Marian Malone

Histopathological reporting of paediatric cutaneous vascular anomalies in relation to proposed multidisciplinary classification system

Background: The terminology applied to vascular anomalies has been variable in previously published literature making interpretation suboptimal. The International Society for the Study of Vascular Anomalies (ISSVA) has proposed a revised classification based on clinical features and histopathological findings. This classification is increasingly being accepted as clinically useful and a platform for future studies. Aims: To examine the extent to which the ISSVA classification can be practically applied to diagnostic histopathological specimens. Methods: Cutaneous vascular lesions received in a single paediatric pathology unit during a 2-year period (2004–5) were reviewed, including glucose transporter protein 1 (GLUT1) immunostaining where required, and lesions were reclassified according to the ISSVA classification. Results: 144 specimens were identified. Appropriate full clinical information was provided in only 17% of cases at submission. Infantile haemangiomas comprised 46% of cases, 18% of which were regressive type, initially inaccurately identified as vascular malformations before GLUT1 immunostaining. 30% of lymphatic malformations and all lymphovenous malformations were previously classified as vascular malformations, not otherwise specified. Conclusions: The ISSVA classification of vascular anomalies provides a useful framework for histopathologists to classify vascular anomalies. However, meaningful and appropriate use of such a system is dependent on the adequacy of clinical information provided and routine use of immunohistochemical markers.

Astrocytoma as a second malignancy in patients with acute lymphoblastic leukemia

Three cases of astrocytoma, two cerebral (grades II and III) and one spinal (grade II) occurring as second malignancies in patients with previously diagnosed acute lymphoblastic leukemia are described. All had received prophylactic cranial irradiation and intrathecal methotrexate. All were in remission at the time of development of the second malignancy. The time interval between central nervous system (CNS) prophylaxis and symptoms of CNS tumor was between 3 and 5 years. The possible causes of the combination of astrocytoma with acute lymphoblastic leukemia are discussed.

Juvenile xanthogranuloma as a sequel to Langerhans cell histiocytosis: a report of three cases

We report three children who had multisystem Langerhans cell histiocytosis (LCH) with cutaneous involvement and subsequently developed juvenile xanthogranuloma (JXG). JXG appeared 3–6 years after the initial manifestation of LCH. JXG lesions, which presented as yellowish papules, revealed typical Touton giant cells and were factor XIIIa positive but S100 and CD1a negative. Non‐LCH histiocyte disorders, such as JXG, are known to occur as a reaction to a variety of external stimuli such as infection and trauma. It is therefore conceivable that the inflammatory reaction associated with LCH may have precipitated the development of JXG in our patients. Alternatively, one could speculate that this association might be due to a common histogenetic precursor of the cell types involved.

BCL‐2 expression by leukaemic blasts in a SCID mouse model of biphenotypic leukaemia associated with the t(4;ll)(q21;q23) translocation

Summary. Acute leukaemia of infancy is associated with abnormalities at chromosome band llq23, and has a poor prognosis. The gene involved, Mixed Lineage Leukaemia (MLL), has been identified and has the characteristics of a transcription factor. The BCL‐2 gene responsible for blocking of programmed cell death is highly expressed in a number of haematological malignancies, both with and without the t(14;18) translocation. Those without the translocation include acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and chronic lymphocytic leukaemia (CLL). In these diseases the BCL‐2 protein is implicated in drug resistance to apoptosis‐inducing chemotherapeutic agents. High BCL‐2 expression is also associated with autonomous growth of leukaemic blasts in culture and predicts a poor prognosis. The SEM cell line, established using blood lymphoblasts from a 5‐year‐old girl in first relapse with t(4;l 1) ALL, expresses lymphoid (CD19) and myeloid (CD13) cell surface markers. In cell culture, a subpopulation of cells (<30%) express the BCL‐2 protein. A reproducible model of true biphenotypic leukaemia in the SCID mouse has been established using the SEM‐K2 cell line (a subclone of the SEM cell line). Between 5 and 50 million cells injected intravenously (i.v.) produce complete replacement of the murine bone marrow by day 30, associated with blood lymphoblastosis and infiltration of the spleen. No tumour masses were seen. Fluorescence in situ hybridization (FISH) analysis of the cell line and blood from the SCID‐human (SCID‐hu) chimaera has confirmed the presence of the t(4;ll). Reverse transcriptional‐polymerase chain reaction (RT‐PCR) reveals that the breakpoint lies between exons 7 and 8 of the MLL‐1 gene on chromosome 11 (the main breakpoint region). A further translocation, t(7;13), has been identified. Fluorescent antibody cell sorter (FACS) analysis of tumour material recovered from the SCID‐hu model confirms expression of CD19 and CD13 identical to that of the cell line. In addition, BCL‐2 expression in SCID‐hu marrow is now seen in the majority of tumour cells. BCL‐2 expression appears to confer a survival advantage to the blast cells in vivo. This reproducible model of biphenotypic leukaemia suggests that BCL‐2 expression may play a role in leukaemogenesis. The model is suitable for the investigation of gene‐targeted therapy, including antisense oligonucleotides, directed towards the MLL and BCL‐2 genes.

Sudden unexpected neonatal death in the first week of life: Autopsy findings from a specialist centre

Objective. Sudden unexpected early neonatal death (SUEND) in the first week of life shares features with sudden unexpected death in infancy (SUDI) but is not included as SUDI, which is limited to post-perinatal deaths. The aim of this study was to review SUEND autopsies performed in a single specialist centre over a 10-year period, (1996–2005). Methods. Retrospective analysis of >1500 consecutively performed paediatric autopsies performed by paediatric pathologists at one centre conducted according to a standard protocol including ancillary investigations. SUENDs were identified and autopsy findings reviewed. Results. Of 1516 post-mortem examinations, 180 were first-week neonatal deaths, 55 (31%) presenting as SUEND. Thirty-two (58%) were explained following autopsy, whilst the remainder were unexplained; most deaths during sleep were associated with adult co-sleeping. Around 40% of explained deaths were associated with undiagnosed congenital abnormalities, mainly congenital heart disease. In addition, there were nine infection-related deaths and three deaths from unsuspected metabolic disease (fatty acid oxidation defects). Conclusion. There are distinct differences between SUEND and SUDI, with significantly more explained deaths in the former and a much greater proportion due to congenital abnormalities and metabolic disease.

Primary hepatic malignant tumor with rhabdoid features : A histological, immunocytochemical, and electron microscopic study of four cases and a review of the literature

Malignant tumors of the liver with rhabdoid features (MTR) are uncommon: Only 14 previous cases are reported in the literature. These tumors are characterised morphologically by sheets of large polygonal cells with abundant eosinophilic cytoplasm containing a periodic acid Schiffs-positive hyaline globular inclusion and vesicular nuclei with a central prominent nucleolus. Immunohistochemically, the inclusions at least show positivity for vimentin and epithelial markers and sometimes for other antigens. Ultrastructurally, the inclusions are composed of whorled intermediate filaments. Despite the superficial resemblance to cells of muscle origin implied in the term rhabdoid, there is no immunohistochemical or ultrastructural evidence to support such a derivation. We describe four additional children with tumors of this type, in three of whom tumor cells showed focal membrane positivity for MIC-2 on immunostaining. Its expression in an hepatic MTR may indicate neuroepithelial differentiation. Hepatic MTR should be considered in the differential diagnosis of an undifferentiated primary liver tumor in an infant in whom the alpha-fetoprotein concentration is normal or only slightly elevated for age.

Aberrant immunohistochemical expression in nonrhabdomyosarcoma soft tissue sarcomas of infancy: retrospective review of clinical material.

Malignant soft tissue tumors other than rhabdomyosarcoma (RMS) are uncommon in infancy, representing approximately 5% of pediatric sarcomas. The pathological categorization of non-RMS soft tissue malignancies from these young patients is complicated by variation in both morphologic and immunohistochemical features. A search covering an 11-year period identified 19 patients presenting at birth or in infancy with a clinical or referral diagnosis of soft tissue sarcoma. After histologic and immunohistochemical review, nine of these tumors were classified as primitive neuroectodermal tumor (PNET), three as infantile hemangiopericytoma (HPC), two as infantile fibrosarcoma (FS), and five as undifferentiated sarcoma. Those identified as undifferentiated sarcomas showed an atypical spindle and ovoid cell morphology, with cellular pleomorphism and high mitotic rate, but lacking the fascicular growth pattern of classic infantile fibrosarcoma. Immunohistochemical staining in this group showed variable weak positivity for a range of markers (desmin, smooth muscle actin, Myo-D1, PGP, NSE, S100, CO56, cytokeratin, and CD99), and did not fit readily into any distinct diagnostic category. In this series, tumors classified as soft tissue PNETs had a poor prognosis despite aggressive treatment. However, once RMS, PNET, and other rare specific lesions are excluded, the remaining undifferentiated sarcomas, despite their unusual morphology and immunohistochemistry, appear to behave in a similar favorable manner to infantile fibrosarcoma.

Pulmonary alveolar microlithiasis in childhood: diagnosis by transbronchial biopsy.

A 7‐year‐old girl of Arabic origin by consanguineous parents presented with a miliary pattern on chest x‐ray. Transbronchial lung biopsy revealed a histological diagnosis of pulmonary alveolar microlithiasis, a condition rarely described in childhood. This report highlights the clinical and radiological features, documents the transbronchial lung biopsy as a useful diagnostic procedure, and suggests a possible genetic etiology with autosomal recessive inheritance. Pediatr Pulmonol. 1996; 21:62–64.

Omenn's syndrome: Differential diagnosis in infants with erythroderma and immunodeficiency

The clinical differential diagnosis of erythroderma plus immunodeficiency and failure to thrive in neonates includes graft-versus-host-disease (GVHD), Omenns syndrome (OS), and Nethertons syndrome (NS). In addition to immunological investigations, skin biopsy is an important part of the diagnostic work-up. We reviewed biopsies from 25 patients that were retrieved from the archives of the Department of Histopathology at Great Ormond Street, of which 9 were OS, 11 were GVHD, and 5 were NS. Five patients had two biopsy specimens. Both OS and GVHD show dyskeratosis and basal vacuolation. OS always shows acanthosis and almost always parakeratosis. GVHD shows a flat epidermis and rarely parakeratosis. OS and GVHD can be distinguished after immunohistochemistry for LCA and CD68 by the relative proportions of lymphocytes and macrophages in the dermal infiltrate (predominantly lymphocytes in OS, relatively more macrophages in GVHD). Skin biopsy diagnosis of OS is difficult before 6 weeks of age because the features are poorly developed. NS can be distinguished by psoriasiform acanthosis, thickening of the basement membrane, prominent dermal blood vessels, absence of dyskeratosis, and basal layer vacuolation, and a dermal infiltrate in which lymphocytes and macrophages are equally represented. Thus, the main difference between GVHD and OS is in the proportion of lymphocytes and macrophages in the infiltrate on immunohistochemical staining for LCA and CD68, while OS and NS may be distinguished on H&E morphology alone.

The Fetal Liver in Pizz Alpha-1-Antitrypsin Deficiency: a Report of Five Cases

The lack of information on the state of fetal liver in PiZZ alpha-1-antitrypsin (AAT) deficiency and a single case report claiming a hypoplasia of interlobular bile ducts in a 20-week PiZZ fetus, instigated this histologic study of the liver in five PiZZ fetuses, 17-20 weeks of gestation and five age-matched controls. We found no difference between the percentage of portal tracts with identifiable bile ducts in the PiZZ (median 22.2%, range 21%-23%) and in the control (median 21.4%, range 20%-24%) on hematoxylin- and eosin-stained sections. Immunostaining with AE1, a monoclonal antibody to cytokeratins restricted to normal bile ducts, doubled the number of recognizable ducts in both PiZZ and control livers. In four PiZZ livers, but in none of the controls, granular deposits of AAT could be detected by specific immunoperoxidase staining. We conclude that an apparent paucity of interlobular bile ducts is normal in the 20-week fetal liver, and our data may be taken as reference for future study dealing with similar material. Except for the cytoplasmic deposition of granules immunoreactive to AAT antiserum, there was no evidence of any developmental anomaly, in particular of the bile duct system in these five PiZZ fetal livers.