Personal history of autoimmune disease and other medical conditions and risk of myelodysplastic syndromes.

BACKGROUND: Autoimmune diseases and hematopoietic malignancies are known to cluster within individuals, suggesting intertwined etiologies. A limited number of studies have evaluated pre-existing medical conditions as risk factors for myelodysplastic syndromes (MDS). We evaluated associations between autoimmune disease and other medical conditions and risk of MDS. METHODS: Cases were identified through the Minnesota Cancer Reporting System. Controls were identified through the Minnesota State driver's license/identification card list. History of autoimmune disease and other medical conditions was based on self-report; proxy interviews were not conducted. Unconditional logistic regression was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CI). RESULTS: We included 395 cases and 694 controls. Cases were significantly more likely to report a diagnosis of any autoimmune disease when compared with controls (aOR=1.41, 95% CI: 1.05-1.89) after adjustment for age, sex, education, NSAID use, exposure to benzene and body mass index. When we evaluated specific autoimmune conditions, a statistically significant association was observed for hypothyroidism (aOR=2.16, 95% CI: 1.39-3.34) and odds ratios were elevated for inflammatory bowel disease (aOR=1.75) and systemic lupus erythematosus (SLE; aOR=3.65), although these associations did not reach statistical significance. Presence of an autoimmune condition did not impact overall survival (p = 0.91). CONCLUSION: Our results validate previous findings of an association between autoimmune disease and MDS. Further studies are required to determine whether this association is due to shared etiology, treatment for autoimmune diseases, or altered immune surveillance or bone marrow damage caused by the autoimmune condition.

De novo CD5-positive primary cardiac diffuse large B-cell lymphoma diagnosed by pleural fluid cytology.

Primary cardiac lymphomas are exceedingly rare. The presence and extent of the intracardiac mass is determined by echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI); however, the diagnosis is established by endomyocardial biopsy or by pericardial or pleural effusion cytology. We describe the pleural effusion cytologic features of a primary cardiac lymphoma in a 55-year-old woman who presented with progressive shortness of breath, fatigue, mild dizziness, dull chest ache, and lower extremity edema. Transthoracic echocardiography, CT, and MRI showed a large mass centered in the right atrium and extending into the right ventricle, associated with pericardial effusion and bilateral pleural effusions. Cytologic examination of the pleural fluid showed very large pleomorphic malignant cell, some of which were binucleated and multinucleated and had anaplastic features. Flow cytometry showed a kappa monotypic population of large cells coexpressing CD5, CD19, and CD20; and immunoperoxidase stains performed on the cell block sections showed that the large neoplastic cells were positive for CD20, PAX5, CD5, and MUM1 and showed a very high proliferation rate (over 90%) by Ki67 staining. The cytologic, flow cytometry, and immunohistochemistry findings established the diagnosis of de novo CD5-positive primary cardiac diffuse large B-cell lymphoma (DLBCL), anaplastic variant, which was confirmed by the subsequent endomyocardial biopsy. This is, to the best of our knowledge, the first report of de novo CD5-positive primary cardiac diffuse large B-cell lymphoma, and the first report of the anaplastic variant of DLBCL diagnosed by effusion cytology.

Follicular lymphoma transformed to "double-hit" B lymphoblastic lymphoma presenting in the peritoneal fluid.

Lymphomas showing both MYC/8q24 rearrangement and IGH@BCL2/t(14;18)(q32;q21), also referred to as "double-hit" or "dual-hit" lymphomas (DHL) are rare B-cell malignancies with a germinal center B-cell immunophenotype and heterogeneous cytologic and histologic features. Such lymphomas may arise de novo or through transformation of follicular lymphomas and are classified either as "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL)" (most commonly), DLBCL, or, rarely, as B-lymphoblastic lymphoma. We report a case of B-lymphobastic lymphoma arising through transformation of follicular lymphoma diagnosed on peritoneal fluid cytology, flow cytometry, and cytogenetic studies in a 53-year-old man who presented with abdominal pain, shortness of breath, night sweats, extensive lymphadenopathy, pleural effusion, and ascites. Cytologic examination of the ascitic fluid showed two distinct populations of neoplastic lymphoid cells, a predominant population of larger cells with fine powdery ("blastic") chromatin, visible to prominent nucleoli and occasional small cytoplasmic vacuoles and a less numerous population of smaller cells with centrocytic morphology. Flow cytometry also showed two distinct monotypic B-cell populations, both expressing CD10, and TdT-positivity was demonstrated immunohistochemically. Fluorescence in situ hybridization (FISH) demonstrated both MYC rearrangement and IGH/BCL2 gene fusion and cytogenetic analysis showed a complex karyotype including both t(14;18)(q32;q21) and t(8;22)(q24.1;q11.2). Since DHL pursue an aggressive clinical course, respond poorly to therapy, and have a poor outcome, it is important to suspect the diagnosis when encountering neoplastic lymphoid cells that are difficult to classify in effusion cytology specimens and to order the appropriate immunophenotyping and cytogenetic studies.

Diagnosis of myelodysplastic syndrome among a cohort of 119 patients with fanconi anemia: morphologic and cytogenetic characteristics.

Predisposition to myelodysplastic syndrome (MDS) and acute leukemia is a hallmark of Fanconi anemia (FA). Morphologic criteria for MDS in FA are not well established, nor is the significance of clonal chromosomal abnormalities. We reviewed bone marrow samples of 119 FA patients: 23 had MDS, with the most common subtype refractory cytopenia with multilineage dysplasia. The presence of MDS was highly correlated with the presence of clonal abnormalities. Neutrophil dysplasia and increased blasts were always associated with the presence of a clone, in contrast with dyserythropoiesis. The most frequent clones had gains of 1q and 3q and/or loss of 7. Karyotype complexity also correlated with MDS. One third of patients with 3q as a sole abnormality had no MDS; patients with 3q and an additional abnormality all had MDS. The data provide a rationale for integrating cytogenetic findings with independently evaluated morphologic findings for monitoring bone marrow status in FA.

Positron emission tomography scanning in the setting of post-transplant lymphoproliferative disorders.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of transplantation. We examined the role of positron emission tomography (PET) scanning in PTLD. METHODS: All patients treated for PTLD from 2001-2006 who also underwent PET scans were reviewed. RESULTS: Nineteen PTLD patients were included. Seventeen patients had PET scans for staging at diagnosis. Of these, two patients with primary central nervous system lymphoma and one patient with only bone marrow involvement after complete surgical resection of a bowel lesion had no abnormalities on CT or PET scan. The remaining patients had measurable, extracranial disease by CT scan and PET scan. The median maximum standard uptake value was 8.2 (range 3-30). Thirteen patients had a PET scan following treatment. Eleven of 13 patients had a complete response (CR). Two of 13 patients had persistent disease following therapy; in one of these patients, relapsed disease was documented by PET scan alone. Of the 11 patients with CR, three patients relapsed shortly thereafter. In each case, at the time of relapse, the PET scan confirmed recurrent disease regardless of histopathologic subtype. CONCLUSIONS: PET scans may have a role in the staging and follow-up of patients with PTLD. Additional prospective studies are warranted.

Rituximab-induced changes in hematolymphoid tissues found at autopsy.

The effect of rituximab on malignant B cells and normal circulating B cells has been previously studied. In contrast, data on the degree of depletion of nonneoplastic B cells induced by rituximab in lymph nodes and spleen is limited. For this purpose, clinical charts, autopsy records, lymph node and spleen sections, and immunoperoxidase stains were reviewed from 10 patients who had received 1 to 40 doses of rituximab before death. The percentage of nonneoplastic B cells was lower in the lymph node and spleen in rituximab-treated patients when compared with cyclophosphamide, doxorubicin, vincristine, and prednisone-treated patients and patients without lymphoma. The effect of rituximab on nonneoplastic B cells was observed as soon as 1 month after administration and with as few as 3 doses. Reappearance of normal numbers of B cells was not observed 1 to 12 months after the last dose of rituximab was administered. We conclude that rituximab induces prompt, consistent, profound, and prolonged depletion of B lymphocyte populations in human lymphoid tissue.

Light-chain-restricted plasmacellular infiltrates in necrobiosis lipoidica -- a clue to an underlying monoclonal gammopathy.

BACKGROUND: Necrobiosis lipoidica (NL) is a member of the palisading granulomatous dermatitides that is associated, in most cases, with diabetes mellitus. However, there are an increasing number of cases of NL associated with other forms of systemic disease. We describe a novel case of NL associated with a light-chain-restricted plasmacellular infiltrate; subsequent investigations established an underlying monoclonal gammopathy. METHODS: Skin biopsy material was obtained and was processed in the usual fashion for hematoxylin and eosin (H and E) examination. Immunohistochemical staining was performed by utilizing kappa and lambda monoclonal antibodies (Dako Corporation, Carpentiera, CA, USA). Kappa and lambda in situ hybridization was also performed (Ventana Medical Systems, Tucson, AZ, USA). RESULTS: A 55-year-old woman with a 5-year history of bilateral thigh subcutaneous nodules underwent a skin biopsy, showing typical changes of NL; there was a concomitant prominent perivascular plasmacellular infiltrate. Kappa light chain restriction was observed amid the plasmacellular infiltrate. Bone marrow biopsy and immunophenotyping studies revealed a clonal plasmacytosis with kappa light chain restriction. CONCLUSIONS: Granulomatous inflammation, including NL, may be a cutaneous paraneoplastic expression of low-grade B-cell lymphoproliferative disease in the context of an underlying plasma cell dyscrasia.

Microvascular density does not correlate with histopathology and outcome in neuroendocrine tumors of the pancreas.

Microvascular density (MVD), a marker for tumor angiogenesis, has been demonstrated to have prognostic significance in various malignancies. Previous studies have demonstrated that MVD is an independent prognostic factor in pancreatic adenocarcinoma and that longer survival is associated with hypovascular tumors. The prognostic importance of MVD in pancreatic neuroendocrine tumor (NET) has not been documented. We evaluated MVD in pancreatic NET and correlated it with clinicopathologic features and patient outcome to determine whether MVD is a useful prognostic indicator for these patients. Twenty-five pancreatic NETs from our archival files resected between 1981 and 2000 were identified. The mean MVD was determined for each tumor from the 3 most vascularized 200 x fields. Clinical follow-up ranged from 1 to 19 years, with a mean of 4.9 years. At last follow-up, 6 patients were dead of disease, 10 patients were alive without disease, 4 patients were alive with disease, and 5 patients were alive with disease status unknown. Mean MVD ranged from 43 to 527 microvessels per 200 x field. MVD did not correlate with tumor size, the examined histologic parameters, or patient outcome. MVD in pancreatic NET does not correlate with the clinicohistologic features evaluated in this study or with the patient outcome and is not a useful prognostic indicator in these patients. These results suggest that factors other than the simple number of microvessels are important in determining pancreatic NET behavior. However, most tumors were highly vascular, and additional studies may be helpful to clarify further the role of vascularity and assess the utility of antiangiogenic agents in the treatment of pancreatic NET.

Oral plasmablastic lymphomas in AIDS patients are associated with human herpesvirus 8.

Human herpes virus type 8 (HHV8) has been strongly associated with Kaposi sarcoma, primary effusion lymphoma (PEL), and Castleman's disease. To our knowledge, infection by this virus has not been strongly associated with other hematopathologic malignancies. We examined five oral cavity lymphomas from men with AIDS for HHV8 and HIV-1 by reverse transcriptase in situ polymerase chain reaction, as well as for Epstein-Barr virus (EBV) (EBER-1, -2) using in situ hybridization and HHV8 protein with immunohistochemistry. Four of these tumors were plasmablastic lymphomas; the final case was diffuse large B-cell lymphoma. Most of the neoplastic cells in these five lymphomas contained HHV8 RNA and protein. Further, the four plasmablastic lymphoma cases had tumor cells that contained EBV. HIV-1 RNA was not detected in the tumor cells but was noted in surrounding benign T cells. In comparison, HHV8 RNA was not detected in any of the five oral cavity lymphomas from people who did not have acquired immunosuppression nor in five lymphomas from AIDS patients that were located at a site other than the oral cavity. It is concluded that oral cavity lymphomas from people with AIDS are strongly associated with infection by HHV8 and EBV. Given the poor prognosis of oral cavity lymphomas in immunocompromised patients, therapy directed against the HHV8 and EBV infection may be of therapeutic value.

Expression of mu-BCR-ADL transcripts in chronic neutrophilic leukemia.

The classification of chronic neutrophilic leukemia (CNL) is controversial. Our purpose was to correlate clinical, pathologic, and molecular analyses in 2 cases of CNL. In both cases, the patients were referred because of a substantially increased peripheral WBC count noted during routine examination. Bone marrow biopsies and aspirate smears revealed hypercellularity with myeloid/erythroid ratios of 4:1 and 11:1, respectively. The bone marrow aspirate results were as follows: case 1: blasts, 2%; promyelocytes, 2%; myelocytes, 6%; metamyelocytes, 16%; band neutrophils, 13%; segmented neutrophils, 34%; and case 2: blasts, 1%; promyelocytes, 2%; myelocytes, 15%; metamyelocytes, 20%; band neutrophils, 24%; neutrophils, 19%. Reverse transcriptase in situ polymerase chain reaction studies demonstrated expression of mu-BCR-ABL transcripts in 13% and 25% of the bone marrow cells, respectively. In both cases, the positive signal was noted mainly in the early granulocytic precursors and was present in occasional mature neutrophils. To our knowledge, this is thefirst in situ demonstration of mu-BCR-ABL expression in CNL Ourfindings reinforce the usefulness of this messenger RNA as a molecular marker of CNL.

Parvovirus B19 associated adult Henoch Schönlein purpura.

BACKGROUND: Parvovirus B19 has recently been implicated in various vasculitic syndromes including Henoch Schönlein purpura (HSP), Wegener's granulomatosis and microscopic polyarteritis. The association was established through serology, the identification of DNA in the peripheral blood and affected tissues and more recently by RNA localization to cutaneous capillary endothelium. However, direct localization of the viral DNA to the glomerular and cutaneous endothelium in HSP in correlation with the histopathologic findings has not been demonstrated. METHODS: Skin and kidney biopsy tissues were processed for hematoxylin and eosin, immunofluorescent, polymerase chain reaction (PCR) and reverse transcriptase in situ PCR studies. CASE PRESENTATION: A 64-year-old-female presented with palpable purpura and nephrotic range proteinuria. Kidney and skin biopsies showed IgA-associated mesangioproliferative glomerulonephritis and IgA-associated leukocytoclastic vasculitis, respectively. A diagnosis of HSP was rendered. Her clinical course was refractory to prednisone. Parvovirus B19 DNA and tumor necrosis factor alpha DNA were identified in the dermal and glomerular capillary endothelial cells and surrounding dermal inflammatory cells. CONCLUSION: This is the first documentation of B19 localization to dermal and glomerular capillary endothelium in HSP. It is important to recognize parvovirus B19-associated adult HSP cases, as the treatment of choice is intravenous gamma globulin in concert with anti-TNFalpha therapy. In contrast immunosuppressive therapy may lead to a persistent and/or worsening disease course.

Frozen section diagnosis of pancreatic lesions.

BACKGROUND: The clinical and radiologic diagnosis of pancreatic cancer and the safety of pancreatic resections have improved. These improvements, together with the indication for resection in some cases of complicated chronic pancreatitis, have reduced the necessity for confirmed preoperative tissue diagnosis. We investigated the clinical use and accuracy of frozen section diagnosis for pancreatic lesions. DESIGN: We searched archival files for the years 1989-2000 for patients with pancreatic lesions who had received a diagnosis based on frozen section results. We compared the diagnosis of all frozen section slides with that of the permanent sections and reviewed the clinical follow-up notes. We evaluated histologic features useful in differentiating between malignant and benign pancreatic lesions. RESULTS: A total of 538 patients underwent surgical biopsy and/or resection for suspected pancreatic lesions. Frozen section was requested in 131 cases (284 frozen sections). Ninety cases had frozen section of the pancreatic lesions, 70 cases had frozen section of metastatic sites, and 29 cases had frozen section of surgical margins. Of the 90 cases in which frozen section of the pancreatic lesions was requested, malignancy was diagnosed in 44, a benign lesion was diagnosed in 37, and the diagnosis was atypical and deferred in 9. In total, 3 false-negative frozen sections and 1 false-positive frozen section were identified for respective rates of 1.2% and 0.3%. In all cases in which the frozen section diagnosis was deferred or was inconsistent with the operative impression, and the surgeon acted on his/her impression, the operative diagnoses were subsequently confirmed by additional permanent sections and/or clinical follow-up. The most useful histologic features for the diagnosis of pancreatic adenocarcinoma in frozen sections were variation in nuclear size of at least 4:1, disorganized duct distribution, incomplete duct lumen, and infiltrating single cells. CONCLUSIONS: Frozen sections are useful in conjunction with the impression at surgery for the management of patients with pancreatic lesions. Frozen sections of resection margins were 100% accurate; frozen sections of pancreatic lesions or metastatic sites were accurate in 98.3% of cases. We found an acceptable rate of deferred frozen section (6.6%). The experienced surgeon's impression of malignancy is reliable in cases in which frozen section is deferred or has negative findings.

Histologic and in situ viral findings in the myocardium in cases of sudden, unexpected death.

The purpose of this study was to do in situ viral detection in myocardial tissues of individuals who suffered sudden unexpected death and to correlate the results with the postmortem histopathologic findings. Thirteen cases were identified and the heart tissues were analyzed for adenovirus, cytomegalovirus, Epstein Barr virus, herpes simplex virus 1 and 2, human immunodeficiency virus 1 (HIV-1), influenza A, influenza B, parvovirus, rotavirus, picornavirus (including separate primers for enterovirus and Coxsackie virus A and B), varicella zoster virus, and respiratory syncytial virus. Thirteen individuals aged 2 to 67 years were studied. In each case, polymerase chain reaction-amplified viral RNA was detected in situ: Coxsackie virus B (5 cases), rotavirus (4 cases), HIV-1 (2 cases), influenza A (1 case), and influenza B (1 case). Immunohistochemical detection of viral proteins was found in the five Coxsackie virus cases and four rotavirus cases. The mononuclear inflammatory infiltrate was diffuse and marked only in the cases of influenza A and HIV-1, as well as one of the Coxsackie virus and rotavirus cases, respectively. Immunohistochemical analysis showed that the most common cell type in the inflammatory infiltrates was CD68-positive macrophages. Direct myocyte infection was most prominent in the cases of Coxsackie virus infection. In summary, in situ viral detection was documented in each case of idiopathic myocarditis associated with sudden, unexpected death; in 6/13 cases, the myocarditis was focal and minimal. Although Coxsackie virus was, as expected, the most common virus noted, other viruses including rotavirus and HIV-1 were also observed, highlighting the need for comprehensive viral and histologic analyses in such cases.

Cervical biopsy/cytology correlation data can be collected prospectively and shared clinically.

Cervical cytology (Cy) and biopsy (Bx) correlation is used by institutions for the evaluation of their cytodiagnostic capabilities as a part of overall laboratory quality improvement (QI). However, the data obtained from correlation are not routinely included in most surgical pathology (SP) reports. Our laboratory's procedure is to include the correlation of the patient's previous (most recent) cytology smear in the surgical pathology report of all/any gynecologic surgical pathology specimens. We reviewed this process for the time period between July 1998-June 1999. Any noncorrelating cases were assigned a correlation review code by the reviewing cytopathologist: major Cy diagnostic error (DE1), minor Cy diagnostic error (DE2), Cy sampling error (Cy SE), or biopsy sampling error (Bx SE). Of 3,486 cases reviewed, 3,229 cases were satisfactory for correlation studies. Concordant results were found in 86.9%. Cy DE1 due to either Cy screening or interpretation errors or both were found in 0.2% (n = 7) of all cases, while Cy DE2 due to the same were found in 1% (n = 32). Bx SE accounted for discrepancies in 6.8% (n = 220) of all cases, while 5.1% (n = 164) of the total cases were discrepancies due to Cy SE. Follow-up Bx was available in 97.2% (n = 214) of the Bx SE, and showed 16.4% (n = 35) to be major discrepancies and 83.6% (n = 179) to be minor discrepancies. Cervical Cy/Bx correlation is useful for the evaluation of a laboratory's QI. It is also useful for the identification of either Cy or Bx SE. While QI data exist as "internal use only" documents, SE data (as part of the CC (correlation comment) included in SP reports) are vital to a specific/given patient. Bx SE was identified in 6.3% of our patients, indicating a possible need for rebiopsy. This type of QI data may be shared clinically, and may direct the management for maximum diagnostic and patient benefit.