Jun Odawara

Use of Random Skin Biopsy for Diagnosis of Intravascular Large B-Cell Lymphoma

Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma with an aggressive clinical course characterized by proliferation of large lymphoma cells within the lumina of the small vessels. Because of its varied clinical symptoms and the absence of lymphadenopathy, diagnosis of IVL is extremely difficult and requires histological confirmation. We report here 6 consecutive patients with IVL, admitted to Kameda General Hospital, Kamogawa-shi, Japan, from June 7, 2006, to February 28, 2007, whose IVL was diagnosed by random skin biopsy of healthy-appearing skin. Three patients presented with progressive neurological deterioration and 2 others with hypoxemia with interstitial infiltration on chest radiography. One patient presented with confusion and severe hypoxia without apparent interstitial infiltration. Two patients showed localized skin involvement. Irrespective of the presence of skin lesions, almost all skin biopsy specimens showed obliteration of small vessels of subcutaneous fat tissues by lymphoma cells, allowing a prompt diagnosis of IVL. Early institution of rituximab-based chemotherapy induced favorable responses in all patients treated. Because diagnosis based on tissue other than skin is usually difficult in patients with suspected IVL, random skin biopsy should be considered even in patients with no evident skin lesions.

A clinicopathological study of 13 cases of intravascular lymphoma: experience in a single institution over a 9-yr period.

Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma in which the lymphoma cells proliferate exclusively in lumina of small vessels. Here, we report a clinicopathological study of 13 cases IVL diagnosed at our institution between March 1999 and July 2007, and evaluated the clinical characteristics, usefulness of random skin biopsy and response to chemotherapy containing rituximab. Three of 13 patients were diagnosed at autopsy. The most common clinical features were unexplained fever, neurological deterioration, respiratory failure, and poor performance status. Thrombocytopenia, high serum lactate dehydrogenase and soluble interleukin2 receptor levels were the most common laboratory abnormalities. Adrenal tumor was detected in four cases and pituitary involvement was seen in all three autopsied cases and in two surviving patient by brain magnetic resonance imaging. Bone marrow invasion was seen in all 13 cases by bone marrow smear, and it was subtle in trephine biopsy. Immunohistochemical analyses revealed that CD5 was positive in one‐third of the cases. Most of the cases were positive for MUM1/IRF, Bcl‐2 and negative for CD10 and BCL‐6 indicating the postgerminal center cell origin of this peculiar type of lymphoma. On random skin biopsy, the most recent seven patients were diagnosed promptly and chemotherapy containing rituximab was successfully administered. Patients with IVL exhibit the characteristic clinical and immunophenotypic features cited above and the use of random skin biopsy facilitates prompt diagnosis. Early commencement of chemotherapy containing rituximab appears promising for this peculiar lymphoma. As the recent seven patients were diagnosed by random skin biopsy over the past 13 months, the incidence of IVL is thought to be much higher than generally accepted.

Detection of sputum Aspergillus galactomannan for diagnosis of invasive pulmonary aspergillosis in haematological patients

We investigated the diagnostic utility of Aspergillus galactomannan (GM) in sputum for diagnosis of invasive pulmonary aspergillosis (IPA) in haematologic patients and compared the results with those of bronchial lavage fluid (BLF) and serum. Patients were classified into 4 groups using modified European Organization for Research and Treatment of Cancer criteria: group A, proven IPA; group B, probable IPA; group C, possible IPA; group D, others. Groups A and B were considered the IPA group (n = 6); group D was considered non-IPA group (n = 37); group C (n = 13) was equivocal for IPA. As a true negative control, sputa from patients with community-acquired pneumonia (CAP) without risk factors (group E, n = 22) were used. From the receiver-operating characteristic curves, the cut-off levels were determined as 1.2 in sputum, 0.5–1.3 in BLF and 0.5 in serum. The sensitivity and specificity of sputum, BLF and serum GM were 100 and 62.2%, 66.7 and 100%, and 83.3 and 81.1%, respectively. Twenty-two patients with CAP (group E) showed median GM levels in the sputa of 0.1 (range 0.0–1.0). Sputum GM is a useful non-invasive test for screening of IPA in haematological patients, and may also be useful for assessment of the risk of developing IPA.

High risk of hepatitis B‐virus reactivation after hematopoietic cell transplantation in hepatitis B core antibody‐positive patients

We investigated the serological changes in hepatitis B virus (HBV)‐related markers in 55 and 26 hepatitis B surface antigen (HBsAg)‐negative patients undergoing allogeneic and autologous stem cell transplantation, respectively, over the past 4 yr. Five of the 17 allogeneic and one of the five autologous patients with pretransplant anti‐hepatitis B core antigen antibodies (anti‐HBc) were HBsAg‐positive after transplantation, whereas none of the patients negative for anti‐HBc were HBsAg‐positive in both groups. All patients who became HBsAg‐positive received steroid‐containing immunosuppressive therapy for chronic graft versus host disease (GVHD) or myeloma. Four of the six patients developed flare of HBV hepatitis, and two patients did not. One patient developed fulminant hepatitis treated with lamivudine and plasma exchange. Other five patients received entecavir from the detection of HBsAg. Although HBV‐DNA levels became below the limit of detection in all patients, HBsAg positivity remained in three patients after 6 months of treatment. We concluded that anti‐HBc positivity is a risk factor for reactivation of HBV after both autologous and allogeneic transplantation, and HBV‐related markers should be monitored regularly in these patients. We also stress the efficacy of pre‐emptive use of antiviral agents in controlling HBV replication and limiting hepatic injury due to reactivation of HBV in these patients.

18F‐Fluorodeoxyglucose positron emission tomography for evaluation of intravascular large B‐cell lymphoma

A 73-year-old woman was referred to our hospital with a 1month history of recurrent fever, worsening mental state and general weakness. Physical examination showed confusion and mild splenomegaly but no peripheral lymphadenopathy or skin lesions. Her serum lactate dehydrogenase (LDH) and soluble interleukin-2 receptor were elevated to 1110 iu/l and 14 400 U/ml respectively. Computed tomography of the abdomen revealed mild hepatosplenomegaly and a right adrenal mass (top left panel). A bone marrow aspirate from the sternum showed scattered large atypical lymphoid cells (4AE2%) suggesting lymphoma infiltration. Based on our prior experience with intravascular lymphoma (IVL), we performed random skin biopsies from normal appearing skin on the trunk, thigh and upper arms. All specimens showed large lymphoid cells with irregular nuclei filling the small vessels in subcutaneous tissues (middle left panel). These cells were stained positively with CD20 (bottom left panel) and negatively with CD3 monoclonal antibody. A diagnosis of IVL of B-cell origin was made. F-Fluorodeoxyglucose positron emission tomography (F-FDG PET) was performed before treatment. In addition to intense uptake of the adrenal mass, increased F-FDG uptake was observed in the vertebrae, humeri, ulnae, radii and iliac crests (top right panels). After rituximab infusion (375 mg/m), her general condition and mental status improved rapidly. The serum LDH level was elevated transiently but returned to within normal limits over the next few days. After two courses of weekly rituximab and one course of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy, F-FDG PET (bottom right panels) scan was repeated, and no abnormal F-FDG uptake was observed. The patient entered complete remission and continued to receive additional treatment with rituximab and CHOP. IVL is a very rare subtype of non-Hodgkin lymphoma with an aggressive natural course. F-FDG PET scanning appears to be extremely useful for evaluating the early response to the chemotherapy in patients with IVL.

Gross Hematopyuria Presenting As a First Symptom Due to the Bladder Infiltration of Extranodal Burkitt's Lymphoma

We describe the case of a 59-year-old man with no significant past medical history who presented with a 2-week history of abdominal discomfort, fatigue, and poor appetite. The physical examination revealed a poor performance status, abdominal swelling, and edema in the left lower extremity. In addition, he had gross hematopyuria (Fig 1) and perirectal mass and no evidence of peripheral lymphadenopathy or hepatosplenomegaly. Initial laboratory data revealed a WBC count of 6.3 K/ L, mild anemia (hemoglobin count of 9.5 g/dL), and platelet count of 127 K/ . Serum chemistry showed an elevation of lactate dehydrogenase (1,324 U/L; normal levels between 119 and 229 U/L). The patient’s urine was macroscopically turbid and urine sediment showed more than 100 nucleated cells and red cells per high-power field. A computed tomography (CT) scan of the thorax, abdomen, and pelvis represented an edematous bladder and large mass from perirectal to common iliac artery bifurcation area, and massive tumor infiltration was suspected (Fig 2). Urine was analyzed in cytology and showed large atypical lymphoid appearance cells with basophilic cytoplasm, prominent cytoplasmic vacuoles, visible nucleoi, and round clumped chromatin (Fig 3). As reported about use of urine flow cytometry of malignant lymphoma, quick processing, collection, centrifugation, resuspension, and fixation of the urine was done with pathology team. We suspected hematologic malignancy and felt numbers of lymphoid appearance cells could enable us to use urine flow cytometry with hematopyuria and lead to diagnosis. The result of urine flow cytometry showed an abnormal B-cell population expressing CD10, CD19, CD20, and lambda surface light chain restriction. Expression of n-terminal deoxynucleotidyl transferase was not detected. We suspected Burkitt’s lymphoma and tried biopsies from perirectal mass. The specimens demonstrated thick, diffuse lymphoid infiltration (Figs 4, 5) of adipose tissues by moderately large nucleoi lymphocyte positive for CD10, CD20, and high proliferative rate (Ki67 100%). No bone marrow, peripheral blood, or CNS infiltration was identified. The karyotyping and fluorescent in situ hybridization studies on excited specimen demonstrated t(8;14) c-myc translocation and immunoglobulin (Ig) heavy chain rearrangement. As a result, we diagnosed Burkitt’s lymphoma. The patient received induction chemotherapy with hyperfractionated cyclophoshamide, vincristine, doxorubicin, and dexamethasone (the hyper-CVAD protocol) and rituximab. He could tolerate its toxicity, but the protocol was less effective and attained only short-term stable disease. After the first regimen, we tried two courses of CODOX-M (cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate) and one course of IVAC therapy (ifosfamide, etoposide, and high-dose cytarabine). At each course he received rituximab. He

Use of tranexamic acid for disseminated intravascular coagulation with excessive fibrinolysis associated with aortic dissection in a patient with chronic renal failure

Disseminated intravascular coagulation (DIC) is characterized by systemic activation of coagulation, which leads to the intravascular formation of fibrin and depletion of platelets and coagulation factors [1]. Secondary fibrinolysis is seen in patients with DIC, but the degree to which the fibrinolytic system activated varies according to underlying diseases. Aortic aneurysm and aortic dissection are rare but well-recognized causes of DIC [2–4]; however, the degree of activation of fibrinolytic system seems to differ and the optimal medical treatment strategy, especially in inoperable cases, has not been established yet. Furthermore, there have been few reports which referred to the DIC treatment in patients with renal failure and optimal treatment such as the choice and the dosage of drugs in these conditions is unclear. We report here a case of chronic DIC accompanied by excessive fibrinolytic activity with marked bleeding tendency due to inoperable aortic dissection in a patient with chronic kidney disease under hemodialysis, which was successfully controlled by combined use of tranexamic acid (TA, an antifibrinolytic agent) and anticoagulant. A 67-year-old man with end-stage renal failure was admitted to our hospital for the assessment of progressing anemia and spontaneous massive subcutaneous bleeding in his left elbow (Fig. 1) in June 2007. He had past surgical history for thoracic to abdominal aortic dissection 6 years ago which was not completely repaired. Massive proteinuria developed 3 years ago and renal dysfunction had gradually worsened which resulted in end-stage renal failure and regular hemodialysis started soon after current admission. On admission, a physical examination revealed several ecchymoses on his extremities without hepatosplenomegaly. He developed intramuscular hematoma in his right gastrocnemius after 10 days of admission. Complete blood count showed severe anemia of hemoglobin (Hb) 3.4 g/dl and thrombocytopenia of platelet count 7.2 9 10/ll. Red cell fragments were not observed. Liver function tests were within the normal limits and serum creatinine level was 5.2 mg/dl. Marked abnormalities on coagulation study were observed, prothrombin time (PT) 14.3 s (normal 10–13 s), activated partial thromboplastin time (aPTT) 32.3 s (normal 25–40 s), fibrinogen (Fbg) 110 mg/dl (normal 150–380 mg/dl), fibrin/fibrinogen degradation product (FDP) 109.7 lg/ml (normal \5 lg/ml), D-dimer 78.5 lg/ml (normal\0.5 lg/ml), antithrombin-III (AT-III) 89.9% (normal 70–120%), thrombin antithrombin complex (TAT) 60 ng/ml (normal \3 ng/ml), plasminalpha 2 antiplasmin complex (PIC) 9.8 lg/ml (normal \0.8 lg/ml), plasminogen (Plg) 65.6% (normal 70– 120%), alpha 2 plasminogen inhibitor (a2-PI) 47% (normal 85–115%). Thoracic to abdominal enhanced computed tomography (CT) demonstrated the residual aortic dissection communicated with descending aorta, which was classified as type B by Stanford classification. Clinical and laboratory findings suggested the diagnosis of chronic DIC associated with aortic dissection, in which local activation of coagulation system in the false channel resulted in the systemic depletion of locally consumed coagulation factors, and locally activated coagulation factors reached the S. Kimura J. Odawara T. Aoki M. Yamakura M. Takeuchi K. Matsue (&) Division of Hematology/Oncology, Department of Medicine, Kameda General Hospital, 929 Higashi-chou, Kamogawa, Chiba 296-8602, Japan e-mail: kmatsue@kameda.jp

18F-Fluorodeoxyglucose avid liver lesion in a patient with multiple myeloma

A 49-year-old man presenting with back pain was diagnosed with immunoglobulin (Ig) G kappa myeloma. On admission, he had bone marrow plasmacytosis with 80% of atypical CD38-, CD56-, and CD138-positive plasma cells. His serum IgG level was 11 200 mg ⁄dL (normal range, 819–1590 mg ⁄dL) with immunoparesis of the other immunoglobulin classes. He was treated with high dose dexamethasone and thalidomide, and underwent a liver ultrasound (US) examination and an abdominal computed tomography (CT) scan following the detection of a mild elevation of aminotransferases. Liver US disclosed a hypoechoic mass 15 · 20 mm in diameter (Fig 1Afl), and abdominal CT revealed an enhanced focal lesion (Fig. 1Bfl) in the right hepatic lobe. F-Fluorodeoxyglucose (FDG) positron emission tomography ⁄ computed tomography (PET ⁄CT) revealed an abnormal uptake of FDG [standardized uptake value (SUV) 7.47] in the right hepatic lobe (Fig. 2fl), in addition to a slight increase in bone marrow uptake (SUV, 4.00) in the left clavicle and sacroiliac region. A percutaneous needle biopsy of the liver disclosed a plasmacytoma (Fig. 3A and Fig. 3B) positive for CD138 immunostaining. Despite treatment with high dose dexamethasone and thalidomide followed by a combination of high dose dexamethasone and bortezomib (Velcade), which resulted in complete remission of the myeloma, the size of the hepatic plasmacytoma remained unchanged. He received percutaneous ethanol injection into the plasmacytoma followed by autologous peripheral blood stem cell transplantation with high dose melphalan preconditioning (200 mg ⁄m). The liver plasmacytoma disappeared completely and the patient was discharged in stringent complete remission (sCR). He is currently well and remains in sCR after 8 months post-transplant. Involvement of multiple myeloma is usually restricted to the bone marrow, although extramedullary spread can occasionally occur. Hepatic involvement of myeloma was found in 30–50% of patients in a previous autopsy series, but it has rarely been reported as a solitary mass in living patients. However, FDG-PET ⁄CT is a whole body imaging technique that is able to identify occult disease

Use of urine cytology in the diagnosis of genitourinary relapse of acute promyelocytic leukemia after allogenic stem cell transplant

A 43-year-old woman was admitted to Kameda General Hospital for multiple subcutaneous nodules in trunk and extremities on 12 September 2007. She was diagnosed as having acute promyelocytic leukemia (APL) with t (15;17) in January 2003. She obtained complete remission by combined chemotherapy and all-trans retinoic acid. However, she relapsed on September 2005, and received unrelated bone marrow transplantation on September 2006 for her resistant leukemia. Although her clinical course was complicated with the persistent positivity of PML/RAR mRNA after transplant, the development of acute and chronic graft versus disease (GVHD), which was induced by rapid tapering of post-transplant immunosuppressive therapy, she obtained complete molecular remission with mild skin GVHD and was discharged on February 2007. Although complete blood count and bone marrow smear were unremarkable at the time of admission, biopsy of cutaneous nodule revealed massive infiltration of leukemic promyelocytes. The diagnosis of skin relapse of APL was made. Ultrasonography performed as an initial workup revealed right hydronephrosis. Although, drip infusion pyelography (Fig. 1) showed a non-functioning pattern of right kidney, a magnetic resonance imaging (MRI) study of genitourinary system revealed tumors at vesicoureteric junction involving the urinary duct (Fig. 2). Cystoscopical finding was compression of bladder wall by the extrinsic tumor (Fig. 3). A microscopic urine examination appeared to unremarkable with negative red blood cells and 5–9 white blood cells under high power field, however, cytospine preparation of the urine revealed many leukemic cells with abundant pathologic azur granules (Fig. 4) with positive CD33 and 13, verified the relapse of APL in genitourinary tract. The patient subsequently developed bone marrow relapse that was treated by ATO, gemtuzumab ozogamicin and cytosine arabinoside without success. She eventually died for intracranial bleeding due to disseminated intravascular coagulation. Although detection of leukemic cells in urine might be extremely rare, urine cytology should be considered when the genitourinary tract involvement by leukemia is suspected as in the cases of genitourinary cancers where routine urine cytology is important tool for diagnosis.

Identification of cardiac metastasis of primary gastric diffuse large B-cell lymphoma.

A 72-year-old man was admitted to our hospital with a 10-day history of appetite loss. He had been diagnosed with primary gastric diffuse large B-cell lymphoma (DLBCL) 1.5 years prior to this admission. The patient had achieved complete remission after six courses of rituximab and cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy. Although the results of physical examination were unremarkable, laboratory data revealed mild anaemia (haemoglobin, 103 g/l), and elevation of serum lactate dehydrogenase (530 IU/l; normal, 250–450 IU/l) and soluble interleukin 2 receptor levels (1230 U/ml; normal, 220–450 U/ml). Gastroendoscopy showed an ulcerated mass in the inferior gastric corpus and biopsy revealed recurrence of DLBCL. F-Fluorodeoxyglucose positron emission tomography (F-FDG PET) before treatment showed intense uptake in the gastric wall and the heart (left panel). Marked thickening of the atrial septum (arrows) measuring 17 mm was detected on a transoesophageal echocardiography (TEE) (top right panel: LA, left atrium; RA, right atrium). These observations were strongly suggestive of cardiac metastasis of the disease. After two courses of rituximab and ifosfamide, carboplatin and etoposide (ICE) chemotherapy, the patient’s general condition improved. Repeated F-FDG PET scan showed complete disappearance of FDG uptake on whole-body imaging (centre panel). TEE also showed marked regression of atrial septal thickening (arrows), with the septum measuring 6 mm (bottom right panel). The patient entered complete remission and continued to receive additional treatment with rituximab and ICE. Cardiac metastasis of DLBCL is extremely rare, and F-FDG PET scanning appears to be useful for its detection. The incidence of cardiac metastasis in advanced lymphoma may be higher than generally accepted and the increasing use of PETcomputed tomography is likely to lead to a higher rate of detection.