Multicentric Mucinous Adenocarcinoma in the Periorbital Region.

Primary mucinous adenocarcinoma of the skin is an uncommon malignancy in clinical practice, but multicentric presentation of the malignancy is considered even more rare. In this case report, the authors present a 70-year-old woman with multicentric primary mucinous adenocarcinoma of the skin manifesting with 2 separate lesions located on the right eyelid and cheek. Lesion removal and immunohistochemical staining ruled out mucinous adenocarcinoma of the skin secondary to lung or thyroid carcinoma, however, was inconclusive for breast carcinoma. A negative breast examination and mammography determined the lesions were primary mucinous adenocarcinoma of the skin. Lesion removal resulted in a large defect, which was repaired using a tarsoconjunctival flap and right cheek rotational/advancement flap. Six months postoperatively, the patient's vision returned to baseline with excellent eyelid position and no evidence of local recurrence. Oral consent for the report and photographs was obtained from the patient and filed.

Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma.

An altered anti-Epstein-Barr virus (EBV) serologic profile preceding diagnosis is associated with an increased risk of Hodgkin lymphoma. It is unknown whether this atypical pattern predicts Hodgkin lymphoma risk further subdivided by determination of EBV in tumor cells. A nested case-control study of 128 incident Hodgkin lymphoma cases and 368 matched controls from active-duty military personnel with archived serum in the US Department of Defense Serum Repository was conducted to determine whether a panel of anti-EBV antibody titers differed in EBV(+) and EBV(-) Hodgkin lymphoma. Among 40 EBV(+) Hodgkin lymphoma cases and matched controls, statistically significant increased risks were associated with elevated anti-EBV VCA IgG antibody titers (relative risk = 3.1; 95% confidence interval [CI], 1.1-8.7), and an anti-EBNA-1/anti-EBNA-2 antibody ratio ≤ 1.0 versus > 1.0 (relative risk = 4.7; 95% CI, 1.6-13.8). In contrast, no significant associations were found among 88 EBV(-) Hodgkin lymphoma cases relative to their matched controls. In case-case analysis, EBV(+) disease was significantly associated with a low anti-EBNA-1/anti-EBNA-2 antibody ratio. This distinctive serologic response to EBV latent antigens, indicative of immune dysfunction in other clinical settings, is associated with an increased risk of developing EBV(+) but not EBV(-) Hodgkin lymphoma.

Increase in GLUT1 in smooth muscle alters vascular contractility and increases inflammation in response to vascular injury.

OBJECTIVE: The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease. METHODS AND RESULTS: A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non-insulin-dependent glucose transporter protein, was overexpressed in smooth muscle using the sm22α promoter. Overexpression of GLUT1 in smooth muscle led to significant increases in glucose uptake (n=3, P<0.0001) as measured using radiolabeled 2-deoxyglucose. Fasting blood glucose, insulin, and nonesterified fatty acids were unchanged. Contractility in aortic ring segments was decreased in sm22α-GLUT1 mice (n=10, P<0.04). In response to vascular injury, sm22α-GLUT1 mice exhibited a proinflammatory phenotype, including a significant increase in the percentage of neutrophils in the lesion (n=4, P<0.04) and an increase in monocyte chemoattractant protein-1 (MCP-1) immunofluorescence. Circulating haptoglobin and glutathione/total glutathione were significantly higher in the sm22α-GLUT1 mice postinjury compared with controls (n=4, P<0.05), suggesting increased flux through the pentose phosphate pathway. sm22α-GLUT1 mice exhibited significant medial hypertrophy following injury that was associated with a significant increase in the percentage of VSMCs in the media staining positive for nuclear phosphoSMAD2/3 (n=4, P<0.003). CONCLUSIONS: In summary, these findings suggest that increased glucose uptake in VSMCs impairs vascular contractility and accelerates a proinflammatory, neutrophil-rich lesion in response to injury, as well as medial hypertrophy, which is associated with enhanced transforming growth factor-ß activity.

Colon Cancer Metastatic to the Thyroid Gland in the Setting of Pathologically Diagnosed Papillary Thyroid Cancer: A Review and Report of a Case.

Colon cancer metastases to the thyroid gland are a particularly rare occurrence. Despite the relative amenability of the gland to clinical, radiologic, and pathologic assessment, preoperative distinction between primary and secondary thyroid neoplastic processes remains difficult. Here we describe a case of a patient with a known history of stage IV colon cancer with multiple pulmonary metastases, presenting with a thyroid lesion initially diagnosed as papillary thyroid cancer on fine-needle aspiration biopsy but found to be metastatic colonic adenocarcinoma on post-thyroidectomy pathologic evaluation utilizing immunohistochemical techniques. A review of the literature is also included.

Profound Increase of Lung Airway Resistance in Heart Failure: a Potential Important Contributor for Dyspnea.

Dyspnea is a major symptom of heart failure (HF). Here, we have studied the lung remodeling and airway resistance in HF mice. We demonstrated that aortic banding-induced HF caused a dramatic decrease of lung compliance and an increase of lung airway resistance. The decrease of lung compliance was correlated with the increased lung weight in a linear fashion (γ2 = 0.824). An HF-induced increase of lung airway resistance and a decrease of lung compliance were almost identical in anesthetized mice and in the isolated lungs from these mice. HF caused profound lung fibrosis in mice with increased lung weight. Moreover, HF patients of NYHA class III-IV showed increased lung density as revealed by high-resolution CT scanning. These data indicate that lung compliance and lung airway resistance may be useful in determining lung remodeling after HF, and lung structure changes may contribute to dyspnea in HF.

Cytopathologic findings in "POEMS" syndrome associated with Castleman disease.

A 34-year-old man with a history of a scorpion bite followed by increasing polyneuropathy and IgG lambda monoclonal gammopathy was referred for fine-needle aspiration of a lytic bone lesion and an enlarged axillary lymph node. The findings in the bone lesion were consistent with a plasmacytoma. The FNA of the lymph node showed a peculiar capillary proliferation in a background of polymorphous mature lymphocytes. Flow cytometric analysis showed a mixed lymphoid population. The lymph node was originally signed out descriptively, but review of the case showed features consistent with Castleman disease. After the pathologic findings and clinical features were discussed with the clinical team, the diagnosis of POEMS syndrome was established. Subsequent surgical excision of the lymph node was diagnosed as hyaline vascular-variant Castleman disease.

The usefulness of CD71 expression by flow cytometry for differentiating indolent from aggressive CD10+ B-cell lymphomas.

We studied 34 low- and 30 high-grade CD10+ B-cell lymphomas. Forward light scatter (FSC) and CD71 fluorescence intensity (CD71i) of tumor cells were measured and normalized by corresponding values for resting T cells. Significant differences in CD71i values between low- and high-grade lymphomas were observed by the Mann-Whitney U test (P < .001) and receiver operating characteristic (ROC) curve analysis (P < .001). FSC was not significantly different between low- and high-grade lymphomas; the area under the ROC curve was less than that for CD71i. Neither FSC nor CD71i significantly differentiated follicular lymphoma (FL) grades. A comparison of all FLs (grades 1-3) and non-FL high-grade lymphomas (Burkitt lymphoma [BL] and large B-cell lymphoma [LBCL]) showed significant differences in CD71i (P < .001) and FSC (P = .021). Differences were significant in CD71i and FSC between FL and LBCL (P < .001) but not between FL and BL. CD71i is more potent than FSC for distinguishing CD10+ low- from high-grade lymphomas and FL from non-FL high-grade lymphomas. Sensitivity and specificity are limited owing to inability to identify FL3. In ROC analysis, a high value for CD71i can identify BL and LBCL with a high degree of certainty.

Redox regulation of ion channels in the pulmonary circulation.

SIGNIFICANCE: The pulmonary circulation is a low-pressure, low-resistance, highly compliant vasculature. In contrast to the systemic circulation, it is not primarily regulated by a central nervous control mechanism. The regulation of resting membrane potential due to ion channels is of integral importance in the physiology and pathophysiology of the pulmonary vasculature. RECENT ADVANCES: Redox-driven ion conductance changes initiated by direct oxidation, nitration, and S-nitrosylation of the cysteine thiols and indirect phosphorylation of the threonine and serine residues directly affect pulmonary vascular tone. CRITICAL ISSUES: Molecular mechanisms of changes in ion channel conductance, especially the identification of the sites of action, are still not fully elucidated. FUTURE DIRECTIONS: Further investigation of the interaction between redox status and ion channel gating, especially the physiological significance of S-glutathionylation and S-nitrosylation, could result in a better understanding of the physiological and pathophysiological importance of these mediators in general and the implications of such modifications in cellular functions and related diseases and their importance for targeted treatment strategies.

Childhood social environment and Hodgkin's lymphoma: new findings from a population-based case-control study.

BACKGROUND: Risk of Hodgkin's lymphoma in young adults has previously been associated with higher childhood socioeconomic status (SES) and other markers of delayed infection with common childhood pathogens, especially the Epstein-Barr virus. This study examines the current role of childhood social environment in the development of Hodgkin's lymphoma. METHODS: A population-based case-control study of 565 Hodgkin's lymphoma cases and 679 controls was conducted in the Boston, MA metropolitan area and the state of Connecticut to investigate the viral etiology of Hodgkin's lymphoma. RESULTS: A novel association was detected between attendance of nursery school or day care and reduced risk of Hodgkin's lymphoma among individuals ages 15 to 54 years. The odds ratio (95% confidence interval) for having attended preschool for at least 1 year was 0.64 (0.45-0.92). Risk of young-adult Hodgkin's lymphoma was also associated with family history of hematopoietic cancer, Jewish ethnicity, and cigarette smoking. Other indicators of childhood SES were not associated with young-adult Hodgkin's lymphoma. Among older adults ages 55 to 79 years, Hodgkin's lymphoma was associated with lower childhood SES but not with preschool attendance. CONCLUSIONS: Early exposure to other children at nursery school and day care seems to decrease the risk of Hodgkin's lymphoma in young adults, most likely by facilitating childhood exposure to common infections and promoting maturation of cellular immunity. This finding supports the delayed infection model of Hodgkin's lymphoma etiology in young adults while introducing a new major determinant of age at infection. Hodgkin's lymphoma seems to have a separate pathogenesis among older adults.

Primary central nervous system posttransplant lymphoproliferative disorders.

Posttransplant lymphoproliferative disorders (PTLDs) represent a spectrum ranging from Epstein-Barr virus (EBV)-driven polyclonal lymphoid proliferations to EBV+ or EBV- malignant lymphomas. Central nervous system (CNS) PTLDs have not been characterized fully. We reviewed the clinical, radiologic, and pathologic features of 12 primary CNS PTLDs to define them more precisely. Patients included 10 males and 2 females (median age, 43.4 years) who were recipients of kidney (n = 5), liver (n = 2), heart (n = 2), peripheral blood stem cells (n = 2), or bone marrow (n = 1). All received immunosuppressive therapy. CNS symptoms developed 3 to 131 months (mean, 31 months) after transplantation. By neuroimaging, most showed multiple (3 to 9) intra-axial, contrast-enhancing lesions. Histologic sections showed marked expansion of perivascular spaces by large, cytologically malignant lymphoid cells that were CD45+, CD20+, EBV+ and showed light chain restriction or immunoglobulin gene rearrangement. In distinction to PTLDs in other organ systems, CNS PTLDs were uniformly high-grade lymphomas that fulfilled the World Health Organization criteria for monomorphic PTLDs. Extremely short survival periods were noted for each CNS PTLD that followed peripheral blood stem cell transplantation. Survival of others with CNS PTLD varied; some lived more than 2 years.

Lymphoma, leukemia, and pleiocytosis in cerebrospinal fluid: is accurate cytopathologic diagnosis possible based on morphology alone?

The differentiation of benign versus malignant hematologic processes on cerebrospinal fluid (CSF) is difficult given the significant morphologic overlap and frequently scant specimen. Our study compared the diagnostic power of cytomorphologic analyses and FC analyses in the context of CSF hematologic malignancies. We identified 32 cases of CSF submitted for cytopathologic analysis with corresponding FC data, histologic, or clinical follow-up. The slides were blinded and the study participants (one hematopathologist, two cytopathologists, and one cytotechnologist) reviewed the key slides of each case without additional information. These diagnoses were compared with the original diagnoses made in the context of clinical information and ancillary studies. The spectrum of disease ranged from acute myeloid leukemia, mantle cell lymphoma, chronic lymphocytic lymphoma, Burkitt lymphoma, large cell lymphoma, T cell lymphoma, and non-Hodgkin lymphoma. Parallel diagnoses were made in 62.5% of the cases. Interestingly, the correct diagnoses were rendered in 73% of benign cases, compared with 52% of malignant cases. Of the malignant cases, there was a higher proportion of correct diagnosis based on morphology in the acute malignancies (67%) versus the chronic malignancies (47%). The sensitivity, specificity, positive predictive value, and negative predictive value were 73, 52, 60, and 66% respectively. Features most useful for diagnosis of malignancy included cellular monotony and nuclear contour irregularity. The diagnosis of malignancy based on morphology alone is difficult in CSF. Ancillary studies such as FC analyses greatly enhance the ability to accurately distinguish between benign and malignant hematologic processes.

Chronic villitis in untreated neonatal alloimmune thrombocytopenia: an etiology for severe early intrauterine growth restriction and the effect of intravenous immunoglobulin therapy.

OBJECTIVE: The objective of the study was to examine placental histopathology in intravenous immunoglobulin-treated and untreated neonatal alloimmune thrombocytopenia and correlate pathological findings with clinical outcomes. STUDY DESIGN: Placentas from 14 neonatal alloimmune thrombocytopenia-affected pregnancies were identified. Maternal antepartum treatment with intravenous immunoglobulin and pregnancy outcomes were abstracted from medical records. Placental histopathology and clinical outcomes were compared between intravenous immunoglobulin and no intravenous immunoglobulin treatment groups using Fisher's exact test. One subject, treated only after an intracranial hemorrhage (ICH) was diagnosed, was excluded from the analysis. P < .05 was considered significant. RESULTS: Untreated pregnancies demonstrated a lymphoplasmacytic chronic villitis not seen in the intravenous immunoglobulin-treated pregnancies (P = .005). Intrauterine growth restriction and intrauterine fetal demise occurred as frequently as ICH in the untreated group. No ICH, intrauterine growth restriction, or intrauterine fetal demises occurred in the treated group, although the P value was not significant. CONCLUSION: Chronic villitis is frequently manifest in neonatal alloimmune thrombocytopenia, with intravenous immunoglobulin alleviating this inflammatory immunologic response. We suspect a more universal role for the maternal antibody, such as fetal endothelial cell damage, in the sequelae of neonatal alloimmune thrombocytopenia.

Hepatoblastoma: cytomorphologic characteristics in serious cavity fluids.

BACKGROUND: Hepatoblastoma (HBL) represents the most common primary hepatic tumor in children. Although the cytologic features of this tumor have been amply elucidated on fine-needle aspiration, exfoliative cytomorphologic characteristics have not been reported. The authors reviewed the cytopathologic features of six serous cavity fluids (SCF) from four patients with histologically proven HBL. METHODS: Five of the specimens evaluated were peritoneal fluids, and one specimen was pleural fluid from a patient with suspected pulmonary metastasis. Slides were prepared by cytocentrifugation and stained with Diff-Quik and Papanicolaou stains. The cytomorphologic features of each specimen were characterized, subclassified, and correlated histopathologically. RESULTS: All specimens showed hypercellular smears in a relatively clean background. Mixed embryonal and fetal subtypes of HBL disclosed three-dimensional clusters of neoplastic cells that formed straight or branched cords and acinus-like structures. The cells were moderately pleomorphic and had high nuclear-to-cytoplasmic (N/C) ratios. Occasional cells had eccentrically placed nuclei and vacuolated cytoplasm. Numerous mitotic figures were present. Rare intranuclear inclusions were noted. The anaplastic (small cell) subtype of HBL showed tight clusters of small, round, primitive cells with hyperchromatic nuclei, high N/C ratios, and prominent nuclear molding. In addition, there were numerous single cells with naked nuclei, often in an Indian-file configuration. Bile pigment, osteoid, and other mesenchymal components were absent in all specimens. CONCLUSIONS: The cytomorphologic features of HBL in SCF are quite characteristic. Although the differential diagnosis includes other childhood small, round, blue cell tumors and hepatocellular carcinoma, the above findings in the appropriate clinical-radiologic setting warrant a diagnosis of HBL.

Incidental small lymphocytic lymphoma/chronic lymphocytic leukemia in pelvic lymph nodes excised at radical prostatectomy.

CONTEXT: Incidental non-Hodgkin lymphoma is often unrecognized at the time of radical prostatectomy in patients with prostate cancer because of nonspecific symptoms and an inconspicuous pathology. The early identification of lymphoma allows optimal long-term management and prevention of significant morbidity. OBJECTIVE: To show the subtlety of pathologic findings in cases of non-Hodgkin lymphoma in pelvic lymph nodes and the need for scrupulous attention to detail for diagnostic accuracy. DESIGN: Histologic and immunohistochemical profiles of 18 consecutive cases of small lymphocytic lymphoma (SLL) incidentally identified in pelvic lymph node dissections were reviewed and compared with 22 cases of benign pelvic lymph node dissections. RESULTS: Malignant nodes were grossly enlarged and averaged 3.2 cm in their greatest dimension. Histologically, 16 of the SLL cases were characterized by diffuse architectural effacement with obliterated sinuses and rare cortical follicles. Twelve of these cases showed evidence of pseudofollicles. Two cases showed an interfollicular growth pattern with occasional small pseudofollicles. In contrast, benign pelvic lymph nodes averaged 1.7 cm in their greatest dimension. Although most were architecturally distorted by fibrosis, all benign nodes were notable for patent sinuses. Immunohistochemistry was diagnostically helpful in several cases with equivocal morphology. All malignant cases had a B-cell phenotype with aberrant coexpression of T-cell-related antigens typical of SLL. CONCLUSION: Incidental low-grade non-Hodgkin lymphoma identified at radical prostatectomy is often overlooked by both the urologist and the pathologist. Although malignant pelvic lymph node dissections frequently lack overt manifestations of lymphoma, attention to subtle morphologic features coupled with lymph node size and immunohistochemical findings should permit diagnostic accuracy.

CD56 expression of neuroendocrine neoplasms on immunophenotyping by flow cytometry: a novel diagnostic approach to fine-needle aspiration biopsy.

BACKGROUND: CD56 antigen or NCAM (neural cell adhesion molecule) has an established role in the diagnosis of non-Hodgkin lymphoma (NHL)-natural killer cell type and other hematologic malignancies. Therefore, it is included routinely in the panel of antibodies for flow cytometric (FC) analysis of suspected lymphomatous tissue specimens obtained from fine-needle aspiration biopsy (FNAB). The authors evaluated the role of CD56 expression on FC of neuroendocrine (NE) tumors. An initial diagnosis of NHL was suspected based on an on-site FNAB evaluation. METHODS: Ten FNABs were identified from the cytopathology files at The Johns Hopkins Hospital, Baltimore, MD (2000-2001). Flow cytometric analysis was negative for NHL but revealed a CD56-positive nonlymphoid cell population. An FNAB evaluation was performed on air-dried Diff-Quik-stained smears and FC analysis used a fixed panel of 12 antibodies (B-cell markers, T-cell markers, CD33, CD56, and CD71). Immunoperoxidase staining (IPOX) was performed on the cell block sections from four of the tissue specimens using epithelial and NE markers, CD56, desmin, and O13 antibodies. Sites of FNAB included the lung (five cases), liver (one case), lymph node (three cases), and peritoneum (one case). Only one patient had a history of cancer at the time of FNAB. RESULTS: All cytologic diagnoses were confirmed by histopathologic follow-up on resection or biopsy or both. Diagnoses included small cell carcinoma (eight cases), Merkel cell carcinoma (one case), and primitive neuroectodermal tumor/Ewing sarcoma (one case). All tissue specimens that underwent IPOX stained strongly with NE markers, with one tissue section staining only with O13. CONCLUSIONS: CD56 expression by FC in the presence of negative immunostaining with lymphoid markers represented a unique yet highly specific method for the diagnosis of NE tumors by FNAB. This procedure eliminated the need for further IPOX studies on the already limited cytologic sample and provided a timely and accurate diagnosis.

Extraosseous (extramedullary) plasmacytoma of the adrenal gland.

Plasmacytomas are clonal proliferations of atypical plasma cells that manifest a localized osseous or extraosseous growth pattern. Although many represent solitary lesions of bone, fewer arise in extraosseous (extramedullary) tissues. We report a case of a primary extraosseous plasmacytoma of the adrenal gland. Magnetic resonance imaging (MRI) with contrast revealed a 3.5-cm, right adrenal mass with heterogeneous enhancement. Although the mass was small and nonfunctioning, concern for malignancy based on MRI findings prompted laparoscopic resection. Histologic and immunohistochemical findings were consistent with a plasmacytoma. This is the third reported case, to our knowledge, of a primary plasmacytoma of the adrenal gland. The present case is unique in that a contrast MRI was performed, which showed heterogeneous enhancement of the mass, providing further evidence beyond heterogeneous hyperintensity on T2-weighted images for a possible malignant process. Another unique feature is that a biopsy specimen of the lesion was taken, although it was nondiagnostic.

Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPalpha expression.

Constitutively activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in approximately one third of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Altered FLT3 signaling leads to antiapoptotic and proliferative signaling pathways. We recently showed that these mutations can also contribute to the differentiation arrest that characterizes leukemia. In this report we investigated the mechanism by which internal tandem duplication (ITD) mutation of FLT3 signaling blocks differentiation. Normally, myeloid differentiation requires the induction of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and PU.1 expression. Expression of both genes was repressed by FLT3/ITD signaling in 32Dcl3 (32D) cells and this repression was overcome by treatment with a FLT3 inhibitor, allowing differentiation to proceed. We also observed increased expression of C/EBPalpha and PU.1 accompanied by signs of differentiation in 2 of 3 primary AML samples from patients with FLT3/ITD mutations receiving a FLT3 inhibitor, CEP-701, as part of a clinical trial. Forced expression of C/EBPalpha was also able to overcome FLT3/ITD-mediated differentiation block, further proving the importance of C/EBPalpha in this process.

Primary pancreatic lymphomas: a cytopathologic analysis of a rare malignancy.

BACKGROUND: Primary pancreatic lymphomas (PPL) are extremely rare. Clinically, PPL usually present with symptoms of carcinoma of the pancreatic head. An accurate cytopathologic diagnosis by fine-needle aspiration (FNA) is imperative because the primary treatment is nonsurgical, based on a combination of chemotherapy and radiation therapy. METHODS: Eight cases of PPL were identified from the pathology files of The Johns Hopkins Hospital over a 14-year period (1989-2003). All cases were diagnosed on FNA performed under radiologic guidance. Needle rinses were used to perform flow cytometric (FC) analysis. No tissue studies were performed after the FNA diagnosis was made. RESULTS: A strong male predominance (male-to-female ratio of 7:1) was noted. The patients ranged in age from 35-75 years (mean age, 55 years). The tumors varied in size from 2-14 cm, as evaluated on the radiologic scans (mean dimension of 8.0 cm). Abdominal pain was the most common presenting symptom (six patients) followed by jaundice, acute pancreatitis, small bowel obstruction, and diarrhea. The cytomorphologic features included hypercellularity with discohesive cells with round nuclei, often prominent nucleoli, mitoses, and karyorrhexis. By FC analysis, all eight cases demonstrated a monoclonal pattern of immunoglobulin light chain expression. The patients were treated with either chemotherapy alone or in conjunction with radiation therapy or stem cell transplantation. CONCLUSIONS: PPL is an extremely rare pathologic entity. FNA coupled with FC analysis appears to be highly accurate in the diagnosis of PPL and is the sole diagnostic modality used clinically. Based on cytomorphology, the main differential diagnoses of PPL involve secondary lymphoma, pancreatic endocrine neoplasm, and florid chronic pancreatitis. An accurate FNA diagnosis of PPL is critical for timely, nonsurgical management and obviates the need for an exploratory laparotomy.