients with subtype 6 (11 patients) followed a clinical course that mirrored the more severe subtype 11 patients. These patients expressed the disease at a younger age (P < 0.0002) and showed higher levels of E6 and E7 oncogenes compared to the patients with the more indolent course. Although HPV subtype and early onset of RLP are well characterized prognostic factors, our study documents the significance of E6 and E7 oncogene expression as potential biologic mediators of proliferation and thereby clinical behavior.

Kawasaki disease (KD) is a systemic vasculitis condition with a relatively unknown etiology. First described in 1967 by Tomisaku Kawasaki in Japan, KD has come to be widely diagnosed in every region of the world. The disease has a high prevalence in children ages 6 months to 5 years, particularly in those of Japanese descent. Patients often present with a high fever, rash, lymphadenopathy, and conjunctival injections, but there is no diagnostic test for KD. This paper presents data from our Kawasaki registry including 99 patients with emphasis on Kawasaki cardiopathy. Three patients died from complications of KD, and 1 patient underwent heart transplant for massive aneurysmal dilatation. The 4 explanted hearts showed a spectrum of pathological findings (acute thrombosis, vasculitis, and myocarditis), and 1 patient showed the long-term sequelae of vasculitis in the form of massive aneurysmal dilatation. Among the survivors, 30% showed aneurysmal dilatation. This paper reviews the most recent information regarding Kawasaki cardiopathy and underlying molecular mechanisms.

We present a case of an infant with Down syndrome (trisomy 21) who was affected by alveolar capillary dysplasia and other complications including endocardial cushion defect, hypothyroidism, and intrauterine growth restriction. The patient was the product of a third pregnancy to a 33-year-old woman with no significant risk factors. The child lived for 3 months, during which he developed intractable dyspnea, hypoxemia, and cardiac dysfunction and he eventually died from septicemia and multiorgan failure. In addition to the facial phenotypic features and cardiac anomalies, the autopsy revealed the characteristic microscopic pulmonary findings of alveolar capillary dysplasia with misalignment of pulmonary veins. This appears to be the first reported case of this anomaly associated with trisomy 21. In addition to the many reasons for pulmonary hypertension that occur in children with trisomy 21, alveolar capillary dysplasia may have to be included in the differential diagnosis although it appears to be a rare association.