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H P Kozakewich

Publications and source records attributed to H P Kozakewich.

At least 19 recordsLinked to original sources
PubMed2001

Identification of a basal/reserve cell immunophenotype in benign and neoplastic endometrium: a study with the p53 homologue p63.

BACKGROUND: Metaplastic differentiation, including squamous, mucinous, and tubal (ciliated), is common in both benign and neoplastic endometrium, and the cell of origin for this pathway is poorly understood. In this study, expression of a marker for basal and reserve cells in cervical squamous mucosa, designated p63, was investigated in a spectrum of endometrial alterations. METHODS: One hundred ninety different endometria from 132 patients were examined, including fetal (6), premenarchal (3), benign cyclic (29) and noncyclic (54), hyperplastic (14), and neoplastic (93) endometrial glandular epithelia. The latter included conventional endometrioid carcinomas with and without mucinous, ciliated, and squamous metaplasia, and uterine papillary serous carcinoma (UPSC). RESULTS: p63 expression was identified in basal/subcolumnar cells in the fetal endometrium in a distribution similar to that in basal/reserve cells of the cervix. Staining was confined to individual scattered basal and suprabasal cells in cycling endometrium. In polyps and postmenopausal endometria, focal clusters of p63-positive cells were identified in inactive glands or surface epithelium. Metaplastic (squamous or mucinous) epithelia, either alone or in conjunction with hyperplasias or carcinomas, exhibited the most intense staining, primarily in basal or subcolumnar cells. In some cases, immediately adjacent nonmetaplastic columnar epithelium also stained positive. UPSCs contained only rare scattered p63-positive cells. CONCLUSIONS: Cells with a basal or reserve cell phenotype exist in the endometrium during fetal life, are not conspicuous during the reproductive years, but may emerge during shifts in differentiation. Whether these cells signify specialized multipotential endometrial cells is not clear, but the similarity of these cells to basal/reserve cells of the cervix and their association with neoplasia merit further study.

Animals↗
PubMed2001

PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms.

Lipoblastomas are rare soft tissue tumors that occur primarily in young children. They typically contain variably differentiated adipocytes, primitive mesenchymal cells, myxoid matrix, and fibrous trabeculae. Abnormalities in chromosome 8, leading to rearrangements of the PLAG1 gene, were demonstrated recently in four lipoblastomas. In the present report, we determine the frequency of PLAG1 alterations in 16 lipoblastomas from children aged 13 years or younger, and we also evaluate the stages of lipoblastoma differentiation at which PLAG1 genomic alterations are found. Eleven lipoblastomas (69%), including those with either classic or lipoma-like histology, had rearrangements of the 8q12 PLAG1 region. Another three lipoblastomas had polysomy for chromosome 8 in the absence of PLAG1 rearrangement. Only two cases (13%) lacked a chromosome 8 abnormality. Notably, the lipoblastomas with chromosome 8 polysomy had up to five copies of chromosome 8 as an isolated cytogenetic finding in an otherwise diploid cell. We also demonstrate that PLAG1 alterations are found in a spectrum of mesenchymal cell types in lipoblastomas, including lipoblasts, mature adipocytes, primitive mesenchymal cells, and fibroblast-like cells. This finding is consistent with neoplastic origin in a primitive mesenchymal precursor and with variable differentiation to a mature adipocyte end-point. Hence, our studies provide biological validation for the clinical observation that lipoblastomas can evolve into mature, lipoma-like, lesions. They also suggest that PLAG1 dosage alterations caused by polysomy 8 might represent an alternative oncogenic mechanism in lipoblastoma.

Child↗
PubMed2001

Aggressive multimodal treatment of pleuropulmonary blastoma.

Pleuropulmonary blastoma is a rare intrathoracic neoplasm almost solely confined to childhood. Survival is poor. The authors report 2 children with extensive intrathoracic disease who are long term survivors after multimodal therapy. Both children received multiagent neoadjuvant chemotherapy, followed by surgical resection to remove all gross tumor. Postoperative chemotherapy was given to both children; radiotherapy was also given in the second case because of a question of positive tumor margins. Experience supports the use of multimodal therapy, including an aggressive surgical approach in the potentially curative treatment of this tumor.

Child↗
PubMed2001

Giant cell angioblastoma: three additional occurrences of a distinct pathologic entity.

Giant cell angioblastoma was described previously in a single case report as a congenital soft-tissue tumor with a unique morphology. In the current report, we describe three cases of giant cell angioblastoma found in three infants; one case was congenital and located in the hand, one appeared neonatally in the palate, and one on the scalp of an infant. Clinical findings and results of light microscopy, immunohistochemistry, and electron microscopy were evaluated. All tumors were ulcerated; the hand and palate tumors also infiltrated soft tissue and bone. They exhibited a solid, nodular, and plexiform proliferation of oval-to-spindle cells with a frequent striking, concentric aggregation around small vascular channels. These cells had characteristics of undifferentiated mesenchymal cells, fibroblasts, myofibroblasts, and pericytes. Co-mingled with these cells were large mononuclear and multinucleate giant cells with histiocytic features. The palatal giant cell angioblastoma, excised with positive margins, was managed with interferon-alpha and showed no progression after nearly 5 years. The hand tumor diminished in size after management with interferon-alpha, was subtotally excised, and did not progress after 27 months. Follow-up data are unavailable for the patient with the scalp lesion. Our findings validate the classification of giant cell angioblastoma as a distinct and rare entity that is locally infiltrative but slow growing. The morphology and diverse cellular differentiation are consistent with an unusual form of neoplastic angiogenesis.

Biomarkers, Tumor↗
PubMed2001

Noninvoluting congenital hemangioma: a rare cutaneous vascular anomaly.

The authors studied a rare, congenital, cutaneous vascular anomaly that grows proportionately with the child and does not regress. A total of 53 patients were compiled from three vascular anomaly centers. These patients' lesions were analyzed for presentation, physical findings, radiologic and histopathologic characteristics, natural history, and outcome after resection. The lesions occurred slightly more often in male patients, always appeared alone, and were located (in order of frequency) in the head/neck region, extremities, and trunk. They were round-to-ovoid in shape, were plaque-like or bossed, occurred in variable shades of pink to purple, and had an average diameter of 5 cm. The overlying skin was frequently punctuated by coarse telangiectasia, often with central or peripheral pallor. The lesions were warm on palpation; fast-flow was further documented by Doppler ultrasonography. Magnetic resonance imaging and angiographic findings were similar to those of common hemangioma of infancy. All lesions were easily excised without recurrence.Histologic examination revealed lobular collections of small, thin-walled vessels with a large, often stellate, central vessel. Interlobular areas contained predominantly dilated, often dysplastic veins; arteries were also increased in number. Small arteries were observed "shunting" directly into lobular vessels or into abnormal extralobular veins. "Hobnailed" endothelial cells lined the small intralobular vessels. Mast cells were increased. Tests for glucose transporter-1, a recently reported reliable marker for common hemangioma of infancy, were negative in all 26 specimens examined. In conclusion, the authors think these clinicopathologic and radiologic features define a rare vascular lesion for which the term "noninvoluting congenital hemangioma" is proposed. These lesions of intrauterine onset may be a variant of common hemangioma of infancy or another hemangiomatous entity with persistent fast-flow.

Adolescent↗
PubMed2000

PLAG1 fusion oncogenes in lipoblastoma.

Lipoblastomas are pediatric neoplasms resulting from transformation of adipocytes. These benign tumors are typically composed of adipose cells in different stages of maturation within a variably myxoid matrix, and they contain clonal rearrangements of chromosome band 8q12. Because lipoblastomas resemble embryonic adipose tissue, characterization of their transforming mechanisms might reveal biological pathways in physiological adipogenesis. Herein, we demonstrate that lipoblastoma chromosome 8q12 rearrangements bring about promoter-swapping events in the PLAG1 oncqgene. We show that the hyaluronic acid synthase 2 (HAS2) or collagen 1 alpha 2 (COL1A2) gene promoter regions are fused to the entire PLAG1 coding sequence in each of four lipoblastomas. PLAG1 is a developmentally regulated zinc finger gene whose tumorigenic function has been shown previously only in epithelial salivary gland cells. Our findings reveal that PLAG1 activation, presumably resulting from transcriptional up-regulation, is a central oncogenic event in lipoblastoma.

Adipose Tissue↗
PubMed2000

Residual lesions after Kasabach-Merritt phenomenon in 41 patients.

BACKGROUND: Kasabach-Merritt phenomenon (KMP) is the association of a vascular tumor and thrombocytopenic coagulopathy. Vascular tumors are either kaposiform hemangioendothelioma or tufted angioma but not "true" common hemangioma of infancy. There is a conspicuous absence in the literature regarding the late outcome and possible residual lesions after apparent clinical cure of KMP. OBJECTIVE: The purpose of the study was to analyze these residua in a large number of patients. METHODS: Clinical data on 41 patients who had KMP were accrued in an international cooperative study. The emphasis was on the residual lesions after resolution of the thrombocytopenia and other coagulation abnormalities. Imaging studies (follow-up magnetic resonance imaging studies available for 10 patients) and histologic specimens (30 specimens available for 26 patients, 18 biopsies done during the KMP and 12 concerning the sequelae) were reviewed. RESULTS: Residual lesions after "cure" of KMP were common. They exhibited 3 clinical patterns: type I lesions (n = 28) showed a cutaneous red stain, with or without associated red papules. The stain might overlap a minor fibrotic infiltration or a significant poorly delineated diffuse fibrotic infiltration. These cutaneous vascular lesions varied in size and appearance over time and were occasionally painful. Type II lesions were telangiectatic streaks and swelling (n = 5), and type III lesions showed a minor, firm, irregular, subcutaneous mass assessed by palpation or deep infiltration evidenced by computed tomography or magnetic resonance imaging (n = 8). A fourth feature was sequelae in muscles and/or joints. Histologically, tufted angioma was more common in the specimens from residual lesions, whereas kaposiform hemangioendothelioma was more common during the active phase of KMP. Imaging findings were remarkably reproducible and revealed a persistent vascular tumor. CONCLUSION: Residua of tumors associated with KMP are common after the resolution of thrombocytopenia and coagulopathy. They are (more or less) prominent dormant vascular tumors, not "scars" and, clinically as well as histologically, they differ markedly from involuted hemangioma.

Adolescent↗
PubMed2000

Soft-tissue vascular anomalies: utility of US for diagnosis.

PURPOSE: To determine the ultrasonographic (US) features that distinguish soft-tissue hemangioma from vascular malformation and one type of malformation from another. MATERIALS AND METHODS: Eighty-seven vascular anomalies were evaluated by means of US. Lesions were assessed for the presence of solid tissue and abnormal arteries, veins, or cysts. Vessel density, peak flow velocities, and resistive indexes were compared. RESULTS: There were 49 hemangiomas and 38 vascular malformations. A significantly greater proportion of hemangiomas (48 of 49) compared with vascular malformations (zero of 38) consisted of a solid-tissue mass (P < .001). Vessel density was comparable for hemangioma and arteriovenous malformation (AVM) but significantly greater compared with the other vascular malformations (P < .001 in each case). No differences in mean arterial peak velocity were detected between hemangiomas and malformations. Mean venous peak velocity was significantly higher for AVM than for other vascular malformations and hemangioma. Mean resistive index was greater for lymphatic malformation than for hemangioma or AVM. Abnormal veins, arteries and veins, or cysts were univariate predictors for distinguishing between venous, arteriovenous, and lymphatic malformations (P < .001 in all cases). Solid-tissue mass was the only multivariate predictor for differentiating hemangioma from vascular malformation (likelihood ratio test = 109.8, P < .001). CONCLUSION: US can be used to distinguish hemangioma from vascular malformation and detect arterial flow. These distinctions are critical for subsequent management and assessing prognosis.

Adolescent↗
PubMed1999

Renal cell carcinomas in children and young adults: increased incidence of papillary architecture and unique subtypes.

Renal cell carcinomas in children and young adults are rare, and the pathologic features of these tumors have not been well described. We reviewed 24 renal cell carcinomas in children and young adults ages 6 to 29 years, 14 of whom were younger than 18 years of age. Fourteen were female. In 19 (79%) of 24 cases, the tumor met histologic criteria for papillary renal cell carcinoma, with at least 50% papillary architecture. Four of the remaining five cases were typical clear cell tumors in patients known to have von Hippel Lindau syndrome, and one case was of chromophobe type. In the papillary tumors, calcifications, high nuclear grade, extracapsular extension (American Joint Commission on Cancer stage T3), and lymph node metastases were common. Among these papillary tumors, four distinct histologic patterns could be identified. Collecting duct-like tumors (two cases) involved the large collecting ducts, were multifocal and predominantly papillary, and had focal tubular and solid areas. These tumors were reactive for epithelial membrane antigen (EMA) and keratins, including CK7, but negative for Ulex europeaus and high molecular weight keratin 34BE12. Voluminous cell tumors (four cases) were composed of cells with extremely voluminous clear cytoplasm and, although predominantly papillary, had areas that also resembled clear cell tumors. These tumors were reactive for keratins AE1/AE3 but were otherwise negative for all other keratins, EMA, and U. europeaus. One of these tumors showed an X;7 translocation. Adult type tumors (12 cases) resembled papillary tumors of adults. These tumors were reactive for EMA and keratins, including CK7, and all but one were negative for U. europeaus and keratin 34BE12. This last case had trisomies of chromosomes 7, 16, 17, and 20. The final neuroendocrinelike case was multifocal, organoid, and composed of nests of small cells in a neuroendocrinelike pattern. Three of 13 patients were alive with disease at last follow-up, and three additional patients died of disease, all within 2 years. Progression was highly associated with lymph node involvement at the time of resection. We conclude that the clinicopathologic features of renal cell carcinomas in children and young adults differ from those arising in older adults. These tumors are characteristically high-grade, high-stage, papillary tumors with numerous calcifications, and several subtypes can be identified based on histologic, immunohistochemical, and cytogenetic features. Some subtypes appear to be unique to this age group.

Adolescent↗
PubMed1998

Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma.

Morphological, cytogenetic, and biological evidence supports a relationship between congenital (infantile) fibrosarcoma (CFS) and congenital mesoblastic nephroma (CMN). These tumors have a very similar histological appearance, and they are both associated with polysomies for chromosomes 8, 11, 17, and 20. Recently, CFS was shown to contain a novel t(12; 15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. The aims of this study were to determine whether congenital mesoblastic nephroma contains the t(12;15)(p13;q25) translocation and ETV6-NTRK3 gene fusion and whether ETV6-NTRK3 fusions, in CMN and CFS, antedate acquisition of nonrandom chromosome polysomies. To address these aims, we evaluated 1) ETV6-NTRK3 fusion transcripts by reverse transcriptase polymerase chain reaction and sequence analysis, 2) genomic ETV6-region chromosomal rearrangement by fluorescence in situ hybridization, and 3) chromosomal polysomies by karyotyping and fluorescence in situ hybridization. We report ETV6-NTRK3 fusion transcripts and/or ETV6-region rearrangement in five of six CMNs and in five of five CFSs. The ETV6-NTRK3 fusion transcripts and/or ETV-region chromosome rearrangements were demonstrated in two CMNs and one CFS that lacked chromosome polysomies. These findings demonstrate that t(12;15) translocation, and the associated ETV6-NTRK3 fusion, can antedate acquisition of chromosome polysomies in CMN and CFS. CMN and CFS are pathogenetically related, and it is likely that they represent a single neoplastic entity, arising in either renal or soft tissue locations.

Artificial Gene Fusion↗
PubMed1998

Pleural effusions in lymphoblastic lymphoma: a diagnostic alternative.

BACKGROUND: Children with large anterior mediastinal masses frequently present with severe respiratory compromise and often pose a difficult diagnostic dilemma. A biopsy is preferred for diagnosis before treatment can begin; however, many of these children are at risk of acute clinical deterioration and cardiovascular arrest with the induction of anesthesia. The authors noted a correlation between pleural effusions and lymphoblastic lymphoma and recently diagnosed three cases of lymphoblastic lymphoma in children with a large anterior mediastinal mass and pleural effusion through cytological and flow cytometric examination of the pleural fluid. METHODS: To focus on this problem, 101 pediatric patients presenting with an anterior mediastinal mass between January 1980 and September 1994 were reviewed to determine if pleural effusions occur more frequently at initial presentation with lymphoblastic lymphoma than with Hodgkin's disease, thus offering a means of diagnosis in children with severe respiratory compromise. The patients' chest radiographs and/or computed tomograms for the 88 cases in which they were available were reviewed retrospectively in a blinded fashion to identify those children with pleural effusions at the time of presentation. RESULTS: In this study, 71% of patients with lymphoblastic lymphoma (10 of 14) had a pleural effusion at presentation, whereas only 11.7% of patients with Hodgkin's disease (7 of 60) had a pleural effusion on initial presentation. (P < .002 Fisher's Exact test). CONCLUSION: This retrospective review suggests that there is a significantly greater association of pleural effusions in patients with lymphoblastic lymphoma than with Hodgkin's disease. Our experience supports the conclusion that thoracentesis may provide a means of diagnosis in children presenting in severe respiratory compromise obviating the need for anesthesia and open biopsy.

Adolescent↗
PubMed1998

Inflammatory cell distribution within and along asthmatic airways.

Asthmatic airways are infiltrated with inflammatory cells that release mediators and cytokines into the microenvironment. In this study, we evaluated the distribution of CD45-positive leukocytes and eosinophils in lung tissue from five patients who died with severe asthma compared with five patients with cystic fibrosis. For morphometric analysis, the airway wall was partitioned into an "inner" area (between basement membrane and smooth muscle) and an "outer" area (between smooth muscle and alveolar attachments). Large airways (with a perimeter greater than 3.0 mm) from patients with asthma or cystic fibrosis had a greater density of CD45-positive cells (p < 0.05) and eosinophils (p < 0.001) in the inner airway region compared with the same airway region in small airways. Furthermore, in small airways, asthmatic lungs showed a greater density of CD45-positive cells (p < 0.01) and eosinophils (p < 0.01) in the outer compared with the inner airway wall region. These observations indicate that there are regional variations in inflammatory cell distribution within the airway wall in patients with asthma that are not observed in airways from patients with cystic fibrosis. We speculate that this inflammatory cell density in peripheral airways in severe asthma may relate to the peripheral airway obstruction characteristic of this condition.

Adolescent↗
PubMed1998

MR lymphangiography in infants, children, and young adults.

OBJECTIVE: Our objective was to offer a preliminary description of MR lymphangiography; its uses and limitations; and its findings in infants, children, and young adults. SUBJECTS AND METHODS: Twenty-nine patients underwent 32 MR lymphangiographic examinations for evaluation of vascular malformations, other masses, soft-tissue swelling, gigantism, fluid accumulation, or pain. MR lymphangiography was based on a heavily T2-weighted fast spin-echo sequence and a maximum-intensity-projection algorithm. We assessed the axial and off-axial lymphatic channels in conjunction with MR venography to help differentiate veins from lymphatics. Correlation was made with published lymphangiograms and anatomic diagrams to assist interpretation and (when available) with histologic specimens (n = 11) for validation. RESULTS: Presumed lymphatic channels were seen universally, although 14 examinations showed incomplete venous signal suppression. Lymphatic channels appeared normal in eight children and in 20 of the 21 asymptomatic contralateral limbs. Ten patients had an increased number and size of off-axial channels, including seven children with large, diffuse low-flow vascular malformations. Enlarged axial and off-axial channels were seen in five patients, four of whom had Klippel-Trénaunay syndrome. Six patients, each with an extensive hemangioendothelioma, Klippel-Trénaunay syndrome, Gorham syndrome, or unilateral body edema, showed absence or interruption of axial channels. CONCLUSION: MR lymphangiography appears to be a useful noninvasive technique to study superficial and deep lymphatic channels in children with local or diffuse vascular lesions or swelling of extremities. Its limitations notwithstanding, the technique may offer further insight into the nature of vascular anomalies, may direct therapy, and may predict prognosis.

Adolescent↗
PubMed1998

The pericentromeric inversion, inv (6)(p25q13), is a novel diagnostic marker in chondromyxoid fibroma.

Chondromyxoid fibroma is a benign bone tumor that arises most commonly in the metaphysis of long bones in young adults. The cytogenetic features of this tumor are not well known. In this study, four chondromyxoid fibromas were karyotyped after short-term cell culture. All of the tumors contained clonal rearrangements of chromosome 6, and each of these rearrangements involved band 6q13. Two tumors contained a pericentromeric inversion, inv (6)(p25q13), which was described recently in chondromyxoid fibroma. 6q13 rearrangements are not associated with other types of bone and soft tissue tumors, and the inv (6)(p25q13) is reported only in chondromyxoid fibroma. Hence, this cytogenetic marker might be helpful in distinguishing chondromyxoid fibroma from chondrosarcoma and other histologic mimics. The consistent occurrence of 6q13 rearrangements suggests a specific oncogenic mechanism in chondromyxoid fibroma, most likely involving oncogene activation.

Adolescent↗
PubMed1997

Nephrogenic adenoma after urethral reconstruction using bladder mucosa: report of 6 cases and review of the literature.

PURPOSE: To our knowledge nephrogenic adenoma, an unusual benign metaplastic lesion of the urothelium, has not been reported previously following urethral reconstruction using bladder mucosa. Histopathological features, etiological factors and clinical features are discussed. MATERIALS AND METHODS: We reviewed the records of 117 patients who underwent hypospadias repair with free grafts of bladder mucosa from 1982 to 1995. RESULTS: Five children 6 to 11 years old and a 39-year-old man had nephrogenic adenoma of the urethra. Hematuria or dysuria was the usual reason for presentation. The lesions were located at the site of anastomosis between the graft and proximal urethra in 3 cases and the distal graft in 2, and they involved the whole graft in 1. Successful treatment consisted of endoscopic resection of the polyps in 4 patients, while open surgical correction was performed in 2, requiring complete excision of the previous graft in 1 and segmental resection in 1. CONCLUSIONS: The gross appearance of the lesion may be confused with that of transitional cell carcinoma or clear cell adenocarcinoma of the urethra, necessitating biopsy to rule out malignancy. Endoscopic management is possible for small tumors, although severe nephrogenic adenoma involving most of the reconstructed urethra may require complete resection of the graft and creation of a new urethra.

Adenoma↗
PubMed1997

Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma.

Children with a large vascular tumor and associated Kasabach-Merritt coagulopathy respond inconsistently to therapy and have a high mortality rate. For this reason, we undertook a retrospective study of 21 such patients, and focused on clinical, radiographic, and histopathologic features. The male to female ratio was 1:1.6. Tumor was noted at birth in 50 percent of patients; the remainder appeared throughout infancy. The location was cervicofacial (n = 2), shoulder/upper limb (n = 4), trunk including retroperitoneum (n = 11), and lower limb (n = 4). These tumors grew rapidly to large size and were characterized by cutaneous purpura, edema, and an advancing ecchymotic margin. In contrast to common hemangioma, magnetic resonance imaging showed diffuse enhancement with ill-defined margins, cutaneous thickening, stranding of subcutaneous fat, hemosiderin deposits, and small feeding and draining vessels. All tumors were Kaposiform hemangioendothelioma (KHE); none were infantile hemangioma. Light microscopy showed irregular lobules or sheets of poorly formed, small vascular channels infiltrating and entrapping normal tissues. Characteristic features included spindle-shaped endothelial cells, diminished pericytes and mast cells, microthrombi, and hemosiderin deposits. Wide endothelial intercellular gaps and incomplete basement membranes were seen by electron microscopy. Dilated, hyperplastic, lymphaticoid channels were prominent in one tumor. KHE in 14 infants was treated with interferon alpha-2a: 6 had accelerated regression; 2 had stabilization of growth; and 6 evidenced no response. The mortality rate was 24 percent (5 of 21); this included three infants with retroperitoneal KHE. Kasabach-Merritt phenomenon does not occur with common hemangioma. Rather it is associated with the more aggressive KHE and rarely with other vascular neoplasms. Variable response to current pharmacologic therapy underscores our inadequate knowledge of the pathogenesis of thrombocytopenia in KHE.

Adipose Tissue↗