Masayuki Yamakura

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.

The utility of positron emission tomography/computed tomography in the staging of extranodal natural killer/T‐cell lymphoma

Natural killer (NK)/T‐cell lymphoma cases are rarely discovered using positron emission tomography/computed tomography (PET/CT). We compared the utility of PET/CT and that of conventional methods (CMs; CT with IV contrast, biopsies from primary sites, and bone marrow examinations) in the staging of extranodal NK/T‐cell lymphoma. Nineteen untreated patients with extranodal NK/T‐cell lymphoma at three institutions were analyzed. PET/CT and CMs were applied for initial workups following diagnosis. PET/CT and CMs were compared and evaluated for their ability to detect tumor lesions and their influence on the staging and treatment strategies. In total, 116 lesions were detected by CM and PET/CT. Using PET/CT, 108 lesions (93%) were discovered. The number of nodal lesions was 28: all were positive by PET/CT and 26 (93%) by CMs. The number of extranodal lesions was 89: 84 (94%) and 54 (61%) lesions were positive by PET/CT and CMs, respectively. PET/CT was superior to CMs in detecting cutaneous lesions [31/31 lesions (100%) vs. 20/31 lesions (65%), respectively; P = 0.042]. Bone marrow involvement was confirmed pathologically in only seven patients; four cases (57%) were positive by PET/CT. Using CMs, ten patients (53%) were stages I–II and nine (47%) were stages III–IV. Using PET/CT, eight patients (42%) were in stages I–II and 11 (58%) were in stages III–IV. PET/CT findings altered the stage and treatment strategy in two cases (11%). Our study demonstrated that PET/CT is a useful tool for detecting extranodal lesions in NK/T‐cell lymphoma, particularly cutaneous lesions. PET/CT may therefore influence future staging and treatment strategies.

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.

Acquisition of t(11;14) in a patient with chronic lymphocytic leukemia carrying both t(14;19)(q32;q13.1) and +12.

A rare recurrent chromosomal translocation, t(14;19)(q32;q13), has been identified in a variety of B‐cell malignancies, including chronic lymphocytic leukemia (CLL). We report a unique case of CLL in a patient carrying both trisomy 12 and t(14;19) (q32;q13.1), in whom t(11;14)(q13;q32) developed at relapse. The patient was a 77‐yr‐old woman, and her lymphoma cells at presentation showed CD5+, CD10−, CD19+, CD20+(dim), CD23+, CD38+, and CD11c+. At relapse, the patients lymphoma cells showed positive staining for cyclin D1 in addition to CD5, CD20, and CD23. Lymphoma cells in specimens at both presentation and relapse were positive for lymphoid enhancer factor 1 (LEF1) and negative for sex‐determining region Y‐box 11 (SOX11). IGH‐BCL1 FISH became positive at relapse. Split FISH assay using BCL1, BCL3, IGH, and CCND1 probes on lymph node specimens obtained at presentation and at autopsy confirmed that the translocation of BCL3 was solely detected in the lymph node at presentation and detected BCL3 and CCND1 translocations in the specimen at autopsy. These observations indicated that IGH‐BCL3 and IGH‐CCND1 had occurred in the same clone after treatment of the disease. In line with immunohistochemical and cytogenetic studies, additional PCR analysis of the FR3‐JH region showed the same sequence derived from IGHV4‐34 in specimens obtained at disease onset and relapse.

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.