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Kaposiform lymphangiomatosis is an uncommon generalized lymphatic anomaly with distinctive clinical, radiologic, histopathologic, and molecular findings. Herein, we document the pathology in 43 patients evaluated by the Boston Children's Hospital Vascular Anomalies Center from 1999 to 2020. The most frequent presentations were respiratory difficulty, hemostatic abnormalities, and a soft tissue mass. Imaging commonly revealed involvement of some combination of mediastinal, pulmonary, pleural, and pericardial compartments and most often included spleen and skeleton. Histopathology was characterized by dilated, redundant, and abnormally configured lymphatic channels typically accompanied by dispersed clusters of variably canalized, and often hemosiderotic, spindled lymphatic endothelial cells that were immunopositive for D2-40, PROX1, and CD31. An activating lesional NRAS variant was documented in 9 of 10 patients. The clinical course was typically aggressive, marked by hemorrhage, thrombocytopenia, diminished fibrinogen levels, and a mortality rate of 21%.

Vascular anomalies represent a diverse group of disorders classified broadly as malformations or tumors and include the second most common hereditary bleeding disorder worldwide, hereditary hemorrhagic telangiectasia (HHT). Patients with HHT and other vascular anomalies suffer morbid consequences of these diseases, including bleeding, thrombosis, anemia, localized intravascular coagulation, tissue overgrowth, infections, and other complications. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis, and the treatments for vascular anomalies are rapidly evolving. Recent discoveries have elucidated the molecular basis of a number of common and uncommon vascular anomalies. HHT occurs due to mutations in the transforming growth factor beta (TGF-β) pathway, resulting in vascular endothelial growth factor excess. Complex vascular anomalies including Klippel-Trénaunay syndrome (KTS) and arteriovenous malformation (AVM) may occur due to mutations in the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. The discovery of the pathophysiologic mechanisms driving these diseases has led to improved phenotype-genotype correlation and the opportunity to target molecular pathways with medical therapies. Therefore, targeted agents have quickly become a standard of care in the treatment of vascular disorders (particularly HHT). Herein, we provide a case-based approach to the use of antiangiogenic therapies including bevacizumab and pazopanib for the treatment of bleeding in HHT and the use of mammalian target of rapamycin (sirolimus), PIK3CA (alpelisib), and MEK (trametinib) inhibitors in the treatment of complex vascular anomalies.

Vascular anomalies (VAs) are a heterogeneous group of primarily congenital tumors and malformations. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis. Recent discoveries evaluating the genetic causes of VAs have revealed that they are due to mutations in cancer pathways, including the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. These discoveries have led to improved phenotype-genotype correlation and have expanded medical therapy for this group of unique disorders.

OBJECTIVE Clinical manifestations of blue rubber bleb nevus syndrome (BRBNS) and multifocal venous malformation (MVM) vary depending on the location of the lesions. The aim of this study was to assess the risk of developing CSF leaks in patients with epidural venous malformations (VMs). METHODS The authors retrospectively investigated the relationship between the development of a CSF leak and the presence of epidural VMs. RESULTS Nine patients (5 females) had epidural VMs and presentation that was confirmatory or suggestive of a CSF leak: 4 had BRBNS, 4 had MVMs, and 1 had a solitary VM. Of 66 patients with BRBNS, clinical and imaging features of CSF leak were noted in 3 (4.5%) with epidural VMs at the age of 11–44 years. A fourth patient had suggestive symptoms without imaging confirmation. An epidural blood patch was ineffective in 2 patients, both with more than one source of leakage, requiring surgical repair or decompression. Symptomatic downward displacement of the cerebellar tonsils was noted in 3 patients with MVM and 1 with a solitary VM; 3 required surgical decompression. CONCLUSIONS These findings suggest an increased risk of CSF leak in patients with epidural VM, including BRBNS, MVMs, and solitary VMs. Awareness of the association between epidural VM and CSF leakage may facilitate earlier diagnosis and therapeutic intervention.

Bockenheimer disease is a venous malformation involving all tissues of an extremity. Patients have significant morbidity, and treatment is palliative. The purpose of this study was to identify the cause of Bockenheimer disease to develop pharmacotherapy for the condition. Paraffin-embedded tissue from nine individuals with Bockenheimer disease obtained during a clinically indicated operation underwent DNA extraction. Droplet digital polymerase chain reaction (ddPCR) was used to screen for variants most commonly associated with sporadic venous malformations (TEK [NM_000459.5:c.2740C > T; p.Leu914Phe], PIK3CA [NM_006218.4:c.1624G > A; p.Glu542Lys and NM_006218.4:c.3140A > G; p.His1047Arg]). ddPCR detected a TEK L914F variant in all nine patients (variant allele fraction 2%–13%). PIK3CA E542K and H1047R variants were not identified in the specimens. Sanger sequencing and restriction enzyme digestion confirmed variants identified by ddPCR. A pathogenic variant in the endothelial cell tyrosine kinase receptor TEK is associated with Bockenheimer disease. Pharmacotherapy targeting the TEK signaling pathway might benefit patients with the condition.

Overgrowth syndromes represent a diverse group of disorders with overlapping features. Interdisciplinary management by a team of experts in vascular anomalies is crucial for establishing the correct diagnosis and optimizing outcomes for these patients. Unique management considerations include increased risk for thrombosis and in some cases, cancer. In recent years, research has demonstrated that these disorders are primarily caused by somatic mutations in growth pathways, particularly the PI3K-mTOR pathway. This improved understanding had led to promising new therapies for this group of patients.

Background: Disorders of somatic mosaicism (DoSM) are caused by mutations that arise post-zygotically and are present in only a specific part of the body. These mutations alter the function and regulation of key genes in cell proliferation pathways, including the PI3K/AKT/mTOR pathway, and show significant overlap with mutations identified in cancer(McNulty et al. Am J Hum Genet, 2019). PIK3CA-Related Overgrowth Spectrum (PROS) is an umbrella term that encompasses a variety of overgrowth syndromes caused by post-zygotic, somatic gain-of-function PIK3CA mutations with low-level mosaicism (Luks et al. J Pediatr, 2015). The clinical phenotype of PROS is heterogeneous and many tissue types can be affected. This often makes clinical diagnosis challenging. The use of cancer genomics in patients with vascular anomalies may aid in establishing a genetic diagnosis and expand use of targeted medical therapies. Methods: Three patients who presented with clinical symptoms of PROS underwent targeted next generation sequencing of affected tissue using OncoPanel. Oncopanel is a genomic assay that detects somatic mutations, copy number variations and structural variants in 447 genes implicated in cancer. Results: Three patients with a PROS phenotype demonstrated somatic mutations in genes distinct from PIK3CA. Case 1: A 15-year-old female presented with a painful right leg mass, calf atrophy, contracture of the knee, leg-length discrepancy, and severe limp. Histology was consistent with fibroadipose vascular anomaly (FAVA) versus kaposiform hemangioendothelioma (KHE). Given her significant functional impairment, treatment with Sirolimus was initiated with significant improvement in appearance and functionality. OncoPanel testing revealed a PIK3C2B c.2881G>A (p.G961S) mutation. Case 2: A 12-month-old male was noted at birth to have a diffuse capillary malformation, multiple lymphatic malformations, macrodactyly of his bilateral hands and leg length-discrepancy, consistent with Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Spinal/Skeletal Anomalies/Scoliosis (CLOVES) syndrome. He underwent numerous surgical de-bulking procedures, epiphysiodesis, sclerotherapy, and laser therapy with continued disease progression. OncoPanel revealed a PIK3R1c.1731_1738delAGACCAATinsATGTAAGAAAG (p.D578_Y580delinsCKKD) mutation. Case 3: A 10-month-old female presented with a diffuse capillary malformation and leg-length discrepancy. She subsequently developed multiple painful and progressive lymphatic lesions over her left arm and chest which did not respond to sclerotherapy. Due to high clinical suspicion for PROS, she underwent targeted genetic testing via droplet digital PCR (ddPCR) to detect the five most common variants (C420R, E542K, E545K, H1047L, H1047R) in PIK3CA, but no hotspot mutations were identified. Over the next year and a half, the patient had two biopsies performed, PIK3CA ddPCR testing performed twice, and OncoPanel testing performed twice. OncoPanel testing of the second tissue biopsy ultimately resulted in the identification of a PIK3R1 c.1723-1731del p.K575_R577del mutation. Conclusion: The clinical diagnosis of DoSM is often challenging. While the use of cancer genomics for diagnostic purposes in vascular anomalies is uncommon, its use continues to broaden our understanding of syndromes related to alterations in the PI3K/AKT/mTOR pathway. PIK3CB encodes a catalytic subunit of PI3K, p110β, and is dysregulated in certain types of cancer. PIK3R1 encodes multiple regulatory subunits of PI3K and acts as a negative regulator of PIK3CA function. Both gain-of-function of PIK3CB or loss-of-function of PIK3R1 lead to inappropriate activation of PIK3CA, and our cases highlight that mutations in other genes can lead to the clinical phenotype of PROS. It is reasonable to expect that patients with alterations in genes that activate PIK3CA may benefit from medical treatment with direct PIK3CA inhibitors. Limiting diagnostic testing to evaluation of the PIK3CA gene alone may yield negative results and preclude patient eligibility for treatment with novel therapies. The use of next-generation sequencing (NGS) designed to detect somatic variations in cancer will likely play a pivotal role in detecting variants in vascular anomalies in the future and in expanding our understanding of genetic alterations involved in PROS. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Sirolimus is used off-label for the treatment of vascular anomalies.

Introduction Infantile hemangioma (IH) is the most common benign vascular tumor of childhood. It typically appears as a single cutaneous mass in the head, neck, and trunk area. IH that does not arise in the skin most commonly presents in the liver. The lesion emerges shortly after birth, rapidly enlarges within the first six months of life, and then spontaneously involutes by 5-10 years of age. Risk factors associated with IH complications include lesional size, location, and growth characteristics. Pulmonary IH is rare with limited reports of clinical presentations and outcomes. Methods An IRB-approved, retrospective review of pediatric patients with a diagnosis of pulmonary IH was conducted. Cases were identified within the Department of Pathology at Boston Children's Hospital from surgical or autoptic specimens evaluated between 1918 and 2021. Analysis of histopathological slides confirmed pulmonary IH in eight infants. We describe the diagnostic workup, radiological, and histopathological findings of these eight patients. Results All patients presented with symptoms of respiratory distress, including tachypnea, subcostal retractions, and hypoxia. The median age at initial symptoms was 1.5 months (range, birth to 12 months). Five patients had a single pulmonary hemangioma ranging in size from 0.2 to 8.0 cm; three patients had multiple pulmonary hemangiomas. Four patients had co-occurrence of multifocal hepatic IH. The median age at histologic diagnosis of pulmonary IH was 6.5 months (range, 5 weeks to 16 months). Glucose transporter-1 (GLUT-1) immunostaining was positive in seven cases. Chest radiography demonstrated nonhomogeneous, mass-like consolidative opacities or rounded nodules. Treatment was primarily supportive. Three patients received medical therapy; two were treated with interferon, and one received propranolol. The infant treated with propranolol responded well with decreased lesional size and resolution of respiratory symptoms. Half of the patients in the cohort died; causes of death included cardiac failure from hepatic involvement, sepsis, hemorrhage, and liver failure. Conclusions Although IH is a common childhood tumor, IH of the lung is rare. Most (80%) IHs are focal, with hepatic co-involvement in 50-60% cases (Zavras et al. Eur J Pediatr, 2020; Hinen et al. Front Pediatr, 2020). Given that all patients who had concomitant hepatic hemangiomas died-albeit before the widespread availability of medical therapy-the presence of hepatic hemangiomas may confer high risk of complications. Patients with hepatic hemangiomas presented with pulmonary symptoms. Biopsy may be necessary to confirm the diagnosis of pulmonary IH and inform treatment. In this series, only treatment with propranolol or surgical resection was curative. Pulmonary IH should be considered in the differential diagnosis of infants with unexplained pulmonary masses, especially when accompanied by hepatic IH. Early recognition is critical for patients to receive proper and potentially life-saving treatment. Disclosures No relevant conflicts of interest to declare.

Parkes Weber syndrome is a vascular malformation overgrowth condition typically involving the legs. Its main features are diffuse arteriovenous fistulas and enlargement of the limb. The condition has been associated with pathogenic germline variants in RASA1 and EPHB4. We report two individuals with Parkes Weber syndrome of the leg and primary lymphedema containing a somatic KRAS variant (NM_004985.5:c.35G > A; p.Gly12Asp). KRAS variants, which cause somatic intracranial and extracranial arteriovenous malformations, also result in Parkes Weber syndrome with lymphatic malformations.

Background: Vascular anomalies are diverse entities and can range in severity from self-limiting to life-threatening. Diagnosis and care of these patients is challenging due to overlapping clinical and histologic features. Recently, it has been established that many vascular anomalies arise from somatic mutations in cancer genes (PIK3CA, AKT, NRAS). Use of cancer genomics in patients with vascular anomalies may establish a genetic diagnosis and expand use of targeted medical therapies. We evaluated the utility of targeted next generation sequencing for vascular anomalies patients at a single pediatric center. Methods: Using OncoPanel, a hybrid-capture and massively parallel sequencing assay that surveys DNA sequences of 447 genes implicated in cancer, we analyzed genetic variants in lesional tissue from vascular anomalies patients evaluated at Boston Children's Hospital between 5/2/2017 and 3/23/2020. Results: A total of 276 patients were consented and sequenced under the Dana Farber Cancer Institute Profile protocols DFCI 11-104 (n= 68) and DFCI 17-000 (n= 208). Clinical diagnoses prior to testing were varied and 11 patients (7%) had an unknown diagnosis. Tissue was analyzed for 138 patients. Targeted sequencing resulted in diagnostically significant alterations in 80 of 138 (57%) of patients and therapeutically significant alterations in 58 of 138 (42%) patients. To date, 18 patients in our cohort have been treated with medical therapy informed by their genetic diagnosis. Several more await enrollment on clinical trials. For patients with diagnoses previously categorized as unknown (n=11), sequencing led to identification of a genetic variant in 6 patients (54%). Additionally, 8/138 patients had variants requiring further evaluation for potential germline involvement. Discussion: Next generation sequencing in vascular anomalies patients identified actionable variants in a large proportion of the patients in our cohort. The mTOR inhibitor sirolimus has been used to treat a variety of vascular anomalies, but not all patients respond to this treatment. Targeted therapies based on specific genotypes hold promise as clinical trials in vascular anomalies are emerging. Additionally, sequencing in this cohort identified several variants suggesting a germline cancer predisposition requiring follow-up. Use of next generation sequencing has clinical utility and increased use of this testing may improve diagnosis, prognosis, and treatment for patients with vascular anomalies. Disclosures Adams: Novartis: Consultancy; Venthura: Consultancy. OffLabel Disclosure: Sirolimus is used off-label for the treatment of vascular anomalies.

The purpose of this study was to compare cervical cancer knowledge and prevention strategy participation among Chinese-American women compared with Southeast-Asian-American women.We performed a cross-sectional survey of Chinese and Southeast Asian women in Rhode Island. Anonymous surveys were administered following informed consent. The survey included demographics and questions related to health care practices, cervical cancer, and the human papilloma virus (HPV). Categorical variables were compared by Fisher's exact test. Mean scores of correct answers on the knowledge questions were compared by Student's t-test and analysis of variance.Ninety-six Chinese women and 132 Southeast Asian women were included in the analysis. Sixty-seven percent of Chinese women had at least a college education compared with 37% of Southeast Asian women (p.0001). Nineteen percent of Chinese women reported annual household incomes of greater than $100,000 compared with 3% of Southeast Asian women (p = .0003). Twenty percent of Southeast Asian women did not have health insurance compared with 10% of Chinese women (p = .06). Among both groups, 25% of participants either never had a pap test or did not know if they ever had a pap test. There was a greater lack of knowledge about the relationship between HPV and cervical cancer among Chinese (mean 2.9 out of 8 questions) compared with Southeast Asian (mean 3.6 out of 8 questions; p = .02).Regardless of ethnic subgroup, education, or income, all participants had a poor knowledge of cervical cancer and HPV. This study supports the need for improvement in cervical cancer prevention education among all Asian women.

Background Of 1174 new human immunodeficiency virus (HIV) cases diagnosed in Philadelphia, Pennsylvania, in 2008, a total of 771 (66%) were among African Americans. Philadelphia recently introduced a citywide rapid HIV testing program in public clinics. Methods We conducted a qualitative study among 60 African Americans undergoing rapid HIV testing in one of Philadelphia's public clinics located in a zip code with high HIV incidence. Employing grounded theory, we used semistruc- tured interviews to assess patients' motivations, perceptions, and clinical experiences with rapid HIV testing. Interviews were transcribed and coded; 20% were double coded to enhance reliability. Results Primary motivations for undergoing rapid HIV testing included: testing during routine clinical care, presenting for care with symptomatic sexually transmitted infections or opportunistic infections, knowing someone living with HIV/ AIDS, and perceiving oneself at risk for HIV. Most patients reported positive experiences with rapid testing and preferred it to conventional testing because it eliminated the need for return visits and decreased anxiety; however, many expressed concerns about accuracy of rapid HIV testing. Barriers to HIV testing among this population included low self-perceived risk, HIV stigma, and reported homophobia in respondents' communities. Conclusion This rapid testing program was acceptable, convenient, and preferred over conventional HIV testing. Providing educational information about rapid and confirmatory HIV testing may further enhance acceptability of rapid HIV testing in this population. Nationwide expansion of rapid HIV testing in public health centers is an important and acceptable means of achieving President Obama's National AIDS Strategy goals of reducing racial disparities in HIV infection and improving linkage to HIV/AIDS treatment and care services.

Background: Kaposiform lymphangiomatosis (KLA) is a rare, aggressive lymphatic malformation that can lead to significant morbidity and mortality (Croteau et al 2014). First described as a distinct entity from generalized lymphatic anomaly (GLA) in 2014, KLA is histologically defined by spindled "kaposiform" endothelial cells associated with abnormal proliferation of lymphatic vessels. High risk features include pleural/pericardial effusions and coagulopathy. Respiratory failure, infections, and hemorrhage are common causes of death. In the largest case series of patients with KLA (n=20), five-year survival was 51%. Mean interval between diagnosis and death was 2.75 years. In recent years, the oral agent sirolimus has been used to treat KLA as a single agent or in combination with steroids and vincristine. No update has been published about overall outcomes for patients since the more widespread use of sirolimus. Methods: We conducted a retrospective chart review of 44 patients with biopsy-proven KLA referred to the Vascular Anomalies Center at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center between 1995 and 2018. Twenty patients were previously analyzed in a retrospective review. Patient data were gathered through the electronic medical record and and the Lymphatic Anomalies Registry. Response to treatment was defined by clinical assessment via extraction from the medical record, improvement in patient or parent-reported quality-of-life, improved coagulopathy, and decreased size of lesions on imaging. Toxicities were graded according to the NIH CTCAE grading scale. Clinical outcomes were evaluated up until July 2018. Results: Among 44 patients with KLA, the median age at onset of symptoms was 7 years (range=0-40.6 years). The median time from development of first symptoms to diagnosis of KLA was 16.4 months (range=0-12 years). Seventy-eight percent of patients had pleural or pericardial effusions at presentation (Figure 1). Anatomic involvement varied, with 65% of patients having bony involvement and 68% of patients having visceral disease. Bleeding was also common, with 14% of patients requiring transfusions of blood products. Twenty-four (56%) of 44 patients were treated with sirolimus. Of those 24 patients, 20 (83%) patients reported ever having a sustained response to sirolimus (>6 months) based on our criteria. Despite improvement in disease symptoms, there was no significant difference in overall survival between patients who were treated with sirolimus and those who were not (log-rank p=0.62; Figure 1). Of the 44 patients evaluated in our study, fourteen died. Nine of the patients did not receive sirolimus (they died prior to its use in treating vascular anomalies). Of the 5 patients who received sirolimus and subsequently died, one reported marked improvement in his quality of life, but died from a pneumothorax during chest tube placement for a pleural effusion. The other patient who responded died from respiratory failure after a period of non-adherence with taking sirolimus. The remaining three patients did not respond to sirolimus and died of multi-organ failure. Among the 14 patients who died, the median time from diagnosis to death was 2.2 years (range 0.2- 7.1 years). Among 24 patients treated with sirolimus, 16 (67%) patients were treated concurrently with either vincristine (n=10) and/or steroids (n=15). Eight patients had sustained response with sirolimus alone. Minimal side effects were observed; there was only one grade 3 thrombocytopenia that did not require cessation of sirolimus. Sixteen patients remained on sirolimus at last follow-up. Conclusions: Most patients treated with sirolimus report stabilization of their disease symptoms and improvement in quality of life. Sirolimus is well-tolerated and most patients who respond remain on sirolimus as a form of chronic therapy. However, overall mortality for KLA remains high, even for those patients treated with sirolimus. More research is needed to investigate possible risk factors for poor outcomes. Investigation regarding phenotype-genotype correlation for KLA is ongoing, with the hope of identifying additional treatment options. In our study, there was a gap of > 1 year between time of symptom onset and diagnosis of KLA, highlighting a need for increased awareness of this unique disease entity and prompt referral of patients to a center with expertise in vascular anomalies. Disclosures No relevant conflicts of interest to declare.

Purpose Few transgender youth eligible for gender-affirming treatments actually receive them. Multidisciplinary gender clinics improve access and care coordination but are rare. Although experts support use of pubertal blockers and cross-sex hormones for youth who meet criteria, these are uncommonly offered. This study's aim was to understand barriers that transgender youth and their caregivers face in accessing gender-affirming health care. Methods Transgender youth (age 14–22 years) and caregivers of transgender youth were recruited from Seattle-based clinics, and readerships from a blog and support group listserv. Through individual interviews, focus groups, or an online survey, participants described their experiences accessing gender-affirming health care. We then used theoretical thematic analysis to analyze data. Results Sixty-five participants (15 youth, 50 caregivers) described barriers spanning six themes: (1) few accessible pediatric providers are trained in gender-affirming health care; (2) lack of consistently applied protocols; (3) inconsistent use of chosen name/pronoun; (4) uncoordinated care and gatekeeping; (5) limited/delayed access to pubertal blockers and cross-sex hormones; and (6) insurance exclusions. Conclusions This is the first study aimed at understanding perceived barriers to care among transgender youth and their caregivers. Themed barriers to care led to the following recommendations: (1) mandatory training on gender-affirming health care and cultural humility for providers/staff; (2) development of protocols for the care of young transgender patients, as well as roadmaps for families; (3) asking and recording of chosen name/pronoun; (4) increased number of multidisciplinary gender clinics; (5) providing cross-sex hormones at an age that permits peer-congruent development; and (6) designating a navigator for transgender patients in clinics.