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Tbx4 protein, expressed in mesenchyme of the developing lung, contributes to airway branching and distal lung growth. An association between pediatric onset of pulmonary arterial hypertension (PAH) and genetic variations coding for the T-box transcription factor 4 gene ( TBX4 ) has been increasingly recognized. Tbx4-related PAH onset has a bimodal age distribution, including severe to lethal PAH in newborns and later onset PAH. We present an autopsy study of a 24-year-old male with a heterozygous TBX4 variant, who developed pulmonary arterial hypertension at age 12 years. This unique case highlights the complex pulmonary histopathology leading to lethal cardiopulmonary failure in the setting of TBX4 mutation., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Intraocular teratomas are rare neoplasms with only three previously reported cases. We present the fourth case of intraocular teratoma and the second associated with sacrococcygeal teratoma. While the nature of the association between intraocular teratomas and sacrococcygeal teratomas is unclear, it suggests a need for careful ophthalmologic follow-up of infants with congenital sacrococcygeal teratomas.

Osteopetrosis (OP) is a clinically and genetically heterogeneous disease. Defects in the TCIRG1 gene are most frequently implicated in the osteoclast-rich form of OP. Little is known about the content and/or function of monocytes and macrophages of various organs rich in those cells in patients with OP. We report a patient with a novel TCIRG1 gene mutation that led to an osteoclast-rich OP. A bone marrow transplant failed to engraft, and the patient developed pulmonary hypertension. At autopsy he was found to have abnormal remodeling of the pulmonary vasculature and alveolar proteinosis. Alveolar macrophages were decreased. Pulmonary findings in this patient could be at least partially explained by abnormal surfactant metabolism due to depleted or defective alveolar macrophages.

Anomalies of the cardinal vein system (CVS) are uncommon but if unidentified can lead to life-threatening complications. We report a case with a novel malformation of the CVS. Autopsy with in situ dissection of heart and large vessels in a 25-day-old infant was performed. The infant was diagnosed with congenital heart disease, and systemic venous malformations were suspected by imaging. Correlation between premortem imaging and postmortem anatomy was performed. The superior and inferior left venous systems developed abnormally. A persistent left superior vena cava (PLSVC) drained into the right atrium via the coronary sinus. A persistent left inferior vena cava (PLIVC) continued with the hemiazygos vein (HV), which drained into the PLSVC. The innominate vein was absent. The left renal vein was connected to the HV. Two common iliac veins were identified. The left drained into the PLIVC and the right into the right inferior vena cava (IVC). Perinatal echocardiography identified only the dilated HV draining to an LSVC and a small IVC. Congenital heart disease included hypoplastic left ventricle with hypoplastic aortic arch and subaortic stenosis, which were diagnosed by fetal ultrasound. Remodeling of components of CVS takes place during development, and unknown mechanisms guide this process. Defects of this process can lead to variable malformations, as demonstrated by this case. To our knowledge, the combination of complex malformations of both superior and IVC systems that extends to the common iliac veins has not been reported. We recommend identifying vascular anomalies in situ during autopsy before anatomic relationships are altered.

Electron microscopy (EM) using a "lift technique" (EM-lift) of suspect cells has been used when a question of viral infection is raised by light microscopy and is not otherwise confirmed. We demonstrate how, in this unique circumstance, EM can complement or even supersede immunohistochemistry (IHC) and culture studies. Cases with suspected viral inclusions followed by EM-lift were collected over 25 years; hematoxylin and eosin, IHC, and culture findings were reviewed. Immunohistochemistry results were not available in 15 of the 30 samples found; tissue blocks were obtained in 6 of the samples, and additional IHC studies were performed. Nine cases had viral cultures. The usual clinical question was "rejection versus infection" in a transplant setting (56%). The gastrointestinal tract/liver was most frequently sampled (76%). The EM-lift technique confirmed virus in 18 cases, including adenovirus (58%), cytomegalovirus, herpes, papillomavirus, and parvovirus. Twenty-one cases had informative EM but IHC findings were positive in 8. Both EM-lift and IHC findings were positive in 5 cases and negative in 8 cases. All IHC-positive cases were positive by EM-lift. Of the 6 cases with new IHC, 2 negative cases stained with a newer antibody (EM-positive for adenovirus) and 4 remained negative. Nine had culture findings; 1 was positive, with positive EM-lift. Eight were culture-negative; 4 of these were EM-positive. We conclude that in clinical settings in which virus identification is critical and infection is not otherwise confirmed, the lift technique can be more sensitive than IHC (missed inclusions) and culture studies (often not done) or polymerase chain reaction test, which can be overly sensitive.

The mechanism of lymphangiogenesis is poorly understood, and controversy exists whether it is part of the inflammatory response to tissue injury. Utilizing markers specific to lymphatics, we aimed to study if lymphangiogenesis plays a role in the tissue response of mucoceles. Twenty-three extravasated mucoceles were selected. They were grouped by using widely accepted histologic criteria of wound healing into early-, intermediate-, and late-phase lesions. To identify lymphatic vessels we used lymphatic endothelium-specific antibodies (VEGFR3, Prospero-related homeobox gene-1 [Prox-1], and D2-40). To assess the proportion of lymphatic channels to all lesional vessels we used the panendothelial marker CD31. The presence, distribution, and proportion of lymphatic channels were assessed and compared among the groups. To investigate the involvement of lymphangiogenic signals, the expression of VEGFC was determined. To assess for proliferative activity of lymphatic endothelial cells we utilized Ki-67 antibody. Early-phase lesions (n = 6) were characterized by the presence of centrally located mucicarmine-positive material (mucin pools) with numerous inflammatory cells dominated by mucin-laden CD163-positive macrophages. Only scattered peripheral thin-walled large and small vessels were seen in the stroma surrounding the central mucin pool. Less than half of these vessels were of lymphatic nature as determined by Prox-1, VEGFR3, and D2-40 positivity. The histology of the intermediate-phase lesions (n = 6) was dominated by numerous lymphatics of varying size, not seen in the early phase. The histology of late-phase lesions (n = 11) resembled a "pseudo-cyst," with dense granulation tissue containing rare macrophages and rare lymphatic vessels. Although VEGFC was present in all phases, the highest expression was in the early phase. Low-grade proliferative lymphatic endothelium was noted in the intermediate lesions with a Ki-67 index of 4%. Early lymphangiogenesis and late lymphatic vessel regression were observed during mucocele evolution. The abundant newly formed ectatic lymphatic vessels seen in the intermediate phase may play a role in the clearance of extravasated material (mucin, edema, and lymph fluid) and in the initiation of the young fibroblast-rich granulation tissue. Mucocele appears to be an excellent human model for studying the factors that play a role in new lymphangiogenesis and regression.

We previously reported that D2-40 antibody identifies lymphatic endothelial cells (LECs) of lymphatic malformations (LM) with high specificity but only moderate sensitivity. The aim of this study was to compare the sensitivity and specificity of the markers Prospero-related homeobox gene-1 (Prox-1) and VEGFR3 to those of D2-40 for LECs in LM. Seventeen LM and 6 other vascular malformations with venous component (VM) were stained with D2-40, Prox-1, VEGFR3, CD31, and CD34 antibodies. The staining characteristics of vessels by each marker were assessed. Prox-1 and VEGFR3 specificity for LECs was examined by endothelial staining of VMs. Prox-1 and VEGFR3 stained substantially more large vessels than did D2-40 (15 of 17 cases). Small vessel staining was uniformly positive with all vascular markers except CD34, which did not stain lymphatic vessels. Eight cases had no or minimal D2-40 staining of large vessels, but the selected D2-40-vessels stained positive with VEGFR3, and 7 of 8 vessels were Prox-1 positive. Nine cases had variable D2-40 staining of large vessels; the selected D2-40 channels were all Prox-1 positive, and 8 of 9 were VEGFR3 positive. Two had rare vascular channels with no lymphatic marker stain but were positive for CD31 and CD34. Endothelial cells of VM had no Prox-1 but were VEGFR3/CD31/CD34 positive. VEGFR3 and Prox-1 antibodies have greater sensitivity for large lymphatic vessels than does D2-40. All lymphatic markers have high sensitivity for LECs of small lymphatic channels. Prox-1 has superior sensitivity and specificity to LECs. We recommend utilizing an immunohistochemical panel consisting of Prox-1, VEGFR3, CD31, and CD34 antibodies to differentiate lymphatic from venous malformations in pathologic practice.

Angiosarcomas are rare tumors in children, usually occurring in soft tissue and liver. By contrast, angiosarcoma in adults usually occurs in the extremities in conjunction with lymphedema. Mesenteric angiosarcoma has only rarely been reported. When angiosarcomas arise in this location, they usually represent a 2nd malignancy following Hodgkin's lymphoma. We report a child who presented to the emergency room with an acute abdomen and underwent emergency surgery for a mesenteric angiosarcoma with associated lymphangiectasia of the bowel and mesentery. A brief review of the literature and the nomenclature of these unusual tumors are discussed.

Immunoperoxidase techniques for demonstration of complement split product C4d on paraffin-embedded endomyocardial biopsy samples have been used for the evaluation of humoral rejection mainly in adult heart transplantation. Interpretation of suspected humoral rejection in children requires knowledge of the pattern and frequency of C4d deposition in nonpresensitized pediatric heart transplantation patients. Paraffin-embedded endomyocardial biopsy samples of 65 patients with no rejection, acute cellular rejection (ACR), or early ischemic/reperfusion injury were studied. Six biopsies within each grade of ACR both early (<6 months) and late (>6 months) after heart transplantation were reviewed, as were 5 biopsies of ischemic/reperfusion injury. None of the subjects was sensitized prior to transplant. All slides were blindly evaluated for histologic features traditionally associated with humoral rejection. C4d staining was quantified by counting the number of positive capillaries in 10 random high-power fields (hpf). C4d positivity (C4d+) was defined as >10 capillaries/10 hpf. C4d+ was observed in 6 (9%) endomyocardial biopsy samples; 2 in the early and 4 in the late ACR groups. Four had ACR grades 1A/B, and 2 had grade 3B/4. Thirteen (20%) endomyocardial biopsy samples had histologic features suggestive of humoral rejection. Of these, only 2 were C4d+ and both had ACR grade 3B/4. No C4d+ staining was found in the ischemic/reperfusion injury group. C4d immunostaining was negative in endomyocardial biopsy samples of the majority of our patients (91%). Endomyocardial biopsy samples with C4d+ did not show consistent ACR grade or time specificity. Contrary to previously reported data, none of the ischemic/reperfusion injury endomyocardial biopsy samples was C4d+, and histologic features alone were poor predictors of C4d+.

In this era of rapidly advancing vascular biology research, a vast array of growth factors and signaling molecules have been recognized as key players in the mechanisms that control lung vascular development. In the lung, vascular development is a complex, multistep process that includes specialization of primitive cells to vascular progenitors; formation of primitive vascular networks; remodeling with local regression and branching; specialization toward arteries, veins, and lymphatics; stabilization of vessels by matrix production and recruitment of supporting cells; and maintenance of the vascular structure. This complex, highly organized process requires exquisite orchestration of the regulatory activity of multiple molecules in a specific temporospatial order. Most of these molecules are members of 3 major growth factor families that have been recently identified. They are the vascular endothelial growth factor, angiopoietin, and ephrin families. Understanding the functional reach of several members of these growth factor families is integral to an appreciation of the etiology and pathogenesis of developmental lung vascular disorders affecting newborns. This review summarizes recent advances in the molecular bases of lung vascular development and some of the pulmonary diseases resulting from aberrant vascular growth, including bronchopulmonary dysplasia, alveolar capillary dysplasia, congenital cystic pulmonary disorders, congenital pulmonary hemangiomatosis, and lung hypoplasia.

This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in Pediatric Pathology over the coming months. The series will include practical issues, such as this protocol for handling lung biopsies and another on bronchoalveolar lavage in childhood, as well as reviews of advances in various areas in pediatric pulmonary pathology. It has been 11 years since the last Perspectives on pulmonary disease. Much has happened since then in this area, and this collection will highlight some emerging and rapidly advancing areas in pediatric lung disease. These will include a review of molecular mechanisms of lung development, and another of mechanisms of pulmonary vascular development. The surfactant system and its disorders, as well as recent advances in the biology of the pulmonary neuroendocrine system and mechanisms of respiratory viral disease, will be addressed. Articles on pulmonary hypertension, pulmonary neoplasia, and pediatric lung transplantation, with their implications for the pediatric pathologist, are also planned. The contributors to this series are a diverse group with special interests and expertise in these areas. As Dr. William Thurlbeck noted in his foreword to the previous volume, Pulmonary Disease, volume 18 of Perspectives in Pediatric Pathology, pediatric pathology had been largely concerned with phenomenology, rather than with mechanisms, model systems, and experimental investigation. I think he would have been pleased to see the changes that have occurred over the past 10 years in pediatric lung biology and pathology in particular, because these were particularly favored interests of his later years.

Tissue and cellular elements generally attributed to the central nervous system (CNS) are infrequently found in areas outside the CNS proper. Most of these lesions contain predominantly glial tissue. In rare instances, heterotopic CNS tissue is found in the scalp, many associated with an intracranial connection and overlying skin and hair anomalies. In follow-up of these patients, development is normal. We present a case of a temporal scalp mass in a 19-month-old girl with a seizure disorder beginning at about age 1 year. At the time of excision, the mass was not associated with intracranial connection or overlying cutaneous abnormalities and demonstrated abundant neuronal and glial elements with features of dysplastic CNS tissue. We speculate that, in certain circumstances, aberrantly localized CNS tissue may be related to abnormal CNS development.

The distinction between lymphatic and other vascular vessels on microscopic sections is a challenging task. D2-40, a novel antibody, has been reported to be selective for lymphatic endothelium. We studied the specificity and sensitivity of D2-40 in pediatric vascular tumors and malformations. Fourteen lymphatic and 11 vascular lesions were randomly selected and stained with D2-40 and CD31 antibodies. The lymphatic lesions included 6 lymphatic malformations, 5 cystic hygromas (macrocystic lymphatic malformation), 2 lymphovenous malformations, and 1 lymphangioma, and the vascular lesions comprised 3 infantile hemangiomas, 3 Kaposiform hemangioendotheliomas, 2 tufted angiomas, 1 pyogenic granuloma, 1 arteriovenous, and 1 venulocapillary malformations. The staining patterns of the vascular channels were compared. In all lesions D2-40 labeled only the endothelium of thin-walled vascular channels morphologically consistent with lymphatic vessels (25 of 25). No staining of the vascular lesions (0 of 11) or of arteries and veins (0 of 25) was observed. All lymphatic lesions had D2-40-positive vessels; however, the percentage of vessels that stained varied. Five lymphatic lesions showed more than 75% D2-40-positive channels, 5 lesions had approximately 50%, and 4 cases showed fewer than 25% D2-40-positive channels. There was a tendency of more consistent D2-40 staining of small versus large lymphatic channels. CD31 constantly labeled arteries, veins, capillaries, and lymphatics in all lesions and all endothelial cells in the vascular lesions. D2-40 is a very specific antibody for lymphatic endothelium, with variable sensitivity. CD31 more reliably identifies lymphatic endothelium. Currently, D2-40 appears to be a good marker to identify lymphatic vessels in pediatric vascular tumors and malformations.