Takatomo Yoshida

Ataxia telangiectasia with vascular abnormalities in the brain parenchyma: report of an autopsy case and literature review.

A 25‐year‐old man was admitted to the Department of Neurology, Gunma University Hospital, in June 1997. He had an intellectual disability and had suffered from repeated infection since childhood. Cerebellar ataxia had developed at 19 years of age and he had been clinically diagnosed with ataxia telangiectasia (AT) comprising cerebellar ataxia and oculocutaneous telangiectasia at 24 years of age. He died from pneumonia and renal failure at 26 years of age. Neuropathological examination revealed Purkinje cell loss and atrophy of the dentate nuclei in the cerebellum, anterior horn‐cell atrophy and demyelination of the gracile fasciculi in the spinal cord, and the existence of nucleocytomegalic cells in the anterior pituitary gland. These neuropathological findings correlated with previously reported cases of AT. In addition, spongy degeneration was found, predominantly around the blood vessels in the cerebral cortex. Diffuse spongy degeneration and multiple foci of coagulative necrosis with calcification were noted in the white matter. Abnormal vasculature was noted in both degenerative and necrotic areas in the cerebral cortex and in the white matter. The vessels at the center of the areas of spongy degeneration in the cerebral cortex had irregularly arranged and enlarged smooth‐muscle‐cell nuclei and a distorted, narrow lumen. The vessels present in the white matter were hyalinized. To our knowledge, these vascular abnormalities in the brain parenchyma have not been reported previously.

Pigmented squamous cell carcinoma with dendritic melanocyte colonization in the external auditory canal

A case of pigmented squamous cell carcinoma (SCC) with dendritic melanocyte colonization in the external auditory canal is reported and the previous cases are reviewed. A 65‐year‐old Japanese female was referred with a 7‐year history of otitis. The patient also had a darkly pigmented 9 × 8 mm nodule in the external auditory canal. Microscopically, the tumor was SCC, but in some areas melanin pigments were found in the cytoplasm of the tumor cells. The tumor was thus diagnosed as pigmented SCC. As well as the tumor cells, dendritic‐shaped cells colonized the tumor parenchyma and were immunohistochemically defined as melanocytes. The authors believe this is the first case of pigmented SCC with dendritic melanocyte colonization in the external auditory canal.

Characterization of refractile eosinophilic granular cells in oligodendroglial tumors

Abstract. Refractile eosinophilic granular cells (rEGCs), which are distinct from the previously reported eosinophilic granular cells in oligodendroglial tumors, were characterized. The granules of rEGCs showed intense eosinophilia and prominent refractility, and were arranged in clusters or piled up in the perikaryon. The rEGCs tended to distribute in the vicinity of fibrovascular stroma and collagenous areas. They appeared in oligodendroglial tumors with numerous minigemistocytes and gliofibrillary oligodendrocytes. More rEGCs were present in WHO grade III oligodendroglial tumors. Histochemically, the granules stained blue with Klüver-Barrera and vividly red with Massons trichrome stain, but negative with periodic acid-Schiff reagent. Almost all of the rEGCs were immunopositive for glial fibrillary acidic protein (GFAP) and heat shock protein 27 (HSP27), and some of them showed immunopositivity with αB-crystallin. No MIB-1 immunopositivity of rEGCs was found. Ultrastructurally, the rEGCs had many ellipsoidal structures associated with bundles of glial fibers in the cytoplasm. The morphological features of granules of rEGCs were similar to those of Rosenthal fibers except for the size and shape of the structure. We considered that the rEGCs originated from overexpression and accumulation of αB-crystallin and HSP27 in GFAP-positive oligodendroglial cells due to various pathological conditions. The presence of the rEGCs in the oligodendrogliomas may suggest more aggressive clinical behavior of tumors.

Histological variety of floral variant of follicular lymphoma.

To further clarify the histopathological findings of the floral variant of follicular lymphoma (FVFL), we studied 13 Japanese cases. Two histological subtypes of neoplastic follicles of FVFL have been described: (i) A macrogerminal center pattern where the mantle zone lymphocytes were invaginated into the neoplastic germinal center, often reminiscent of a floral design. (ii) A microgerminal center pattern where the massive invasion of mantle zone lymphocytes resulted in almost complete breakage of the neoplastic follicles. In the former pattern, the neoplastic germinal center usually contained large clusters of tumor cells, whereas in the latter, small clusters of up to 20 tumor cells or isolated tumor cells were observed in the neoplastic germinal centers. Moreover, occasional tumor cells showed a lymphocytic and/or histiocytic Reed‐Sternberg cell (L&H cells)‐like morphology. Both types of neoplastic follicles were observed to a varying degree in most cases. The macrogerminal center pattern was predominant in nine cases (70%), whilst the microgerminal center pattern was predominant in only four cases (30%). Three lesions (23%) had a marginal zone component. Immunohistochemistry showed that atypical follicular center cells, including L&H cells, were CD3−, CD5−, CD10+, CD20+, CD43−, bcl‐2+, cyclinD1−. The overall histological findings of the macrogerminal center are similar to those of florid progressive transformation of germinal center (PTGC), whilst the microgerminal center pattern is similar to that of nodular lymphocyte‐predominant Hodgkin lymphoma. Initially, the differential diagnosis between FVFL and florid PTGC was emphasized. However, the present study indicates that nodal marginal zone B‐cell lymphoma possessing floral follicles and nodular lymphocyte‐predominant Hodgkin lymphoma should be added to the differential diagnosis of FVFL. The germinal center B‐cell nature of FVFL is most clearly recognizable by immunohistochemistry, though histological appearance alone may cause some diagnostic problems.

Intranuclear inclusions of meningioma associated with abnormal cytoskeletal protein expression.

We describe a case of meningothelial meningioma with a large number of intranuclear inclusions. Morphologically, these are divided into cytoplasmic inclusions and nuclear vacuoles. The cytoplasmic inclusion has a limiting membrane with cell organelles and filaments. Inclusions of this type are generally eosinophilic, like the cytoplasm. However, there are many inclusions that are more eosinophilic than the cytoplasm or that have a ground-glass appearance. Some of them may contain fine or coarse granules. On the other hand, the nuclear vacuole lacks a limiting membrane and appears empty. In most of the inclusions of this type, there is a faintly basophilic substance in the margin. Generally, the cytoplasmic inclusions are as immunopositive as cytoplasm with vimentin, but some of these cytoplasmic inclusions are more reactive. Under the electron microscope, abnormal aggregation of intermediate filaments is recognized in the cytoplasmic inclusions. It is considered that a strong reaction of cytoplasmic inclusions with vimentin immunostaining is due to abnormal aggregation of intermediate filaments. The present study distinctly demonstrates abnormal localization of intermediate filaments in the cytoplasmic inclusions, and it is suggested that the cytoskeleton participates in the evolution of the cytoplasmic inclusions.

Rosai-Dorfman disease of the colon presented as small solitary polypoid lesion

Rosai-Dorfman disease (RDD) was formerly known as “sinus histiocytosis with massive lymphadenopathy”, and cases involving the gastrointestinal tract are rare. We present a case of pure extranodal RDD, resected as a polypoid lesion in colonoscopic study. The patient was a 62-year old woman with a history of sigmoidectomy for unexplained peritonitis. Microscopic study of the polypoid lesion showed the submucosal mass with histological and immunological features of RDD. The whole body computed tomography revealed neither lymphadenopathy nor tumor-like mass.

Peripheral T-cell lymphoma resembling Kimura's disease.

We here report a case of peripheral T-cell lymphoma (PTCL) in which the initial lymph node biopsy specimen demonstrated histological and immunohistochemical findings similar to Kimura’s disease (KD). A 52-year-old Japanese man presented with a 2-month history of bilateral cervical and leftsided inguinal lymphadenopathy and left-sided tonsillar swelling. Abnormal laboratory findings included a white blood cell count of 9.5¿109/L (eosinophilsΩ24%) and a serum interleukin-2 receptor (S-IL2R) level of 624 U/ml (normal range 530 U/ml). Serum IgE level was elevated to more than 16000 IU/ml (normal range 173 IU/ml). Left-sided inguinal lymph node biopsy was performed and, under a diagnosis of KD, the patient did not receive any medication. 2 years later, the lymph node enlarged further and was associated with fever. Abnormal laboratory findings included a white blood cell count of 19.955¿109/L (eosinophilsΩ 3.8%), serum lactate dehydrogenese (LDH) level of 247 IU/L (normal 229) and S-IL2R level of 10400 U/ml. Serum IgE was elevated to more than 16 000 IU/ml. Left-sided inguinal lymph node biopsy was performed and diagnosed as PTCL. After six cycles of CHOP (cyclophosphamide, doxorubicin, oncovin, prednisone) the patient underwent autologous peripheral blood stem cell transplantation. He is currently alive without disease 36 months after onset of disease. Histologically, the initial lymph node biopsy specimen demonstrated marked reactive hyperplasia of the germinal centers and interfollicular vascular proliferation (Fig. 1A). Moreover, some of the germinal centers contained small vessels (Fig. 1A). There was diffuse eosinophilia in the interfollicular area (Fig. 1A), and infil-

Ten-Year Survival of a Patient Treated with Stereotactic Gamma Knife Radiosurgery for Brain Metastases from Colon Cancer with Ovarian and Lymph Node Metastases: A Case Report.

Brain metastasis from colorectal cancer is infrequent and carries a poor prognosis. Herein, we present a patient alive 10 years after the identification of a first brain metastasis from sigmoid colon cancer. A 39-year-old woman underwent sigmoidectomy for sigmoid colon cancer during an emergency operation for pelvic peritonitis. The pathological finding was moderately differentiated adenocarcinoma. Eleven months after the sigmoidectomy, a metastatic lesion was identified in the left ovary. Despite local radiotherapy followed by chemotherapy, the left ovarian lesion grew, so resection of the uterus and bilateral ovaries was performed. Adjuvant chemotherapy with tegafur-uracil (UFT)/calcium folinate (leucovorin, LV) was initiated. Seven months after resection of the ovarian lesion, brain metastases appeared in the bilateral frontal lobes and were treated with stereotactic Gamma Knife radiosurgery. Cervical and mediastinal lymph node metastases were also diagnosed, and irradiation of these lesions was performed. After radiotherapy, 10 courses of oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX) were administered. During FOLFOX administration, recurrent left frontal lobe brain metastasis was diagnosed and treated with stereotactic Gamma Knife radiosurgery. In this case, the brain metastases were well treated with stereotactic Gamma Knife radiosurgery, and the systemic disease arising from sigmoid colon cancer has been kept under control with chemotherapies, surgical resection, and radiotherapy.

Mature natural killer cell lymphoma with an unusual immunophenotype: CD16‐, CD56‐, and CD57 negative

To the Editor: Natural killer (NK) cells of the lymphoid lineage are large granular lymphocytes that mediate major histocompatibility complex-unrestricted cytotoxicity targeting tumor and virally infected cells (1). CD16, CD56, and CD57 are considered to be NK cell-associated antigens; of these, CD56 (neural cell adhesion molecule) is expressed most consistently (2). NK cell neoplasms are very rare, accounting for between 2% and 8% of non-Hodgkin’s lymphoma (3), and its diagnosis usually requires expression of NK cell-associated antigens, lack of expression of sCD3 and other lineage markers, and ⁄or presence of TCR genes in germline configuration (4). Here, we describe a patient with mature NK cell lymphoma expressing an aberrant immunophenotype – CD16-, CD56-, and CD57-negative. A 51-year-old man presented with a 1-month history of testicular enlargement and cervical lymphadenopathy and complaining of drenching night sweats and abnormal weight loss of 5 kg during the past 2 months. On physical examination, he was found to be afebrile. Cervical and axillary lymph nodes were palpable, but hepatosplenomegaly was not detected. Laboratory studies revealed severe pancytopenia and markedly elevated lactate dehydrogenase (LDH). Large tumor cells had abundant cytoplasm in pale blue, which contained azurophilic granular, and one or two conspicuous nucleoli in nucleus with moderately dense chromatin. These tumor cells constituted 3.0% of peripheral white blood cells. The bone marrow aspiration was a dry tap; bone marrow biopsy revealed fibrosis. Systemic lymphadenopathy and splenomegaly were noted on chest and abdominal CT scans. Medium-sized cells with irregular folded nuclei and clear nuclear bodies were seen on axillary lymph node biopsy; mitoses were frequent. Immunophenotypical analysis established that tumor cells were positive for CD2, cyCD3, and HLA-DR, but negative for CD1, sCD3, CD4, CD5, CD7, CD8, CD10, CD13, CD16, CD19, CD20, CD30, CD33, CD34, CD56, CD57, CD117, TCR, cyCD22, cyIgM, cyCD79a, TdT, and MPO. Tumor cells were also positive for T cellrestricted intracellular antigen-1 (TIA-1) and granzyme B, but negative for EBV-encoded RNA (EBER). Subsequently, Southern blot analysis demonstrated germline configuration of TCR Cb1 and Jc genes, and flow cytometry analysis revealed expression of CD94, CD122, NKG2D, and NKp30, which are highly specific to mature NK cells (Fig. 1) (5). These results confirmed a diagnosis of mature NK cell lymphoma. The patient was treated with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) alternating with high-dose methotrexate–cytarabine (6), followed by the treatment protocol consisted of cyclophosphamide, vincristine, daunorubicin, prednisolone, and L-asparaginase. However, the disease was progressive and refractory, and death occurred 3 months after diagnosis. Lymphoma cell infiltration into brain, heart, lung, liver, spleen, pancreas, testis, and bone marrow was found on autopsy. Because NK and T cells originate from common progenitor cells, they have similar immunophenotypes (4). Distinguishing between lymphomas of NK and T cell lineage is, therefore, often difficult. To the best of our knowledge, only three cases of CD56-negative NK cell lymphoma have been reported (7). In these, diagnosis was based on expression of cytotoxic molecules and germline configuration of a TCR c gene. However, three cases of peripheral T cell lymphoma were reported in which the TCR d, but not c, gene was rearranged (8) and, therefore, germline configuration of a TCR c gene alone is not sufficient to rule out T cell lineage. In the present case, we did not check TCR d rearrangement. However, expression of CD94, CD122, NKG2D, and NKp30 in our case strongly suggests that the tumor cells were committed to the NK cell lineage. Recently, Freud et al. (5) proposed a classification system for the NK cell development pathway, in which five stages are defined according to immunophenotypic and functional characteristics. According to this system, whereas expression of CD56 begins to be observed from stage 3 immature NK cells, progression to stage 4 is characterized by acquisition of cellular cytotoxicity and surface receptors such as CD94, CD122, and NKG2D. Because of the expression of CD94, CD122, NKG2D, and cytotoxic proteins in our case, we considered the malignancy to be a stage 4 or 5 mature NK cell neoplasm, and the absence of CD56 expression was regarded as an aberrant feature. Although EBER was negative in our case, most patients with NK cell neoplasms are positive for EBV, and clonal growth of these viruses has been identified (9). All three previously reported cases of CD56-negative NK cell neoplasm were also positive for EBV. So, in this regard, too, our case is uncommon. In conclusion, clinicians should keep in mind that a lack of expression of the usual NK cell-associated antigens, including CD56, does not necessarily exclude a doi:10.1111/j.1600-0609.2011.01713.x European Journal of Haematology 88 (181–182)

A case report of intracholecystic papillary neoplasm of the gallbladder resembling a submucosal tumor

BackgroundIntracholecystic papillary neoplasm (ICPN) is defined as papillary tumors detected macroscopically in the gallbladder. We report a case of ICPN which exhibited the atypical form like a submucosal tumor.Case presentationA 70-year-old man was admitted to our hospital because of hepatic disorder. Computed tomography and magnetic resonance imaging showed irregular thickening of the wall within the gallbladder fundus. Because the lesion might have been malignant, we performed laparoscopic cholecystectomy and liver bed resection. Macroscopic findings showed the mucosal surface of the tumor was smooth, and its form was similar to that of a submucosal tumor. Histopathological examination revealed papillary tumors within the mass with low-grade dysplasia; therefore, we diagnosed ICPN.ConclusionIn the present case, ICPN was resembling a submucosal tumor macroscopically because the tumors arose into the Rokitansky-Aschoff sinus and the adenomyomatous hyperplasia was merged with the ICPN. It is necessary to consider the possibility of tumor lesions within adenomyomatous hyperplasia.