Myasthenia gravis with anti-muscle-specific tyrosine kinase antibodies during therapy for multiple myeloma: a case report.

BACKGROUND: The onset of myasthenia (MG) gravis with anti-muscle-specific tyrosine kinase (MuSK) antibodies most commonly peaks in the fourth decade of life, and MG with MuSK antibodies (MuSK-MG) rarely coexists with a malignant tumor. To date, MuSK-MG has not been reported in multiple myeloma (MM). CASE PRESENTATION: A 60-year-old male with MM who was receiving treatment with bortezomib and thalidomide presented diplopia, ptosis, and limb weakness. A diagnosis of MM with Bence-Jones proteinuria was established when he was 56 years old, and he received chemotherapy with four courses of bortezomib and dexamethasone. Although he received thalidomide as maintenance therapy, it was discontinued a year before hospital admission because of sensory neuropathy as a side effect. Six months before hospital admission, he developed mild diplopia. One month before admission, his chemotherapy was interrupted because of viral infection and fatigability. Then he developed neck weakness and bilateral ptosis. A diagnosis of MuSK-MG was made based on neurological and serological examinations. According to the previous relevant literature, this is the first report of MuSK-MG in a patient with MM. CONCLUSIONS: In patients with MM, the possibility of co-existing of autoimmune disease, including MuSK-MG, should be considered. This case emphasizes the need to still consider testing for anti-MuSK antibodies in older MM patients where there is clinical suspicion for possible MG despite negative anti-acetylcholine receptor antibodies and lacking classic MuSK MG phenotype at onset.

[Case of Resected Retroperitoneal Dedifferentiated Liposarcoma Extending to the Posterior Mediastinum].

A 71-year-old woman visited our hospital for the examination and treatment of retroperitoneal tumor. CT showed a retroperitoneal tumor extending to the posterior mediastinum; the tumor pressed the IVC and widely abutted the aorta. On MRI, the tumor showed low intensity on T1WI and high intensity on T2WI and DWI. However, the tumor did not show signal reduction on an ADC map. PET-CT showed high accumulation at the tumor. The patient was diagnosed with sarcoma arising from the retroperitoneum. The tumor located on a part of the diaphragm was resected. Histological examination revealed spindle cells with atypical nuclear and multinuclear cells. There were no lesions of well-differentiated liposarcoma. Both CDK4 and MDM2 tested positive on immunohistological staining. Histopathologically, the tumor was diagnosed as dedifferentiated liposarcoma without any well-differentiated liposarcoma component. The postoperative course was uneventful, and she was discharged on the 13th day after surgery. Two months after surgery, no recurrence has been detected.

Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan.

OBJECTIVES: To determine the tentative diagnostic criteria and disease severity classification for Castleman disease (CD) and describe the clinical and pathologic features among human herpesvirus 8 (HHV-8) negative idiopathic multicentric CD (iMCD) in the Japanese population. METHODS: We established the working groups for the research of CD in Japan and had meetings to discuss and define the tentative diagnostic criteria and disease severity classification for CD. We subsequently analyzed 142 patients classified into iMCD by using the nationwide Japanese patient registry. RESULTS: We proposed the preliminary diagnostic criteria and disease severity classification for CD based on our discussion. In addition, we made a proposal for the disease activity score. We identified clinical and pathological features of patients with iMCD diagnosed by these diagnostic criteria. In the disease severity classification, 37, 33 and 30% patients were categorized into mild, moderate and severe diseases, respectively. CONCLUSION: This is the first proposal for diagnosis and classification of CD by the Japanese group. Further studies are required to validate whether they can distinguish CD from other inflammatory diseases and to determine their sensitivity and specificity.

[Drug-induced immune hemolytic anemia caused by cefmetazole].

A 56-year-old female who was diagnosed with acute calculous cholecystitis received intravenous administration of cefmetazole (CMZ) from the day of admission; she underwent laparoscopic cholecystectomy on the 13th hospital day. She was referred to our department because of hematuria that persisted for 3 days and progressive anemia on the day after the surgery. Laboratory data showed the following results: hemoglobin (Hb) level, 6.8 g/dl; reticulocyte count, 3.4%; serum lactate dehydrogenase, 1,505 IU/l; serum creatinine, 1.1 mg/dl; and undetectable haptoglobin. The direct globulin test showed that the patient was positive for IgG. Thus, drug-induced immune hemolytic anemia (DIIHA) was considered. All drugs, including CMZ, were immediately discontinued, and steroid was administered. The signs of hemolysis began to subside 3 days after the initiation of steroid therapy, and the administration of steroid was discontinued on the 5th day of the treatment. The patient's Hb level gradually increased, and the direct globulin test showed that the patient was negative for IgG on the 21st day from the onset of hematuria. Antibodies against CMZ-coated red blood cells were observed in the serum preserved at the onset of hemolysis. DIIHA is a rare but life-threatening disease. Immediate discontinuation of any suspected drugs and the initiation of steroid therapy as necessary are important in cases wherein DIIHA is suspected.

[Relapse in the nasal cavity of a patient with extranodal NK/T-cell lymphoma initially presenting as plantar subcutaneous tumor].

A 36-year-old woman complained of a mass on the sole of her foot in February 200X. She was diagnosed with extranodal NK/T-cell lymphoma, nasal type (ENKL) by skin biopsy. Because the lesion was localized on the subcutaneous tissue of the sole, she was treated with RT/2/3DeVIC, resulting in a complete response (CR). In March of the following year, PET/CT showed significant uptake and mucosal thickening in the right nasal cavity, and a mucosal biopsy confirmed ENKL infiltration. Because the lesion was localized in the nasal cavity, she was re-treated with RT/2/3DeVIC, with a focus on local control, and she achieved a second CR. She subsequently received allogeneic hematopoietic stem cell transplantation in the hope of preventing systemic relapse. She has remained in CR for four years since the transplantation. Our case suggests that allogeneic hematopoietic stem cell transplantation to be a potentially promising approach to curative treatment for recurrent ENKL in younger patients. As nasal lesions may subsequently appear during the course of primary non-nasal ENKL, ongoing meticulous evaluation for nasal lesions is important.

Cardiac angiosarcoma with pulmonary and adrenal metastases diagnosed by FDG-PET/CT-guided adrenal biopsy.

Primary cardiac angiosarcoma is a high-grade aggressive tumor with a poor prognosis and low incidence. We describe a case of cardiac angiosarcoma, with pulmonary and adrenal metastases, diagnosed via fluorodeoxyglucose-positron emission tomography/computed tomography-guided adrenal biopsy. Learning objective: Cardiac angiosarcoma should be considered in a patient with a cardiac mass with no tumor cells in the pericardial fluid. Fluorodeoxyglucose-positron emission tomography/computed tomography could be useful in determining the biopsy site.

[Development of syndrome of inappropriate secretion of ADH and reversible posterior leukoencephalopathy during initial rituximab-CHOP therapy in a patient with diffuse large B-cell lymphoma].

A 61-year-old woman presented with a right mandibular tumor and was diagnosed with DLBCL clinical stage IIIA from the biopsy results of the tumor and CT examination. An initial rituximab was administrated a week after the first CHOP treatment. During the infusion of rituximab, she exhibited disorientation, seizure, and consciousness disturbance. Hyponatremia due to SIADH and hypertension were coincidentally observed. MRI revealed T2 and FLAIR hyperintense signals involving the bilateral occipital, parietal, frontal lobes and the cerebellum that were consistent with reversible posterior leukoencephalopathy syndrome (RPLS). Her consciousness level recovered in parallel with corrections in serum sodium levels and blood pressure. Although she presented with transient cortical blindness, all neurological abnormalities disappeared 40 hours after the occurrence of seizure. She received a further 7 cycles of CHOP followed by 7 cycles of rituximab treatment with no relapse of RPLS. After irradiation for a residual abdominal tumor, she has maintained complete remission for 2 years. Although RPLS is a rare complication of rituximab-CHOP chemotherapy, it should be considered in patients with DLBCL who present with acute neurological deterioration.

[Primary small intestinal Burkitt lymphoma treated with rituximab-combined CODOX-M/IVAC therapy without surgical resection].

A 38-year-old man complaining of abdominal pain was admitted to our hospital and diagnosed with small bowel obstruction. Whole body computed tomography(CT)scan showed moderate right pleural effusion with pleural and anterior chest wall thickening, with a mass approximately 100 mm in diameter at the terminal ileum. Histopathological and immunohistorical analysis of the endoscopic biopsy from the terminal ileum mass revealed diffuse infiltration of medium-sized, monotonous, atypical B lymphocytes with scanty basophilic cytoplasms carrying the so-called "starry sky" appearance, and primary small intestinal Burkitt lymphoma(BL)was diagnosed. Because of his advanced clinical stage(stage IV with Ann Arbor staging system)and the need for immediate treatment, he was promptly treated with cyclophosphamide and doxorubicin without surgical resection. Fortunately this initial therapy was received without the occurrence of bowel perforation. After initiating additional rituximab combined high-dose chemotherapy consisting of alternating courses of rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate(R-CODOX-M)and rituximab, ifosfamide, etoposide, and cytarabine(R-IVAC), he achieved complete remission and remains without signs of disease now more than seven years after his last treatment. While further investigation will of course be needed, if possible, immediate chemotherapy without surgical resection is a treatment worth considering for improving the prognosis of those with small intestinal BL.

[A case of gastric stenosis due to primary gastric malignant lymphoma during administration of R-CHOP].

A 59-year-old man presented to his general practitioner(GP)complaining of gastric discomfort. Endoscopy revealed an irregular ulcerative region from the gastric lower body to the pylorus. The GP sent the patient to our hospital. With a diagnosis of diffuse large B-cell lymphoma(DLBCL)based on biopsy findings, the patient was treated with R-CHOP chemotherapy. After two courses of this regimen, the patient had vomiting on several occasions. A computed tomography(CT)examination and endoscopy showed that the tumor decreased, but a tight stenosis was located at the pylorus. Because he had trouble continuing chemotherapy, a gastrojejunal bypass operation was performed. The patient did not have vomiting and was able to take meals. After this chemotherapy, CT examination and biopsy findings confirmed that the DLBCL and lymph node metastases had disappeared. Gastrojejunal bypass is expected to be an effective method for treating gastric stenosis during the chemotherapy of DLBCL.

MPL exon 10 mutations other than canonical MPL W515L/K mutations identified by in-house MPL exon 10 direct sequencing in essential thrombocythemia.

MPL exon 10 mutations are one of the driver mutations in essential thrombocythemia (ET) or myelofibrosis (MF). We have established an in-house MPL mutation analysis system, covering the entire region of MPL exon 10 by direct sequencing. Since 2009, MPL exon 10 mutation analysis has been performed for diagnosis of myeloproliferative neoplasms (MPN) without JAK2 V617F or CALR exon 9 mutations. So far, 11 cases of MPL exon 10 mutation have been found in 51 patients with suspected MPN. In patients with ET, we detected five non-canonical MPL mutations including one novel mutation, MPL R514_P518delinsK, and one canonical MPL W515L mutation. Notably, three ET patients without canonical MPL mutations had thrombotic events. Meanwhile, in primary or secondary MF, only canonical MPL W515L/K mutations were found. Further cases need to be examined to elucidate the full MPL mutation profile in MPN. However, our data indicate that analysis of the whole of MPL exon 10 is warranted for the diagnosis of MPL mutations, especially in ET, and that the use of Japanese commercial laboratory tests that only detect canonical MPL W515L/K mutations may miss a significant percentage of MPL exon 10 mutations, which could delay the administration of anti-thrombotic therapy.

[Aggressive NK-cell leukemia with sustained relapse-free survival after allogeneic peripheral blood stem cell transplantation].

A 46-year-old Japanese man was admitted to our hospital because of prolonged fever. Laboratory examination demonstrated leukopenia, thrombocytopenia, marked liver dysfunction, and elevation of serum ferritin. A bone marrow examination showed several hemophagocytic macrophages, and a diagnosis of hemophagocytic syndrome was made. He was treated using HLH-94 protocol, and his clinical symptoms and laboratory data were rapidly improved. After 5 weeks, fever and liver dysfunction reappeared. A repeat bone marrow examination demonstrated that 28.4% of marrow nucleated cells were atypical lymphocytes, which were positive for CD2, CD7, CD16, CD56, and HLA-DR. Clonality of these proliferating NK cells was confirmed by an analysis of EB virus terminal repeat sequence and cytogenetic analysis, and final diagnosis of aggressive NK-cell leukemia was made. After induction chemotherapy consisting of dexamethasone, etoposide, ifosfamide, and L-asparaginase, the patient achieved partial remission. He received allogeneic peripheral blood stem cell transplantation from his one locus mismatched son, and is alive with no evidence of disease 20 months after transplantation.

Mosquito Bite-Induced Localized NK/T-Cell Lymphoma Relapsed in a Patient with Complete Remission of Extranodal NK/T-Cell Lymphoma, Nasal Type.

We report a rare case of localized NK/T-cell lymphoma following a mosquito bite after achieving complete response of extranodal NK/T-cell lymphoma, nasal type (ENKL). T cells and NK cells infected by Epstein-Barr virus (EBV) lead to NK/T-cell lymphoma, including ENKL. Lymphoma related to mosquito bites usually requires a prolonged treatment course, and the disease onset of hypersensitivity begins in early childhood. In the current case, the patient had no history of hypersensitivity to mosquito bites. We speculate that the latently EBV-infected NK/T cells in the blood were reactivated by mosquito gland antigens, expanded abnormally, and accumulated at the site of the mosquito bite.

[Acute myeloid leukemia invasion of the central nervous system, detected only along the Virchow Robin space].

A 66year-old man with sustained fever was diagnosed as having acute myeloid leukemia with multilineage dysplasia. Induction therapy with etoposide and AraC was initiated, but was ineffective. Although fever had persisted for more than a few days, there was no evidence of any infection on radiological examination or culture studies. The patient was disorientated and demonstrated personality change. After a severe convulsive seizure, the patient died. Autopsy findings showed that the leukemic cells had permeated the Virchow Robin space, but without a mass lesion in the cerebral parenchyma. He was diagnosed as having had central nervous system leukemia (CNSL) that provoked sustained fever, consciousness disturbance and convulsive seizure. These findings suggested that the Virchow Robin space plays a particular role in the development of CNSL. Even with repeated cerebrospinal fluid examinations and radiological tests, we were unable to correctly diagnose CNSL before death, which may indicate the intractability of diagnosing CNSL spread along the Virchow Robin space. This case provides useful information about the pathophysiology and diagnosis of CNSL.

[Prolonged survival in a patient with human herpesvirus-8-negative primary effusion lymphoma after combination chemotherapy with rituximab].

Primary effusion lymphoma (PEL) is a unique clinicopathological entity usually associated with human herpesvirus-8 (HHV-8) infection. It occurs almost exclusively in human immunodeficiency virus (HIV) -infected individuals. We presented a rare case of HIV-negative PEL in an elderly HHV-8-negative patient who developed cardiac tamponade due to pericardial effusion. The patient was treated with rituximab and cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). This disease generally has a poor prognosis; however, this patient achieved complete remission and remains without signs of disease 30 months after the last treatment. Because most HIV-negative and HHV-8- negative PEL cases show pan-B-cell markers, there is considerable usage of rituximab, though its optimal usage for PEL is unclear. To the best of our knowledge, there have been five reported cases where rituximab treatment has been used against HIV-negative and HHV-8-negative PEL. The clinical courses of these cases were relatively good without specific adverse effects. HIV-negative and HHV-8-negative PEL appears to be a reasonably new clinicopathological entity. While further investigation will of course be needed, the use of rituximab is worth considering for treatment of such patients.

[Multiple myeloma accompanying splenic amyloidosis and overwhelming pneumococcemia].

We present the case of an 84-year-old woman with multiple myeloma who developed overwhelming pneumococcemia. Significant pathologic findings of amyloidosis were confirmed in the spleen, adrenal glands, kidneys, liver and bone marrow on autopsy. In particular, the spleen was almost replaced by diffuse linear deposition of amyloid, and residual lymphoid tissue was scant. There is a well-established association between asplenia and a predisposition to fulmination, frequently with fatal bacterial infection. In this case, functional hyposplenism as a result of amyloid replacement of the spleen led to overwhelming pneumococcemia. Functional hyposplenism due to amyloidosis predisposes patients to septicemia. As bacterial infections are a common complication in patients with multiple myeloma, it is important to know whether they have accompanying splenic amyloidosis. If there are findings of hyposplenism, it may be necessary to establish strategies to prevent fatal infection. Thought needs to be given to providing detailed education, and prophylactic or stand-by antibiotics for such patients.

Diffuse Large B-cell Lymphoma during Corticosteroid Therapy for TAFRO Syndrome.

Thrombocytopenia, anasarca, myelofibrosis, renal dysfunction and organomegaly (TAFRO) syndrome is a variant of Castleman's disease recently identified in Japan. A 73-year-old man was diagnosed with TAFRO syndrome according to clinical findings, and his symptoms improved after corticosteroid therapy. Ten months later, lymphadenopathy worsened during tapering of corticosteroids. Histological findings of abdominal lymph nodes showed diffuse large B-cell lymphoma. After 6 cycles of R-CHOP therapy, he has remained in sustained complete remission. This is a rare case of the development of malignant lymphoma during the treatment of TAFRO syndrome, which suggests an association between diffuse large B-cell lymphoma and TAFRO syndrome.

A Case of Burkitt's Lymphoma Involving Both Breasts.

Primary malignant lymphoma of the breast is rare, and Burkitt's lymphoma is especially rare. We report the case of a 44-year-old woman in whom Burkitt's lymphoma involving both breasts was diagnosed. The patient was referred to our hospital because of a diffuse, firm swelling, like a bulky ball, in both breasts. Fine-needle aspiration cytology (FNAC) of both breast masses revealed malignant lymphoma(ML), and diffuse large B-cell lymphoma was diagnosed based on the results of immunohistochemical studies of a core needle biopsy specimen. The gallium scan revealed very hot lesions in both breasts, but there was no evidence of disseminated disease. We instituted initial therapy, with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus intrathecal chemotherapy without performing a chromosome analysis, because the clinical course was very aggressive. A CR was achieved, but after eight cycles of CHOP therapy, the ML relapsed. We then resected the mass in the left breast, and when examination of the surgical specimen revealed relapse of ML and t (8;11) (q24;q32) translocation, Burkitt's lymphoma was diagnosed. High-dose chemotherapy followed by peripheral-blood stem cell transplantation was performed, but the patient died 10 months after her initial presentation at our hospital.