Hemophagocytic Lymphohistiocytosis in a Patient with Classical Hodgkin Lymphoma.

Introduction. Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome that can be associated with inherited genetic mutations, malignancy, autoimmune disorders, and viral infections. Though the pathogenesis is not fully known, HLH is understood to be a reactive process in the setting of uncontrolled activation of macrophages, CD8+ cytotoxic lymphocytes, and other immune cells. Hallmark clinicopathological features of HLH include fevers, cytopenias, hepatosplenomegaly, and hemophagocytosis in the bone marrow. Case Presentation. A previously healthy 28-year-old Caucasian male presented with a one-month history of persistent fever, night sweats, and unintentional weight loss. He was diagnosed with classical Hodgkin Lymphoma (HL) by core-needle biopsy of an axillary lymph node. Both bone marrow involvement by HL and hemophagocytosis were seen on subsequent bone marrow biopsy. Other findings included pancytopenia, splenomegaly, and elevated serum ferritin. Extensive work-up for autoimmune and infectious etiologies was unremarkable. The patient had a complete response after chemotherapy with Adriamycin, bleomycin, vincristine, and dacarbazine. Conclusion. This report documents the exceedingly uncommon association between HLH and HL. HLH is a hyperinflammatory syndrome with high mortality, so it is imperative to identify and treat the underlying cause for secondary HLH. Malignancy-associated HLH should be considered in the differential diagnosis for cancer patients who present with fever, cytopenias, and splenomegaly.

[Exclusive intra-operative radiation therapy (IORT) for early stage breast cancer: pilot study of feasibility]. / Radioterapia intraoperatoria (IORT) esclusiva nel carcinoma iniziale della mammella: studio pilota di fattibilità.

AIM: To evaluate feasibility, tolerability and cosmetic outcome of intra-operative radiation therapy (IORT) as an exclusive post-surgery treatment of early stage breast cancer. PATIENTS AND METHODS: From October 2008 to October 2009 30 patients underwent wide breast cancer excision or quadrantectomy followed by IORT on tumor bed with accelerated electrons at the dose of 21Gy. The characteristics of the patients were: ductal breast cancer or invasive lobular cT1, cT2 ≤ 2,5 cm, cN0, G1-2, age over 35 years, M0. RESULTS: The average age was 51.7 (range 38 - 75) with an average follow up of 11.7 months (range 6 - 18). The pathologic stage of the lesions resulted pT1 in 29 cases (96,6%), in particular: one case pT1a (3,3%), 21 cases pT1b (70,0%) and 7 cases pT1c (23,3%). One case (3,3%) was pT2 with a diameter of 2.5 cm. The grading was G2 in 20 cases (66,6%) and G1 in 10 cases (33,3%). The toxicity, evaluated according to the EORTC-RTOG criteria, was G0 (33.3%) in 10 cases, G1 (63,3%) in 19 cases, G2 in one case (3,4%); there was no G3 toxicity. The time needed for a complete healing of the wound was less than 10 days in 96,7% of the cases, with one case of limphocele (3,3%). There were no infections of the surgical wound nor any mastitis, neither in the treated quadrant nor in the other ones. We observed a light fibrosis in 5 cases (16,6%), moderate in 2 cases (6,6%) but never severe. Cosmetics, evaluated in four levels, according to Danoff et al., was excellent in 3 cases (43,3%), good in 15 cases (50%), sufficient in 2 cases (6,7%), never insufficient. As regards local control, there was no local relapse. The global survival was 100%. CONCLUSIONS: The IORT in early breast cancer, at the doses used in this study, proved itself as a secure technique, repeatable, with limited complications. The advantages of its use are the possibility of a direct control, by the surgeon and the radiotherapist, of the structures to treat and those to protect; the absence of time needed for cellular repopulation between surgery and radiotherapy; a good cosmetic outcome; and logistic advantages. It is necessary to have a long term follow up to evaluate the efficacy in terms of long term cosmetic and local control.

Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.

Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.

Discordance of ZAP-70 in patients with chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia has a highly variable clinical course with behavior ranging from indolent to aggressive. Identified prognostic markers include IgV(H) mutational status, and CD38 and ZAP-70 expression. In several studies, ZAP-70 expression correlated with IgV(H) mutational status, and predicted disease progression and overall survival. In addition to its prognostic utility, ZAP-70 expression was found to be constant over time, and did not vary between peripheral blood, bone marrow or lymph node specimens in individual patients. In contrast to these reports, we present three CLL patients with discordant ZAP-70 levels. One demonstrated a change in expression with time; the second and third cases had discordant results in blood, lymph node and bone marrow and between blood and bone marrow specimens, respectively, obtained at the same time.

[Sentinel lymph nodes in breast carcinoma: why, how, when]. / Lo studio del linfonodo sentinella nel carcinoma mammario: perché, come, quando.

Thanks to a retrospective analysis of the first 250 cases of sentinel lymph nodes in breast cancer assessed by the authors over the period from October 1998 to December 2000 in the light of a careful review of the literature, it has been possible to establish the importance of careful patient selection, strict compliance with the execution technique and, above all, the need for an adequate learning curve, before the procedure is used in particular protocols and/or in routine clinical practice in the near future. In particular, the training should first of all ensure that all personnel involved, i.e. surgeons, nuclear medicine specialists, and histopathologists, should attend specific courses at qualified Institutions followed by the actual management of a certain number of consecutive cases. In order to perfect the methodology and organisation, a preliminary study in a group of patients at different stages of evolution of the disease is recommended (50 cases in the study population reported). The next phase should include a group of highly selected patients, numbering at least 50-100. The training may be considered complete when in at least 20 cases, an identification rate of at least 90% is achieved with an incidence of false negatives of not more than 5%. In the authors' experience, these results were reached after 100 selected patients, and were later consistently confirmed after a further 50 cases.

Maternal caffeine intake and intrauterine growth retardation.

This study estimates the effect of maternal caffeine consumption throughout pregnancy on fetal growth. We studied 2,714 women who delivered a liveborn infant between 1988 and 1991. Detailed information regarding coffee, tea, and soda drinking during the first and third trimesters of pregnancy was obtained. Average caffeine intake during month 1 of pregnancy was higher than for month 7 (72.4 vs 54.0 mg per day). Consumption of >300 mg caffeine per day during month 1 (adjusted odds ratio = 0.91; 95% confidence interval = 0.44--1.90) and during month 7 (adjusted odds ratio = 1.00; 95% confidence interval = 0.37--2.70) was not associated with intrauterine growth retardation. There was little evidence for any effect modification due to cigarette smoking on the caffeine associations. This study provides evidence that antenatal caffeine consumption has no adverse effect on fetal growth.

A Chinese patient with non-HFE-linked iron overload.

The gene for hemochromatosis (HFE) was recently identified and contains two missense mutations: C282Y and H63D. The C282Y mutation is found homozygous in approximately 85% to 90% of patients of Northern European ancestry with hereditary hemochromatosis. There are no previous reports with results of genetic testing in Chinese patients with regard to iron overload. In this case report, we describe a Chinese woman with marked hepatic iron overload that was nonfamilial, with unusual biopsy findings, in whom neither the C282Y nor the H63D mutations in HFE were found.

Blastic variant of mantle cell lymphoma following interfollicular Hodgkin's lymphoma.

Infrequently, patients are diagnosed with Hodgkin's lymphoma and a morphologically distinct lymphoma. While specific subtypes of lymphomas (including Hodgkin's lymphoma) may present diagnostic difficulties, fine needle aspiration biopsy (FNAB) is sometimes useful in the evaluation and classification of these lymphoproliferative processes. We report a case of the blastic variant of mantle cell lymphoma following Hodgkin's lymphoma, interfollicular variant. A 66-year-old woman with a history of Hodgkin's lymphoma presented with increasing contralateral cervical adenopathy three years after receiving chemotherapy. FNAB with ancillary immunophenotypic characterization identified mantle cell lymphoma, blastic variant. Subsequent excisional biopsy confirmed this diagnosis and also aided in the exclusion of recurrent Hodgkin's lymphoma. In addition to identifying the previously unreported combination of blastic variant of mantle cell lymphoma and Hodgkin's lymphoma, this case emphasizes the utility of FNAB in evaluation of new masses in patient's with a previous diagnosis of Hodgkin's lymphoma.

Primary biliary malignant lymphoma clinically mimicking cholangiocarcinoma: a case report and review of the literature.

Primary lymphomas of the liver and biliary tract are rare tumors. We describe an unusual case of a diffuse large B-cell lymphoma arising in the extrahepatic bile ducts with local extension to involve the intrahepatic bile ducts. The patient presented solely with obstructive biliary symptoms. The clinical presentation, radiographic studies, and gross findings at surgery suggested that this patient had a Klatskin tumor (cholangiocarcinoma arising at the junction of the left and right hepatic ducts). While rare, the difference in initial patient management emphasizes the importance of including malignant lymphoma in the differential diagnosis of obstructive biliary lesions. Ann Diagn Pathol 5:25-33, 2001.

Efficient recovery of DNA from peripheral blood for diagnostic analysis with a vacuum manifold.

BACKGROUND: The increasing clinical use of diagnostic DNA mutation analysis requires efficient isolation of DNA from peripheral blood. METHODS AND RESULTS: The use of a vacuum manifold to isolate DNA was evaluated and compared with a similar centrifugation-based DNA isolation technique. In PCR-based assays of five-point mutations, identical results were obtained with DNA isolated from peripheral blood using either centrifugation or a vacuum system. Minor modifications to PCR procedures were encountered. CONCLUSIONS: In the clinical setting, this vacuum-driven method of DNA isolation provides an efficient, useful alternative to conventional centrifugation-based DNA isolation from peripheral-blood specimens. Providing sufficient, stable DNA for multiple assays, it is easily implemented without highly specialized, expensive equipment and decreases the time spent isolating DNA from multiple samples. In addition, the potential for specimen contamination is reduced because there are fewer transfer steps.

Low-grade B-cell lymphoma and concomitant extensive sarcoidlike granulomas: a case report and review of the literature.

Sarcoidlike granulomas may occur in association with Hodgkin lymphoma and non-Hodgkin lymphoma. The granulomas may be concomitant and so extensive that they obscure the malignant process. In addition, a sarcoidosis-lymphoma syndrome has been described in which there appears to be a relationship between sarcoidosis and the development of a lymphoproliferative disorder. We report a case of a low-grade B-cell lymphoma with concomitant extensive sarcoidlike granulomas. The patient had no diagnostic clinical evidence of sarcoidosis, although she had an elevated serum calcium level and increased serum angiotensin converting enzyme activity. Increased serum calcium and serum angiotensin-converting enzyme activity have been associated with clinical sarcoidosis but have also occasionally been described in association with Hodgkin lymphoma and non-Hodgkin lymphoma without evidence of sarcoidosis. We describe our findings and illustrate the usefulness of immunoperoxidase immunophenotyping techniques in such a case.

Clinical management of soft tissue sarcomas.

The prognosis of soft tissue sarcomas has dramatically improved over the past few decades thanks to the use of increasingly suitable multidisciplinary therapeutic approaches. An assessment of the results of our series of 21 patients, carried out in the light of the most recent literature data, has led us to revise our approach to a number of problems regarding the natural history, the nosographical classification and the therapy of these cancers. This type of tumour arises in a muscle compartment and then spreads proximally and distally within the compartment without involving adjacent structures, except in a relatively advanced phase, while as regards remote metastases the preferential diffusion route is via the bloodstream. Thorough assessment of the clinical and morphological characteristics is essential for adequate treatment: echotomography, CT, and MRI are particularly useful in preoperative staging; a microscopic examination should always include precise classification and accurate assessment of the tumour grade. Surgical management consists in extensive en bloc resection, followed by radiotherapy in the event of unclear margins and/or high grade tumour even when dealing with small sarcomas. The main indications for chemotherapy are locally advanced cases or cases with distant metastases. Thanks to these therapeutic approaches today, good results can be achieved, with 5-year survival rates of 80 and 67%, respectively, in stages I and II, and of 12 to 50% in the more advanced stages.

CD7 and CD56-positive primary effusion lymphoma in a human immunodeficiency virus-negative host.

Primary effusion lymphoma is an entity with distinctive features. The majority of cases are diagnosed in patients infected with human immunodeficiency virus. We report a case of pleural-based primary effusion lymphoma in an elderly patient negative for human immunodeficiency virus. By flow cytometry, lymphoma cells expressed CD7, CD38, CD45, CD56, HLA-DR, and kappa surface light chains. A monoclonal rearrangement of the immunoglobulin heavy chain and the presence of human herpesvirus 8 genome were detected. Our case lacked CD30 or CD138 with expression of surface light chains. There was strong expression of CD7 and CD56. These findings are unusual or unique in primary effusion lymphoma. Our report suggests that aberrant expression of T cell and natural killer cell markers can be seen in primary effusion lymphoma.

DNA polymerase chain reaction using fine needle aspiration biopsy smears to evaluate non-Hodgkin's lymphoma.

OBJECTIVE: To apply polymerase chain reaction (PCR) analysis to the fine needle aspiration biopsy (FNAB) evaluation of lymphoid proliferations. STUDY DESIGN: We analyzed 37 consecutive archived FNAB malignant lymphoma specimens. Immunophenotypic data from the fine needle aspiration biopsy and excisional biopsy material was available for all specimens. PCR to identify monoclonal rearrangements of the immunoglobulin heavy chain gene, T-cell receptor and translocations involving the bcl-1 and bcl-2 genes was performed. RESULTS: Seventy-eight percent of cases were detected by at least one of these assays. Where DNA analysis was performed on excisional biopsy material, 70% of the cases had identical results; no discordant results for the immunoglobulin heavy chain gene or T-cell receptor were found. In 23% of cases, after review of all available data, a discordant result was thought to be a consequence of a false negative result in DNA analysis of excisional biopsy material. CONCLUSION: These findings indicate that PCR analysis of archived FNAB material, when necessary, provides useful information for diagnosis and staging of malignant non-Hodgkin's lymphomas.

T-cell rich, Ki-1-positive post-transplant lymphoproliferative disorder: a previously undescribed variant following liver transplant.

Post-transplant lymphoproliferative disorders (PTLD) are a consequence of the immunosuppressive therapy following organ transplant. We describe a patient who developed PTLD seven years after liver transplant and while receiving cyclosporine and prednisone. Magnetic resonance imaging demonstrated a paraspinal mass extending from T11 to L1. Microscopically, this was composed of a diffuse infiltrate of small to intermediate sized T-lymphocytes with clusters of large anaplastic tumor cells with amphophilic cytoplasm, large irregular nuclei and prominent nucleoli. A high mitotic rate and atypical mitotic figures were noted in the clusters of large cells. Flow cytometric and immunohistochemical analysis failed identify either a monoclonal B-cell population or a T-cell population with aberrant expression of the T-cell surface markers. Strong positivity for CD30 and focal staining for epithelial membrane antigen (EMA) of the large cells was seen. Leukocyte common antigen (LCA), cytokeratin, vimentin, monocyte/macrophage and B- and T-markers were negative. The small lymphoid cells were positive for CD3, MT-1 and UCHL-1. Based on the immunophenotypic and morphological evaluation, this was characterized as a T-cell rich PTLD. PCR analysis identified a monoclonal population of B-cells. This unusual case emphasizes the morphological and immunophenotypic diversity of PTLD. The utility of PCR analysis in the evaluation of PTLD is also demonstrated.

Leukemic phase of mantle cell lymphoma presenting as anemia: diagnosis by combining flow cytometry and cytomorphology.

We report a case of mantle cell lymphoma in leukemic phase, which was diagnosed by a bone marrow biopsy performed as part of a workup for chronic anemia in a patient without lymphadenopathy. The patient, a 79-year-old man with diabetes mellitus, hypertension, chronic renal failure, congestive heart failure, and atherosclerosis, presented with claudication. On admission, he also had an 8-month history of anemia, during which time he experienced a 18-kg weight loss. On presentation, the patient had normal vital signs, anemia, leukocytosis (as well as an absolute lymphocytosis), and splenomegaly; as mentioned, lymphadenopathy was absent. A bone marrow biopsy showed an increase in small to intermediate-sized, slightly irregular lymphocytes in interstitial nodules. Flow cytometric immunophenotyping of the bone marrow identified a monoclonal population of cells, representing 25% of cells within the bone marrow, with expression of CD19, CD20, immunoglobulin M/D, lambda light chain, HLA-DR, and CD5; reactions for CD10 and CD23 were absent. Based on morphologic and immunophenotypic analysis of the bone marrow, as well as morphologic review of the peripheral blood smear, a diagnosis of mantle cell lymphoma involving the bone marrow and in leukemic phase was made. Subsequent polymerase chain reaction analysis of DNA from peripheral blood identified a population of cells with the bcl-1 rearrangement. This case is unique in that the diagnosis of mantle cell lymphoma was made without lymph node or spleen analysis and the patient, although exhibiting bone marrow and peripheral blood involvement by mantle cell lymphoma at presentation, did not have lymphadenopathy.

Combined fine needle aspiration biopsy, and immunophenotypic and genotypic approach to posttransplantation lymphoproliferative disorders.

OBJECTIVE: To report our experience with a combined approach to posttransplant lymphoproliferative disorders (PT-LPDs) that utilizes fine needle aspiration biopsy. STUDY DESIGN: A review of the files in the Department of Pathology, Saint Louis University Health Sciences Center; from 1988 to 1996 identified six patients with a diagnosis of PT-LPD who underwent either percutaneous or radiologically guided fine needle aspiration biopsy (FNAB). In all cases, material was collected for cytomorphology, flow cytometric analysis and, in selected cases, DNA polymerase chain reaction (PCR). Subsequent evaluations and clinical outcomes were obtained from the medical record. RESULTS: The six transplant recipients (4 men and 2 women; 3 cardiac, 2 renal and 1 hepatic transplant) had an age range of 16-65 years. The aspirate material on these six patients had a polymorphic pattern of lymphoid cells with varying sizes. By flow cytometry, two were monoclonal, while four had a polyclonal pattern. DNA PCR analysis on two FNABs demonstrated a monoclonal rearrangement of the immunoglobulin heavy chain gene. CONCLUSION: FNAB provides cytomorphologic characterization of PT-LPDs in transplantation patients and sufficient material for successful use of flow cytometry immunophenotyping and DNA PCR analysis. FNAB, therefore, has an important role in the evaluation of organ transplantation patients and is a valuable tool for assessing and diagnosing PT-LPD.

Lymphocyte-depleted Hodgkin's disease: diagnostic challenges by fine-needle aspiration.

The diagnosis of Hodgkin's disease by fine-needle aspiration (FNA) can be problematic. A case of Hodgkin's disease, lymphocyte depleted subtype, sample by FNA biopsy is presented. We describe the cytomorphologic features present in this unusual subtype of Hodgkin's disease and discuss the differential diagnosis. Immunohistochemical and morphologic findings of a subsequent biopsy specimen supported the diagnosis. Although FNA is an increasingly used diagnostic modality to evaluate tumors including malignant lymphomas, Hodgkin's disease remains, as in this case, a difficult diagnosis by FNA.

bcl-1 translocations are frequent in the paraimmunoblastic variant of small lymphocytic lymphoma.

To evaluate the usefulness of polymerase chain reaction analysis of translocations involving the bcl-1 and bcl-2 genes in variants of CD5-positive B-cell lymphomas, we analyzed four cases classified as the paraimmunoblastic variant of small lymphocytic lymphoma. This neoplasm, originally identified as an aggressive, diffuse, B-lineage lymphoma related to small lymphocytic lymphoma, can be confused with variants of mantle cell lymphoma (an immunophenotypically and morphologically similar neoplasm). No translocations involving bcl-2 and the immunoglobulin heavy chain gene were identified; two cases had translocations involving the bcl-1 and the immunoglobulin heavy chain genes. The frequency of finding this translocation suggests that these categories of neoplasms might be extremely difficult to distinguish or that a closer relationship between these neoplasms exists than was initially proposed.