Needle core biopsy in the diagnosis of pediatric thyroid neoplasms: a single institution retrospective review.

PURPOSE: Our institution routinely utilizes needle core biopsy (NCB), instead of fine needle aspiration, in the evaluation of pediatric thyroid nodules. This practice initially arose from limited cytopathology services in our hospital. Given the lack of information regarding the utility of NCB in diagnosing pediatric thyroid neoplasms, we set out to review our institution's experience with this technique. METHODS: We performed a single institution retrospective chart review of all children who underwent thyroidectomy for primary thyroid pathology. RESULTS: Seventy-four patients, with a mean age of 12.9 ± 4.5 (SD) years, underwent partial or total thyroidectomy between 2002 and 2010. Seven of these patients had medically refractive hyperthyroidism. The remaining 67 patients had one or more thyroid nodules as identified by ultrasound. 24 (36 %) of these cases were malignant on final pathology. 14 (58 %) of the malignant cases were papillary thyroid carcinoma. 46 of the thyroid nodule cases underwent pre-operative NCB. Biopsy results for these patients were non-diagnostic in 6 (13 %), benign in 11 (24 %), atypical in 17 (37 %), and malignant in 12 (26 %). There were no complications arising from NCB. Sensitivity of NCB for diagnosing papillary carcinoma (PC) and follicular neoplasm was calculated at 0.88 (0.47-1.0, 95 % CI) and 0.84 (0.60-0.97, 95 % CI), respectively. Of the 28 patients not undergoing preoperative NCB, 12 underwent hemithyroidectomy, with one patient (8 %) requiring completion thyroidectomy for PC. Overall, the sensitivity of NCB in diagnosing PC and follicular thyroid neoplasms was 0.85 (0.55-0.99, 95 % CI), while the specificity was 0.63 (0.42-0.82, 95 % CI). CONCLUSIONS: Needle core biopsy appears to have a low rate of associated complications, and its sensitivity for diagnosing PC and follicular neoplasm is comparable to what has been reported for fine needle aspiration biopsy in a similar patient population.

Neuroimaging in Pediatric Patients with Juvenile Xanthogranuloma of the CNS.

BACKGROUND AND PURPOSE: Juvenile xanthogranuloma is a rare clonal, myeloid, neoplastic disorder. Typically, juvenile xanthogranuloma is a self-limited disorder of infancy, often presenting as a solitary red-brown or yellow skin papule/nodule. A small subset of patients present with extracutaneous, systemic juvenile xanthogranuloma, which may include the CNS. The goal of this retrospective study was to evaluate and categorize the neuroimaging findings in a representative cohort of pediatric patients with CNS juvenile xanthogranuloma. MATERIALS AND METHODS: The brain and/or spine MR imaging data of 14 pediatric patients with pathology-proven juvenile xanthogranuloma were categorized and evaluated for the location; the signal intensity of xanthogranulomas on T1WI, T2WI, DWI, and a matching ADC map for the pattern and degree of contrast enhancement; and the presence of perilesional edema, cysts, or necrosis. RESULTS: Fourteen pediatric patients (8 girls, 6 boys; mean age, 84 months) were included in the study. Patients presented with a wide variety of different symptoms, including headache, seizure, ataxia, strabismus, hearing loss, facial paresis, and diabetes insipidus. Juvenile xanthogranuloma lesions were identified in a number of different sites, including supra- and infratentorial as well as intracranial and spinal leptomeningeal. Five patients were categorized into the neuroradiologic pattern unifocal CNS juvenile xanthogranuloma; 8, into multifocal CNS juvenile xanthogranuloma; and 1, into multifocal CNS juvenile xanthogranuloma with intracranial and spinal leptomeningeal disease. In most cases, xanthogranulomas were small-to-medium intra-axial masses with isointense signal on T1WI (compared with cortical GM), iso- or hyperintense signal on T2WI, had restricted diffusion and perilesional edema. Almost all xanthogranulomas showed avid contrast enhancement. However, we also identified less common patterns with large lesions, nonenhancing lesions, or leptomeningeal disease. Four cases had an additional CT available. On CT, all xanthogranulomas were homogeneously hyperdense (solid component) without evident calcifications. CONCLUSIONS: CNS juvenile xanthogranuloma may demonstrate heterogeneous neuroimaging appearances potentially mimicking other diseases, such as primary brain neoplasms, metastatic disease, lymphoma and leukemia, other histiocytic disorders, infections, or granulomatous diseases.

P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice.

The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory response. The importance of the inflammatory response in the development of atherosclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone areas and by protection in mice deficient in various aspects of the inflammatory response. We have quantitated the effect of deficiency for intercellular adhesion molecule (ICAM)-1, P-selectin, or E-selectin on atherosclerotic lesion formation at 20 wk of age in apolipoprotein (apo) E(-/-) (deficient) mice fed a normal chow diet. All mice were apo E(-/-) and CAM(+/+) or CAM(-/-) littermates, and no differences were found in body weight or cholesterol levels among the various genotypes during the study. ICAM-1(-/-) mice had significantly less lesion area than their ICAM-1(+/+) littermates: 4.08 +/- 0.70 mm(2) for -/- males vs. 5.87 +/- 0.66 mm(2) for +/+ males, and 3.95 +/- 0. 65 mm(2) for -/- females vs. 5.59 +/- 1.131 mm(2) for +/+ females, combined P < 0.0001. An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 mm(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5.60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001. The reduction in lesion area for the E-selectin null mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- males vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- females compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01). These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.

Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice.

During the initial phase of the inflammatory response, leukocytes marginate and roll along the endothelial surface, a process mediated largely by the selectins and their ligands. Mice with mutations in individual selectins show no spontaneous disease and have mild or negligible deficiencies of inflammatory responses. In contrast, we find that mice with null mutations in both endothelial selectins (P and E) develop a phenotype of leukocyte adhesion deficiency characterized by mucocutaneous infections, plasma cell proliferation, hypergammaglobulinemia, severe deficiencies of leukocyte rolling in cremaster venules with or without addition of TNF-alpha, and an absence of neutrophil emigration at 4 h in response to intraperitoneal Streptococcus pneumoniae peritonitis. These mice provide strong evidence for the functional importance of selectins in vivo.

Enhancement of the expression of activation markers on human peripheral blood mononuclear cells by in vitro culture with retinoids and carotenoids.

Retinoids (retinol, retinal, retinoic acid, retinyl beta-glucuronide, and 13-cis retinoic acid) and carotenoids (beta-carotene and canthaxanthin) were evaluated for their immunomodulatory effects on human peripheral blood T-lymphocyte subpopulations and natural killer (NK) cells. Peripheral blood mononuclear cells (PBMC) from healthy young volunteers were isolated and incubated for 72 hours at various levels of retinoids and carotenoids including a physiological concentration (10(-8) M). Expression of surface antigens for total T cells, T-helper and T-suppressor cells, and activation markers (transferrin receptor, HLA-Dr antigen, and interleukin 2 receptor) were analyzed with an EPICS V flow cytometer. Retinoic acid and 13-cis retinoic acid (13-cRA) produced significant increases in the percentage of cells with markers for total T-helper cells, with a minimal effect on percentage of lymphocytes with markers for NK cells. However, beta-carotene (BC), canthaxanthin (CTX), and retinyl beta-glucuronide (RBG) dramatically increased the percentage of PBMC with markers for NK cells and produced a smaller increase in lymphocytes with surface antigens identifying them as T-helper cells. Furthermore, retinol and retinal did not show significant change either in the percentage of lymphocytes with markers for T-helper cells or in the helper/suppressor ratio. An increase in the expression of HLA-Dr antigen and transferrin receptors was greater when cells were incubated with 13-cRA than with either BC, CTX, or RBG, while carotenoids produced a greater increase in the expression of IL-2 receptors than 13-cRA. Our study indicates that both retinoids and carotenoids might be activating different subpopulations of immune cells.

Cellular immune functions of adults treated with a daily, long-term, low dose of 13-cis retinoic acid.

The effects of long-term consumption of 13-cis retinoic acid (13-cRA) on cellular immune functions were measured in young, adult volunteers. The retinoid was administered for 9 months at about 0.13 mg/kg/day. The mean 8AM concentrations of 13-cRA ranged between 30 and 60 ng/ml of serum throughout the study. Corticosteroid levels in plasma decreased significantly throughout treatment, declining from 15.2 ug/dL to 9.1 mg/dL (p less than 0.05). T-cell mitogenesis stimulated by PHA or A Con A was not significantly affected, although this parameter was slightly depressed during the first 2 months of treatment. The percentage of B-lymphocytes tended to decrease during treatment and returned to normal after cessation of 13-cRA (p less than 0.05), while the percentage of T-cells as measured by E-rosette and by fluorescent antibody tagging of surface antigens did not change. The percentage of non T-cells tended to increase slightly during treatment.

Terminal lymphoblastic transformation in polycythemia vera.

A patient with polycythemia vera and lymphoblastic transformation is discussed. Phenotypic characterization revealed that the predominant leukemic cells were classic "null" lymphoid cells with a minority component of pre-B cells. This case provides evidence that the stem cell disorder in polycythemia vera may involve the lymphocyte early in development.

Pseudonodular T cell lymphoblastic lymphoma.

T cell lymphoblastic lymphoma usually presents as a rapidly growing lymphoma with histologic features of a diffuse, poorly-differentiated small cell lymphoma with a high mitotic rate. This report describes a patient who presented with an aggressive small cell lymphoma that morphologically had a nodular pattern. Repeated biopsy and use of cell surface markers resulted in reclassifying the cell type as T cell lymphoblastic and in recognizing the original pattern as pseudonodular. The routine application of these immunologic techniques in patients with lymphoma may lead to more accurate diagnoses and improved treatment.

Role of electron microscopy and other special techniques in the diagnosis of childhood round cell tumors.

A series of case presentations show unique challenges associated with childhood round cell tumors and the role of ancillary techniques in diagnosis. Electron microscopy is shown to be the most powerful individual technique. Immunohistochemistry is less effective but also essential. Other ancillary techniques may provide needed additional diagnostic information. Because this is an area where it is of great importance to secure the most rapid, accurate, and specific diagnosis possible, an integrated multimodal approach is recommended--incorporating light microscopic, electron microscopic, and immunohistochemical studies as a matter of routine, and providing for cytogenetic and/or molecular diagnostic studies as indicated.

Clinical usefulness of lymphocyte transformation in patients with coccidioidomycosis.

The development of an appropriate host defense in coccidioidomycosis is predicated on the presence of a positive delayed skin test reaction to coccidioidin. In severe and/or disseminated disease, coccidioidin reactions are routinely negative. By employing serial in vitro spherulin-induced lymphocyte blast transformation (LT) studies in a group of eight severely-ill coccidioidomycosis patients, prognostic clinical data were provided which could not have been obtained from their skin test status alone. Four of the eight demonstrated positive LT responses early in the course of their disease, quickly converted their skin tests to positive, and were cured of their disease. Two patients had negative LT responses until their skin test converted after several months of therapy. The final two have continued to demonstrate negative LT values despite several years of therapy and have experienced exacerbations of their disease when treatment was discontinued. The use of LT data in such patients can be very helpful in guiding therapeutic decisions in this difficult clinical problem.

The maternal immune response in coccidioidomycosis. Is pregnancy a risk factor for serious infection?

Seven subjects with prior coccidioidal disease and three with active Coccidioides immitis infection during their first trimester were studied during pregnancy and postpartum to determine their general and antigen-specific cell-mediated immune status. All ten were white and carried their pregnancies to term without incident. Decreases in total lymphocytes and T-helper and T-suppressor subsets were noted during the third trimester, presumably secondary to an increase in plasma volume. Lymphocyte responses to the mitogens phytohemagglutinin, concanavalin A, and pokeweed were mildly decreased late in pregnancy, with significant intrasubject and intersubject variation. Responses to tetanus antigen were consistently and significantly lower as pregnancy progressed, rising above first trimester levels by 12 weeks postpartum. A similar pattern of response was noted with spherulin antigen for the seven subjects with previously demonstrated coccidioidal immunity. The three subjects with active coccidioidomycosis either failed to mount a significant spherulin immune response or demonstrated an early response that fell as pregnancy progressed. This antigen-specific immune suppression continued for up to 16 months postpartum despite the fact that there was no clinical evidence of coccidioidal activity beyond the first trimester. Thus, while all three completed pregnancy without complication, the data suggest that significantly increased maternal risk may be present when active coccidioidomycosis and pregnancy occur together. This risk may be greatest among darker-skinned individuals who become infected during the latter half of pregnancy.

Prospective study of the safety and financial benefit of ketoconazole as adjunctive therapy to cyclosporine after heart transplantation.

In a prospective study of the relative safety and potential benefit of concomitant ketoconazole and cyclosporine after heart transplantation, 15 transplant recipients were followed up for up to 1 year (mean, 10.7 months) after ketoconazole was added to their immunosuppressive regimen of cyclosporine, prednisone, and azathioprine, and these patients were compared with a matched cohort over the same time. There was an 88% reduction in the mean (+/- SD) dose of cyclosporine, from 394 (115) mg/day to 47 (21) mg/day (p less than 0.0005) in the ketoconazole group, compared with an insignificant change in the control group. The projected annual cost of cyclosporine was reduced by 88%, with a 72% reduction in the projected cost of immunosuppressive drugs and prophylactic antifungal therapy, from a mean of $6800 to $1862 per year per transplant recipient in the ketoconazole-treated group. Other beneficial effects found over the study period included a significant reduction in the mean and diastolic systemic arterial pressure and a significant reduction in serum cholesterol. The mean total serum cholesterol fell from 265 (44) to 204 (38) mg/dl in the ketoconazole group but did not change significantly in the control group (p less than 0.005). Low-density lipoprotein cholesterol also fell from a mean of 167 (32) mg/dl to 112 (28) mg/dl (p less than 0.005). Renal function was not significantly affected by ketoconazole when compared with the control group. Ketoconazole and other drugs of potential use in organ transplant recipients should be evaluated for financial as well as for other potential clinical benefits in the long-term management of these patients.

Evaluation of methodologic variables of the in vitro lymphocyte transformation assay.

Optimum methodologic variables for assessing cellular immunity by in vitro lymphocyte transformation (LT) were determined using spherulin and coccidioidin antigens. This study was conducted in an area endemic for coccidioidomycosis and included healthy, coccidioidomycosis skin test positive (STP) and negative (STN) subjects, and patients with mild, acute disease. The authors examined the relationship between coccidioidin (1:100) and spherulin (low dose) skin test reactivity and lymphocyte transformation (LT) responses to the same antigens. Counts per minute (CPM) and stimulation index (SI) as methods of expressing tritiated thymidine uptake were compared. The LT assays were set up in duplicate test systems using autologous and homologous plasma. Both antigens differentiated between STP and STN groups (P less than or equal to 0.001-0.004), but values obtained with spherulin-induced LT were greater than those using coccidioidin (P less than 0.001). Values in CPM and SI were greater in the spherulin-induced LT assay using autologous compared with AB plasma. Specifically, for detecting cellular immunity to coccidioidomycosis, the combination of spherulin-induced LT using autologous plasma and expressing the results in CPM gave the best discrimination between STP and STN subjects. Based on epidemiologic data, the latter method also appeared more sensitive than the skin test in detecting cellular immunity to coccidioidomycosis. In general, these data illustrate the variable effectiveness of different antigens for inducing LT responses and further show how different plasma sources affect the LT response. Finally, these data suggest that lymphocyte blast transformation results expressed as CPM may give more consistent values and better discrimination between immune and nonimmune subjects than results expressed as stimulation indices.

The effect of lymphocyte recovery on lymphocyte typing results.

This study examines the relationship between percent recovery of lymphocytes and T- and B-cell typing results. Lymphocytes were recovered from heparinized whole blood by density gradient centrifugation. T- and B-cells were enumerated by spontaneous sheep rosetting and direct fluorescent antibody staining for surface immunoglobulin, respectively. The findings indicate that at low recovery levels ( less than 80%) there is a significant increase in variability of lymphocyte typing results and a significant increase in IgG-bearing B-lymphocytes. Possible explanations for these findings are discussed. These results suggest that lymphocyte typing results should be interpreted in relation to recovery level and that recovery levels of greater than or equal to 80% are desirable.

Rheumatoid factor activity by rate nephelometry correlated with clinical activity in rheumatoid arthritis.

The purpose of this study was to evaluate, prospectively, the clinical usefulness of the rate nephelometric method for determining rheumatoid factor (RF) activity, measured in International Units (IU), in patients with rheumatoid arthritis. These results were compared with those of standard latex agglutination titration. The overall correlation between clinical activity and RF activity measured by rate nephelometry and serologic titration are similar, i.e., r = 0.47 (P less than 0.001) and r = 0.43 (p less than 0.001), respectively. However, on an individual patient basis, the nephelometric determination appears to correlate better with disease activity and response to therapy than do titers. The RF activity measured in IU would give the clinician a more sensitive and precise tool with which to follow RF activity in individual patients with active disease.

Antinuclear antibodies and survival in cardiac transplant patients.

Serum from 48 patients with cardiac transplants was tested for the presence of antinuclear antibodies (ANA). Thirty-two of the sera were negative for ANA (ANA-), and 16 were positive for ANA (ANA+). Six of the ANA+ sera had a diffuse pattern, six had a peripheral pattern, three had a combined diffuse and rim pattern, and one had a diffuse and nucleolar pattern. Seven of the ANA+ sera were positive at a 1:40 titer, one at a 1:80 titer, four at a 1:160 titer, two at a 1:320 titer, and two at a 1:640 titer. Thirteen of the 32 ANA- patients have died, at intervals of one month to four years after transplantation. Fourteen of the 16 ANA+ patients have died, at intervals ranging from less than one day to four years after transplantation. The mean time period from transplantation to death was 13 +/- 15 months for the ANA+ patients: these were not statistically significantly different. However, the mean interval from transplantation to death of the ANA+ patients with an ANA titer greater than 1:40 was 0.8 +/- 0.8 months, which was significantly different from the mean survival period of the ANA+ group as a whole (P less than or equal to 0.05) and the mean survival of the ANA- group (P less than or equal to 0.005). Although the mechanism is not clear, there appears to be an association between higher titer serum ANA positivity and increased mortality in patients with cardiac transplants with significantly decreased duration of survival after transplantation.

Age-related changes in mitogen-induced lymphocyte function from birth to old age.

This study examines the relationship between age and mitogen-induced lymphocyte blastogenesis. Lymphocytes were stimulated with PHA; Concanavalin A (Con A), and PWM in 156 normal, healthy subjects ranging in age from birth to 75 years. The findings indicate a gradual but significant decrease in PHA- and Con A-induced blastogenesis with increasing age. The decrease in Con A and PHA induced in vitro lymphocyte function begins in early childhood and young adulthood, respectively, and continues throughout the age range studied. In addition, there appears to be a decreased range of lymphocyte functional capacity among the 50-75-year-old subjects. The clinical and laboratory implications of these observations are discussed.

Peripheral T-cell lymphoma: aggressive disease with heterogeneous immunotypes.

Eleven patients with mature or peripheral T-cell lymphoma (PTL), other than mycosis fungoides, were identified using an extensive battery of T- and B-cell markers. Eight cases had a histologic diagnosis of either diffuse large cell or mixed lymphoma, three of small cell type. All cases had one or more "mature" T-antigens and an absence of B- and immature T-antigens. Assessment of T-antigens included E-rosettes (Er), anti-Leu 1-7 and Tdt. The authors delineated striking heterogeneity of T-antigen expression: 9 different immunotypes in 11 cases. Subset T-antigen assessment indicated T-helper neoplastic cells in five cases and T-suppressor in two. The remaining four had universal T-antigens alone. Seven cases appeared to have "novel" T-phenotypes not corresponding to normal T-ontogeny phenotypes. Novel or idiosyncratic phenotypes may be a key characteristic of PTL. Since no single T-antigen, including Er and Er receptor (Leu-5), was expressed in all cases, a battery of monoclonal antibodies is necessary to detect PTL. Clinically, the authors found PTL unexpectedly aggressive, despite mature immunotype. Most patients were elderly (median age 69); all had extranodal disease with cutaneous involvement (six cases) most frequent. Responses to chemotherapy frequently proved transient, with median survival of nine months. A fulminant course was noted even with localized presentation. Clinical outcome suggests PTL requires new therapeutic strategies.

Expression of type 2 cystatin genes CST1-CST5 in adult human tissues and the developing submandibular gland.

Type 2 cystatins comprise a class of cysteine peptidase inhibitor presumed to mediate protective functions at various locations, including the oral cavity. Seven cystatin genes are clustered within a 300-kb region of human 20p11.2. "Salivary" cystatins, encoded by CST1, 2, 4, and 5, are present in saliva at significant levels but have also been reported in other secretions, such as tears, suggesting that during their evolution, these genes have acquired mechanisms directing differential tissue-specific expression. However, their patterns of expression, which might also provide additional clues to their individual functions, have not been determined. Gene-specific RNase protection assays were used to examine the qualitative and quantitative distribution of expression of these seven genes within a collection of 23 adult human tissues. The CST3 gene, encoding cystatin C, was expressed at modest levels in all tissues examined. The presumptive pseudogenes CSTP1 and CSTP2 were not expressed at detectable levels in any tissue. The CST1, 2, 4, and 5 genes were expressed in differential, tissue-specific patterns. Expression of CST2 and CST5 was restricted to the submandibular and parotid glands, while CST1 and CST4 were expressed in these tissues and in the lacrimal gland. Immunohistochemistry studies localized expression to the serous-type secretory end pieces. Coexpression of CST1 and CST4 was also observed in the epithelial lining of the gallbladder and seminal vesicle. The CST1 product was detected in the tracheal glands and CST4 in the kidney and prostate. Despite their different adult patterns of expression, analysis of CST1, 2, 4, and 5 mRNA levels in infant submandibular glands demonstrated a coordinate upregulation of expression of between 3.5 and 9 months of age. The patterns of cystatin gene expression are consistent with several proposed oral functions of the salivary cystatins but also suggest they are important in other locations and that, despite their close sequence similarity, they are individually specialized.