Harry P W Kozakewich

Boston Children's Hospital, Boston, Massachusetts, United States

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Publications (153)594.98 Total impact

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    ABSTRACT: Verrucous venous malformation (VVM), also called "verrucous hemangioma," is a non-hereditary, congenital, vascular anomaly comprised of aberrant clusters of malformed dermal venule-like channels underlying hyperkeratotic skin. We tested the hypothesis that VVM lesions arise as a consequence of a somatic mutation. We performed whole-exome sequencing (WES) on VVM tissue from six unrelated individuals and looked for somatic mutations affecting the same gene in specimens from multiple persons. We observed mosaicism for a missense mutation (NM_002401.3, c.1323C>G; NP_002392, p.Iso441Met) in mitogen-activated protein kinase kinase kinase 3 (MAP3K3) in three of six individuals. We confirmed the presence of this mutation via droplet digital PCR (ddPCR) in the three subjects and found the mutation in three additional specimens from another four participants. Mutant allele frequencies ranged from 6% to 19% in affected tissue. We did not observe this mutant allele in unaffected tissue or in affected tissue from individuals with other types of vascular anomalies. Studies using global and conditional Map3k3 knockout mice have previously implicated MAP3K3 in vascular development. MAP3K3 dysfunction probably causes VVM in humans. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 02/2015; DOI:10.1016/j.ajhg.2015.01.007 · 11.20 Impact Factor
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    ABSTRACT: To test the hypothesis that somatic phosphatidylinositol-4,5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS). We used next generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children's Hospital who had an isolated LM (n = 17), KTS (n = 21), fibro-adipose vascular anomaly (n = 8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n = 31) from Seattle Children's Hospital. Most individuals from Boston Children's Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), fibro-adipose vascular anomaly (5/8), and congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (31/33) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ∼80% of cases. Seventy-four percent of patients with LM from Seattle Children's Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells. Somatic PIK3CA mutations are the most common cause of isolated LMs and disorders in which LM is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism because the abundance of mutant cells in a malformed tissue can be low. Copyright © 2015 Elsevier Inc. All rights reserved.
    Journal of Pediatrics 02/2015; DOI:10.1016/j.jpeds.2014.12.069 · 3.74 Impact Factor
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    ABSTRACT: Microvillus inclusion disease (MVID) is a rare congenital disorder that manifests early in infancy as intractable watery diarrhea. The entity is characterized morphologically by a deficient brush border and apical cytoplasmic inclusions within absorptive cells (enterocytes) due to misplaced assembly of brush border proteins. The diagnosis is based upon histopathology, special stains, immunohistochemistry (IHC), and ultimately upon electron microscopy. Currently, the periodic acid-Schiff stain (PAS) and CD10 IHC are commonly used as adjuncts, but in addition to brush border structures, they stain a variety of apical cytoplasmic inclusions and organelles, thereby interfering with recognition of microvillus inclusions. Villin is a protein that specifically binds to the actin core bundle of microvilli. We utilized villin IHC in formalin-fixed paraffin-embedded gastrointestinal biopsies from 6 patients with MVID, 5 with celiac disease, and 17 children with normal intestinal biopsies and compared the results with those obtained with CD10 IHC and PAS staining. All MVID cases had confirmatory electron microscopy at the time of diagnosis. Villin immunoreactivity was restricted to the brush border in the control groups. In MVID, villin IHC showed attenuation or loss of the surface brush border and also highlighted the cytoplasmic microvillus inclusions with clarity. In MVID, CD10 IHC and the PAS stain also showed attenuation or loss of the surface brush border, but staining of a variety of cytoplasmic structures largely obscured the microvillus inclusions. In sum, villin IHC is a reliable and superior adjunct in the diagnosis of MVID. Study of additional cases will determine whether villin IHC would obviate the need for electron microscopic confirmation.
    American Journal of Surgical Pathology 12/2014; 39(2). DOI:10.1097/PAS.0000000000000355 · 4.59 Impact Factor
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    ABSTRACT: Multifocal and diffuse hepatic hemangiomas are true infantile hemangiomas, which likely exist in a continuum. We reviewed our hepatic hemangioma registry to identify prognostic indicators for mortality. Registry records entered between 1995 and 2012 were reviewed. Clinical characteristics were evaluated for prognostic significance using the multivariable Cox proportional hazards model. Survival data were analyzed using the Kaplan-Meier product-limit method. We identified 123 patients with multifocal (n=91) and diffuse (n=32) hepatic hemangiomas. Mortality was 16% (n=20); 40% (n=8) had multifocal and 60% (n=12) had diffuse lesions. A diagnosis of diffuse disease (hazard ratio: 9.9, 95% CI: 2.0-50.8, P=.002) and congestive heart failure (CHF) (hazard ratio: 3.9, 95% CI: 1.3-14.2, P=.031) were significant risk factors for mortality across the continuum; age at presentation, cardiomegaly, presence of shunts, and hypothyroidism were not statistically significant independent risk factors. Among patients with diffuse lesions, eight (67%) who died had abdominal compartment syndrome, which was also associated with mortality (P=.002). Hepatic hemangioma patients with CHF or diffuse disease are at higher risk for mortality. Patients with multifocal lesions without CHF may go undetected until lesions become diffuse. Aggressive treatment of symptomatic patients and close follow-up of asymptomatic patients may improve mortality. Copyright © 2014. Published by Elsevier Inc.
    Journal of Pediatric Surgery 12/2014; DOI:10.1016/j.jpedsurg.2014.09.056 · 1.31 Impact Factor
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    ABSTRACT: Uncommon congenital hemangiomas differ from common infantile hemangiomas in their appearance, postnatal behavior, histopathology, and immunohistologic staining. Two types are well described in the literature: noninvoluting congenital hemangioma (NICH) and rapidly involuting congenital hemangioma (RICH). We report a series of infants with another presentation of congenital hemangioma that arises prenatally and is nearly regressed at birth. This was a retrospective case series. We describe six infants with unusual congenital vascular tumors. Each lesion presented at birth as a violaceous, atrophic plaque with a surrounding pale halo. The lesions involuted in infancy, fading in color and becoming atrophic, with prominent central veins, similar to RICH in the final stage of regression. The distinctive morphology and behavior suggests that these tumors undergo a life cycle of proliferation and involution during fetal life. We describe a new variant of congenital hemangioma that we refer to as rapidly involuting congenital hemangioma with fetal involution.
    Pediatric Dermatology 12/2014; DOI:10.1111/pde.12356 · 1.52 Impact Factor
  • Journal of Pediatrics 08/2014; 165(4). DOI:10.1016/j.jpeds.2014.06.042 · 3.74 Impact Factor
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    ABSTRACT: The mechanism for the growth of infantile hemangioma and vascular malformations is unknown. Follicle-stimulating hormone secretion mirrors the life cycle of infantile hemangioma and increases during adolescence, when vascular malformations often progress. The purpose of this study was to determine whether vascular anomalies express the receptor for follicle-stimulating hormone. Human vascular tumors (i.e., infantile hemangioma, congenital hemangioma, kaposiform hemangioendothelioma, and pyogenic granuloma) and vascular malformations (i.e., capillary, lymphatic, venous, and arteriovenous) were subjected to immunofluorescence for follicle-stimulating hormone receptor. Control specimens included normal skin/subcutis, mucosa, liver, spleen, Crohn disease, granulation, pancreatitis, rheumatoid arthritis, and synovitis. Receptor and microvessel density were quantified using imaging software. Follicle-stimulating hormone receptor was found in the endothelium of all vascular anomalies but was not present in control specimens. Expression was greater in proliferating infantile hemangioma (6.0 percent) compared with other vascular tumors (congenital hemangioma, 0.61 percent; kaposiform hemangioendothelioma, 0.55 percent; pyogenic granuloma, 0.56 percent; p < 0.0001), despite similar microvessel density (p = 0.1). Follicle-stimulating hormone receptor was elevated in arteriovenous malformations (2.65 percent) compared with other types of vascular malformations (capillary, 1.02 percent; lymphatic, 0.38 percent; venous, 0.76 percent; p < 0.0001). Vascular anomalies express follicle-stimulating hormone receptor on their endothelium, in contrast to vascular control tissues. Vascular anomalies are the only benign, pathologic tissue known to express this receptor. Because the secretion of follicle-stimulating hormone correlates with the growth pattern of infantile hemangioma and vascular malformations, follicle-stimulating hormone might be involved in the pathogenesis of these lesions.
    Plastic and Reconstructive Surgery 03/2014; 133(3):344e-51e. DOI:10.1097/01.prs.0000438458.60474.fc · 3.33 Impact Factor
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    ABSTRACT: Glomuvenous malformation (GVM) is an inherited autosomal dominant trait. The lesions, which appear as bluish nodules or plaque-like cutaneous elevations, are usually tender and more firm than sporadic venous malformations. Conventionally, the lesions are thought to be limited to the cutaneous and subcutaneous tissue planes. The objective was to characterize the depth of involvement of GVM lesions. Magnetic resonance imaging (MRI) findings in GVM were retrospectively evaluated by two radiologists. The signal characteristics, tissue distribution, pattern of contrast enhancement of the lesions in GVM were documented. Thirty patients (19 female) aged 1-35 years (mean 18 years) were diagnosed with GVM based on clinical features (n = 20) and/or histopathological findings (n = 10). The lesions were present in the lower extremity (n = 15), upper extremity (n = 6), cervico-facial region (n = 6), pelvis (n = 2), and chest wall (n = 1). All patients had skin and subcutaneous lesions. Fifty percent of the patients (n = 15) demonstrated subfascial intramuscular (n = 15), intra-osseous (n = 1), and intra-articular involvement (n = 1). Contrary to the conventional belief that GVMs are generally limited to the skin and subcutaneous tissue, deep subfascial extension of the lesions is common.
    Skeletal Radiology 02/2014; 43(7). DOI:10.1007/s00256-014-1836-3 · 1.74 Impact Factor
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    ABSTRACT: In mice, activated Hedgehog (Hh) signaling induces tumors with myogenic differentiation. In humans, hyperactive Hh signaling due to germline PATCHED1 (PTCH1) mutations has been linked to nevoid basal cell carcinoma syndrome (NBCCS). We report an embryonal rhabdomyosarcoma in a 16-month-old girl with NBCCS and review the literature on myogenic neoplasms in NBCCS, including 8 fetal rhabdomyomas and 3 rhabdomyosarcomas. Of note, 3 population studies, including 255 individuals with NBCCS aged 4 months to 87 years, did not identify any myogenic tumors. Thus, myogenic tumors in NBCCS are rare and include both rhabdomyosarcomas and fetal rhabdomyomas.
    Journal of Pediatric Hematology/Oncology 02/2014; DOI:10.1097/MPH.0000000000000115 · 0.96 Impact Factor
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    ABSTRACT: Infantile hemangiomas demonstrate a pattern of proliferative growth in infancy followed by a slow phase of involution. In contrast a rare type of vascular tumor, intramuscular capillary-type hemangioma, usually presents beyond the period of infancy with nonspecific symptoms and no evidence of involution. The purpose of this study was to characterize the clinical, imaging, histopathological characteristics and management of intramuscular capillary-type hemangioma. We performed a retrospective review of a 20-year period to identify children diagnosed with intramuscular capillary-type hemangioma. Patient demographics, imaging and histopathological findings were recorded. We included 18 children (10 boys, 8 girls) with histologically proven intramuscular capillary-type hemangioma - and adequate imaging. The mean age at presentation was 8.1 years (range 1 day to 19 years). Twelve lesions involved muscles of the extremities, 4 were located in the trunk and 2 were in the head and neck. MRI had been performed in all children and demonstrated a soft-tissue mass with flow voids, consistent with fast flow. The lesion was well-circumscribed in 16 children and intralesional fat was seen in 14. Doppler US demonstrated a heterogeneous lesion, predominantly isoechoic to surrounding muscle, with enlarged arterial feeders. Enlarged feeding arteries, inhomogeneous blush and lack of arteriovenous shunting were noted on angiography (n = 5). The most common histopathological findings were lobules of capillaries with plump endothelium and at least some adipose tissue. The lesions were excised in six children. Two children were lost to follow-up. In the remaining 10, follow-up MRI studies ranging from 3 months to 10 years showed that the lesion enlarged in proportion to the child (n = 7), demonstrated slow growth (n = 2) or remained stable (n = 1). There was no change in imaging characteristics on follow-up. Intramuscular capillary-type hemangioma is a rare benign vascular tumor of skeletal muscle. The most typical imaging features show a heterogeneous intramuscular mass with fast flow, and intralesional fat. Although the lesion is relatively stable in appearance over time, imaging does not obviate the need for a biopsy to rule out sarcoma. The diagnosis can usually be established by typical findings on histopathology.
    Pediatric Radiology 02/2014; 44(5). DOI:10.1007/s00247-014-2876-5 · 1.65 Impact Factor
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    ABSTRACT: The diagnosis and management of vascular anomalies of the extremities can be challenging as these disorders are uncommon and may clinically overlap. The aim of this paper is to describe the clinical, radiologic, and histopathologic features of fibro-adipose vascular anomaly (FAVA), a previously unrecognized disorder of the limb. The clinical, imaging, operative, and histopathologic data from patients with a unique intramuscular lesion of the extremities comprising dense fibrofatty tissue and slow-flow vascular malformations were retrospectively reviewed. Sixteen patients diagnosed with FAVA of the extremity (3 male and 13 female individuals) met the clinical, radiologic, and histopathologic inclusion criteria. The age at presentation ranged from the time of birth to 28 years. The locations of the lesions were: calf (n=10), forearm/wrist (n=3), and thigh (n=3). Fourteen patients presented with severe pain. Seven of the patients with calf lesions had limited ankle dorsiflexion. On imaging, the complex intramuscular lesions replaced muscle fibers with fibrofatty overgrowth and phlebectasia (dilation of the veins). The extrafascial component comprised fatty overgrowth, phlebectasia, and an occasional lymphatic malformation. The histopathologic features comprised dense fibrous tissue, fat, and lymphoplasmacytic aggregates within atrophied skeletal muscle. Adipose tissue also infiltrated skeletal muscle at the periphery of the lesion. There were large, irregular, and sometimes excessively muscularized venous channels and smaller, clustered channels. Other findings include organizing thrombi, a lymphatic component, and dense fibrous tissue-encircled nerves. The constellation of clinical, radiologic, and histopathologic features constitutes a distinct entity comprising fibrofatty infiltration of muscle, unusual phlebectasia with pain, and contracture of the affected extremity. The clinical and radiologic findings permit the diagnosis of FAVA with major therapeutic implications. Level III.
    Journal of pediatric orthopedics 01/2014; 34(1):109-17. DOI:10.1097/BPO.0b013e3182a1f0b8 · 1.23 Impact Factor
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    ABSTRACT: In a retrospective analysis of childhood thyroid nodules, 18% were radiographic incidentalomas and 41% were discovered by a clinician's palpation; 40% were discovered by patients' families. The latter group had the largest nodules and highest rates of thyroid cancer metastasis, suggesting opportunities for earlier detection through annual well-child visits.
    The Journal of pediatrics 12/2013; 164(3). DOI:10.1016/j.jpeds.2013.10.090 · 4.02 Impact Factor
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    ABSTRACT: To describe the clinical and imaging characteristics of a new lymphatic disorder with a unique histological pattern and poor prognosis. An observational, retrospective study identified and characterized 20 patients with distinct lymphatic histopathology referred to the Vascular Anomalies Center at Boston Children's Hospital between 1995 and 2011. The median age at onset was 6.5 years (range, birth to 44 years). Clinical and radiologic findings suggested a generalized process. The most common presentations were respiratory symptoms (50%), hemostatic abnormalities (50%), and an enlarging, palpable mass (35%). All patients had mediastinal involvement; 19 patients developed pericardial (70%) and/or pleural effusions (85%). Extrathoracic disease manifested in bone and spleen and less frequently in abdominal viscera, peritoneum, integument, and extremities. Despite aggressive procedural and medical therapies, the 5-year survival was 51% and the overall survival was 34%. Mean interval between diagnosis and death was 2.75 years (range, 1-6.5 years). We describe a clinicopathologically distinct lymphatic anomaly. We propose the term kaposiform lymphangiomatosis (KLA) because of characteristic clusters or sheets of spindled lymphatic endothelial cells accompanying malformed lymphatic channels. The intrathoracic component is most commonly implicated in morbidity and mortality; however, extrathoracic disease is frequent, indicating that KLA is not restricted to pulmonary lymphatics. The mortality rate of KLA is high despite aggressive multimodal therapy.
    The Journal of pediatrics 11/2013; DOI:10.1016/j.jpeds.2013.10.013 · 4.02 Impact Factor
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    ABSTRACT: Purpose Hepatic hemangiomas are often found in association with multiple cutaneous infantile hemangiomas. Screening abdominal ultrasonography has been recommended for patients with more than five cutaneous lesions. We reviewed our hepatic hemangioma registry to determine if screening has allowed for earlier detection and improved clinical outcomes. Methods Registry records of patients with a diagnosis of hepatic hemangioma entered between 1995 and 2012 were reviewed following IRB approval. Patients without multiple cutaneous lesions or screening data were excluded. Statistical analysis was conducted using Fisher’s exact and Mann-Whitney U tests, as appropriate, with 95% confidence intervals using Wilson’s method. Results We identified 77 patients with multiple cutaneous and hepatic hemangiomas. Forty-six (60%) had hepatic hemangiomas detected through screening, while 31 (40%) were found on work-up for other indications. Median age at diagnosis for screened patients was 46 days and 45 days for those not screened (p=0.636). Screening detected 40 (87%) multifocal, 3 (6.5%) diffuse, and 3 (6.5%) focal lesions, compared to 28 (55%), 16 (31%), and 7 (14%), respectively, in the non-screened group (p=0.005). Patients identified by screening had statistically significant lower incidences of congestive heart failure (CHF) (p<0.001) and hypothyroidism (p=0.005). Only 2 (4%) and 4 (9%) children screened developed CHF and hypothyroidism, respectively, compared to 15 (48%) and 10 (32%), respectively, in those with hepatic hemangiomas not detected through screening. Children who were screened were less likely to receive treatment (35% vs. 87%, p<0.001). Only 1 patient (2%) in the screened group and 4 (13%) in the non-screened group required embolization. Three (27%) of the diffuse patients not detected by screening ultrasonography progressed to abdominal compartment syndrome (ACS); no children in the screened group developed ACS. The mortality rate in the children not identified by screening was 26% (n=8), while none of the patients found by screening died (p<0.001). Conclusion Patients with hepatic hemangiomas found through screening abdominal ultrasonography are less likely to develop serious clinical sequelae. Although screening has probably detected less severe hepatic hemangiomas, it may allow for earlier treatment and closer surveillance of lesions before they can progress, preventing complications and reducing mortality.
    2013 American Academy of Pediatrics National Conference and Exhibition; 10/2013
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    ABSTRACT: CONTEXT:Thyroid cancer is the most common endocrine malignancy but, due to its rare occurrence in the pediatric population, the cancer risk of childhood thyroid nodules is incompletely defined and optimal management of children with suspected nodules is debated.OBJECTIVE:To study the presenting features and cancer risk of sporadic childhood thyroid nodules, using a standardized clinical assessment and management plan.DESIGN AND SETTING:Boston Children's Hospital and Brigham and Women's Hospital collaborated to create a multidisciplinary pediatric thyroid nodule clinic and implement a standardized assessment plan. Upon referral for a suspected nodule, serum TSH was measured and hypothyrotropinemic patients underwent (123)I scintigraphy. All others underwent thyroid ultrasonography and, if this confirmed nodule(s) ≥1 cm, ultrasound-guided fine-needle aspiration was performed. Medical records were retrospectively reviewed and compared to a control population of 2582 adults evaluated by identical methods.PATIENTS AND RESULTS:Of 300 consecutive children referred for the initial evaluation of suspected thyroid nodules from 1997 to 2011, 17 were diagnosed with autonomous nodules by scintigraphy. Neck ultrasonography performed in the remainder revealed that biopsy was unnecessary in over half, either by documenting only subcentimeter nodules or showing that no nodule was present. One-hundred and twenty five children met criteria for thyroid biopsy, which was performed without complication. Their rate of cancer was 22%, significantly higher than the adult rate of 14% (p =0.02).CONCLUSIONS:Neck ultrasonography and biopsy were key to the evaluation of children with suspected thyroid nodules. While the relative cancer prevalence of sonographically-confirmed nodules ≥1 cm is higher in pediatric patients than adults, most children referred for suspected nodules have benign conditions and efforts to avoid unnecessary surgery in this majority are warranted.
    The Journal of Clinical Endocrinology and Metabolism 06/2013; 98(8). DOI:10.1210/jc.2013-1796 · 6.31 Impact Factor
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    Skeletal Radiology 02/2013; DOI:10.1007/s00256-013-1592-9 · 1.74 Impact Factor
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    ABSTRACT: Spindle cell hemangioma (SCH) is a rare, benign vascular tumor of the dermis and subcutis. The lesions can be multifocal and are overrepresented in Maffucci syndrome, in which patients also have multiple enchondromas. Somatic mosaic R132C IDH1 hotspot mutations were recently identified in Maffucci syndrome. We evaluated the presence of mutations in solitary and multiple SCHs in patients without multiple enchondromas and tested a range of other vascular lesions that enter into the differential diagnosis. The R132C IDH1 mutation was identified by hydrolysis probes assay and confirmed by Sanger sequencing in 18 of 28 (64%) SCHs; of the 10 negative cases, 2 harbored a mutation in IDH2 (R172T and R172M) by Sanger sequencing. None of 154 other vascular malformations and tumors harbored an IDH1 R132C mutation, and R132H IDH1 mutations were absent in all 182 cases. All 16 SCHs examined by immunohistochemistry were negative for expression of HIF-1α. In conclusion, 20 of 28 (71%) SCHs harbored mutations in exon 4 of IDH1 or IDH2. Given that mutations were absent in 154 other vascular lesions, the mutation seems to be highly specific for SCH. The mutation does not induce expression of HIF-1α in SCH, and therefore the exact mechanism by which mutations in IDH1 or IDH2 lead to vascular tumorigenesis remains to be established.
    American Journal Of Pathology 02/2013; DOI:10.1016/j.ajpath.2013.01.012 · 4.60 Impact Factor
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    ABSTRACT: PURPOSE: Gorham-Stout disease (GSD) is a rare vascular disorder of lymphatic origin characterized by progressive osteolysis. Generalized lymphatic anomaly (GLA) is a multisystem disorder that also commonly affects bone. We hypothesized that Gorham-Stout disease is different from other osseous lymphatic anomalies. We proposed to discriminate these entities by analyzing findings on skeletal imaging. METHODS: Clinical data, imaging studies, and histopathologic findings were retrospectively reviewed in patients presenting to our Vascular Anomalies Center with lymphatic anomalies of bone. FINDINGS: Within a cohort of 51 patients with lymphatic disorder and radiological evidence of bony involvement, two distinct categories emerged. Nineteen patients met the imaging criteria for GSD: progressive osteolysis with resorption and cortical loss. Thirty-two were categorized as GLA: Discrete radiolucencies and increasing numbers of bone affected over time, but without evidence of progressive osteolysis. The ribs were the most common site in both groups, followed by the cranium, clavicle, and cervical spine in GSD, and thoracic spine, humerus, and femur in GLA. Fewer bones were involved in GSD, with relative sparing of the appendicular skeleton. Associated infiltrative soft tissue abnormality was seen in 18 in GSD, but only six with GLA. Macrocystic lymphatic malformations were identified in 14 with GLA, but none with GSD. CONCLUSIONS: There are significant radiological differences between GSD and GLA, although there are some overlapping features. The major distinguishing characteristic is the progressive osteolysis seen in GSD. Findings suggestive of GLA are more extensive involvement, particularly of the appendicular skeleton, presence of discretemacrocystic lymphatic malformations and visceral organ lesions.
    Skeletal Radiology 01/2013; DOI:10.1007/s00256-012-1565-4 · 1.74 Impact Factor
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    ABSTRACT: Pyogenic granuloma, also called lobular capillary hemangioma, is a condition usually occurring in skin or mucosa and often related to prior local trauma or pregnancy. However, the etiopathogenesis of pyogenic granuloma is poorly understood and whether pyogenic granuloma being a reactive process or a tumor is unknown. In an attempt to clarify this issue, we performed genome-wide transcriptional profiling of laser-captured vessels from pyogenic granuloma and from a richly vascularized tissue, placenta, as well as, from proliferative and involutive hemangiomas. Our study identified a gene signature specific to pyogenic granuloma. In the serial analysis of gene expression (SAGE) database, this signature was linked to 'white blood cells monocytes'. It also demonstrated high enrichment for gene ontology terms corresponding to 'vasculature development' and 'regulation of blood pressure'. This signature included genes of the nitric oxide pathway alongside genes related to hypoxia-induced angiogenesis and vascular injury, three conditions biologically interconnected. Finally, one of the genes specifically associated with pyogenic granuloma was FLT4, a tyrosine-kinase receptor related to pathological angiogenesis. All together, these data advocate for pyogenic granuloma to be a reactive lesion resulting from tissue injury, followed by an impaired wound healing response, during which vascular growth is driven by FLT4 and the nitric oxide pathway.Modern Pathology advance online publication, 7 September 2012; doi:10.1038/modpathol.2012.148.
    Modern Pathology 09/2012; 26(2). DOI:10.1038/modpathol.2012.148 · 6.36 Impact Factor
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    ABSTRACT: OBJECTIVE: To examine the presentation characteristics of patients with Kaposiform hemangioendothelioma (KHE) to describe the spectrum of disease and risk factors for Kasabach-Merritt phenomenon (KMP). STUDY DESIGN: A retrospective review of 163 patients referred to the Vascular Anomalies Center at Children's Hospital Boston for KHE between 1991 and 2009 identified 107 patients with sufficient data for inclusion. RESULTS: The prevalence of KHE in Massachusetts is ∼0.91 case per 100 000 children. KHE manifested in infancy in 93% of cases, with 60% as neonates. Common presenting features included enlarging cutaneous lesion (75%), thrombocytopenia (56%), and musculoskeletal pain or decreased function (23%). Cutaneous KHE favored the extremities, especially overlying joints. In our cohort, 71% developed KMP (11% after initial presentation), and 11% of patients lacked cutaneous findings. Retroperitoneal and intrathoracic lesions, though less common, were complicated by KMP in 85% and 100% of cases, respectively. Compared with superficial lesions, KHE infiltrating into muscle or deeper was 6.3-fold more likely to manifest KMP and 18-fold higher if retroperitoneal or intrathoracic. KHE limited to bone or presenting after infancy did not manifest KMP. CONCLUSION: An enlarging cutaneous lesion is the most common presenting feature of KHE in infancy. Older patients with KHE or those lacking cutaneous manifestations present with musculoskeletal complaints or atypical symptoms. The risk of KMP increases dramatically when tumor infiltrates muscle or when KHE arises in the retroperitoneum or mediastinum.
    The Journal of pediatrics 08/2012; 162(1). DOI:10.1016/j.jpeds.2012.06.044 · 4.02 Impact Factor

Publication Stats

4k Citations
594.98 Total Impact Points


  • 1986–2015
    • Boston Children's Hospital
      • • Vascular Anomalies Center
      • • Department of Radiology
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 1993–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1992–2014
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2009
    • Baylor College of Medicine
      • Division of Plastic Surgery
      Houston, TX, United States
  • 2007
    • Oregon Health and Science University
      • Department of Cell & Developmental Biology
      Portland, Oregon, United States
  • 2004
    • Universität Basel
      • Institut für Pathologie
      Basel, BS, Switzerland
  • 2001
    • Universitair Ziekenhuis Leuven
      Louvain, Flemish, Belgium
    • Children's Memorial Hospital
      Chicago, Illinois, United States
  • 2000–2001
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, MA, United States
  • 1994–1998
    • Dana-Farber Cancer Institute
      • Department of Pediatric Oncology
      Boston, Massachusetts, United States
  • 1981–1996
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1995
    • University of Antwerp
      • Department of Pathology
      Antwerpen, Flanders, Belgium
  • 1991
    • Georgetown University
      • Department of Pathology
      Washington, D. C., DC, United States