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.

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.

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.

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.

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.

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.

ABO blood group is a potent risk factor for venous thromboembolism in patients with malignant gliomas.

BACKGROUND: Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with malignant gliomas. To investigate the pathogenesis of VTE and facilitate targeted prophylaxis strategies, the authors aimed to characterize VTE risk factors in these patients. METHODS: The authors conducted a retrospective chart review of 130 adult patients with glioma who received their primary therapy at the Johns Hopkins Hospital (Baltimore, MD) between 1991 and 2001. Symptomatic VTE was confirmed by objective radiologic testing. The association between clinical and laboratory characteristics and VTE was assessed using parametric and nonparametric statistical tests and survival analysis. RESULTS: VTE developed in 28 patients (21.5%) at a median of 4.8 months after diagnosis (interquartile range, 2.1-13.2). Patients with tumors > 5 cm were more likely to develop VTE than patients with smaller tumors (hazard ratio = 2.2; P = 0.04). For every year increase in age, the hazard ratios for thrombosis increased by 3% (P = 0.011). When stratified by ABO blood group, the hazard ratios for thrombosis were 2.7 and 9.4 for patients with blood groups A (P = 0.045) and AB (P < 0.0001), respectively, compared with patients with blood group O. No association was observed between VTE and the other patient characteristics analyzed. CONCLUSIONS: Patient age, tumor size, and particularly ABO blood group are risk factors for VTE among patients with malignant gliomas. These findings may facilitate the development of a thrombosis risk score that will allow physicians to individualize VTE prophylaxis regimens.

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.

Aspirin and the risk of Hodgkin's lymphoma in a population-based case-control study.

BACKGROUND: Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with decreased risk of several malignancies. NSAIDs may prevent cancer development by blocking the cyclooxygenase-catalyzed synthesis of proinflammatory prostaglandins. Aspirin may also protect against Hodgkin's lymphoma by inhibiting transcription factor nuclear factor kappaB (NF-kappaB), which is necessary for immune function and the survival of Hodgkin's lymphoma cells. We examined the association between regular analgesic use and the risk of Hodgkin's lymphoma. METHODS: A population-based case-control study of 565 case patients with Hodgkin's lymphoma and 679 control subjects was conducted in the metropolitan area of Boston, Massachusetts, and in the state of Connecticut. Participants reported their average use of aspirin, non-aspirin NSAIDs, and acetaminophen over the previous 5 years. Regular analgesic use was defined as consumption of at least two tablets per week on average over the preceding 5 years; non-regular use was defined as consumption of fewer than two tablets per week. RESULTS: The risk of Hodgkin's lymphoma associated with regular aspirin use was statistically significantly lower (odds ratio [OR] = 0.60, 95% confidence interval [CI] = 0.42 to 0.85) than that associated with non-regular aspirin use. The risk was not associated with use of other non-aspirin NSAIDs (OR = 0.97, 95% CI = 0.73 to 1.30). However, the risk associated with regular acetaminophen use was statistically significantly higher (OR = 1.72, 95% CI = 1.29 to 2.31) than that associated with non-regular use. CONCLUSION: The inverse association between aspirin, but not other NSAIDs, and Hodgkin's lymphoma suggests that NF-kappaB signaling may play a key role in Hodgkin's lymphoma pathogenesis.

Lesions missed on prostate biopsies in cases sent in for consultation.

BACKGROUND: There are no reports on how often lesions are missed on prostate needle biopsies. METHODS: Over a 10-month period, 8/99 to 5/00, 3,251 prostate biopsy cases were seen in consultation. RESULTS: We identified 87 (2.7%) patients with missed lesions (n = 9 academic hospitals; n = 44 community hospitals; n = 34 commercial labs). Overall, 119 lesions were missed in 87 patients. Missed lesions were as follows: small atypical glands suspicious for cancer (41 lesions in 35 patients), prostatic adenocarcinoma (39 cancers in 32 patients), high grade prostatic intraepithelial neoplasia (HGPIN) (34 lesions in 30 patients), and HGPIN with adjacent small atypical glands (five lesions in five patients)--some men with more than one type of missed lesion. Detection of the missed lesions would have resulted in either: a definite change in care in 15 of 3,251 (0.5%) patients or a possible change in care (bilateral cancer vs. unilateral cancer; HGPIN vs. atypical) in 17 (0.5%) patients. In 21 (24%) of the cases, the slides were seen by at least two pathologists prior to consultation at our hospital. CONCLUSIONS: Although the number of prostate biopsies with missed lesions in a consult-based population of prostate biopsies appears relatively high (2.7%), the detection of the missed lesions would have only effected a definite change in care in 0.5% of all patients or a possible change in care in another 0.5% of patients. Our data underestimates missed lesions, as the entire specimen was not submitted for review in 41% of cases. Although our incidence of missed lesions gives some indication as to the magnitude of the problem, it cannot be equated with the risk of missing lesions in unselected cases.

Heterogeneity of risk factors and antibody profiles in epstein-barr virus genome-positive and -negative hodgkin lymphoma.

BACKGROUND: Hodgkin lymphoma (HL) tumors that contain the Epstein-Barr virus (EBV) genome may differ etiologically from EBV-negative HL tumors. METHODS: A case-case study examining heterogeneity of risk factors between disease subgroups compared personal characteristics and EBV antibodies between 95 EBV-positive and 303 EBV-negative patients with HL. RESULTS: We confirmed previous associations of EBV-positive HL with older age, male sex, and mixed-cellularity (MC) histological subtypes. EBV-positive patients were less educated and more likely to have smoked cigarettes and had more prevalent and higher EBV antibody titers, compared with EBV-negative patients. After adjustment for all independent risk factors, those most strongly associated with EBV-positive HL were histological subtypes (odds ratio [OR] for MC vs. nodular sclerosis histology, 3.2; 95% confidence interval [CI], 1.4-7.2), elevated anti-viral capsid antigen level (OR, 3.1; 95% CI, 1.6-6.0), and less education (OR, 0.7; 95% CI, 0.5-1.0). Cigarette smoking and a low anti-Epstein-Barr nuclear protein (EBNA) 1 : anti-EBNA-2 ratio were also marginally associated with EBV-positive HL. CONCLUSIONS: EBV-positive HL is more common among individuals who have markers of diminished cellular immunity and an abnormal EBV antibody response. EBV appears to participate in the etiology of EBV-positive HL but may not be involved in EBV-negative HL.