Yasuaki Nakashima

Extranodal non-Hodgkin's lymphoma of the head and neck. A clinicopathologic study in the kyoto-nara area of japan

The clinicopathologic features of 114 Japanese patients with extranodal non‐Hodgkins lymphoma of the head and neck region were analyzed. The median age was 60.5 years and the male:female ratio was 1.5:1. The most common site of involvement was Waldeyers ring, followed by the oral cavity, thyroid gland, paranasal sinuses, nasal cavity, and larynx. Seventy‐five percent of the patients were in Stage I or Stage II at admission. Histologically, diffuse lymphoma accounted for 94% and follicular lymphoma for 6% of cases. The histologic grade according to the Working Formulation System of the National Cancer Institute was low in 11%, intermediate in 75%, and high in 14% of cases. Immunohistochemical study showed that the majority of the cases were of B‐cell type and only 13 cases (11%) were of the T‐cell type. Peripheral T‐cell lymphomas (eight cases) mainly occurred in the nasopharynx and nasal cavity, whereas four of five thymic T‐cell lymphomas were found in the palatine tonsil. The over‐all 5‐year survival rate was 54%, and the factors affecting survival were sex, histologic grade, T/B phenotype, clinical stage, and the site of initial presentation. Five‐year survival with nasal cavity and Waldeyers ring lymphoma was 24% and 46%, respectively. The poor prognosis of lymphomas at these sites might result from the predominance of T‐cell lymphoma, the paucity of low grade lymphoma, and the relatively high incidence of cases that were in an advanced stage at presentation. In Stage II, patients treated with combined therapy tended to have a better 5year survival rate than those treated with radiotherapy alone.

Evaluation of primary brain tumors with FLT-PET: usefulness and limitations.

Purpose of the Report: The purpose of this report was to investigate the potential of positron emission tomography using F-18 fluorodeoxythymidine (FLT-PET) in evaluating primary brain tumors. Materials and Methods: FLT-PET was performed in 25 patients with primary brain tumors. FLT uptake in the lesion was semiquantitatively evaluated by measuring the maximal standardized uptake value (SUVmax) and the tumor-to-normal tissue ratio (TNR). SUVmax and TNR were compared with the histologic grade and the expression of the proliferation marker (Ki-67). Results: FLT uptake in normal brain parenchyma was very low, resulting in the visualization of brain tumors with high contrast. Both SUVmax and TNR significantly correlated with the malignant grade of brain gliomas, in which high SUVmax/TNR was obtained for high-grade gliomas. Patients with primary lymphoma also showed SUVmax/TNR equivalent to glioblastoma. There was a positive correlation between SUVmax/TNR and the Ki-67 index. In contrast, spuriously high SUVmax and TNR were obtained in 3 of 6 patients with suspected recurrent tumors (2 patients with recurrent grade 2 glioma and one patient with postoperative granuloma), all of which showed lesion enhancement on MRI after Gd administration. Conclusions: FLT-PET can be used to evaluate the malignant grade and proliferation activity of primary brain tumors, especially malignant brain tumors. However, the presence of benign lesions showing blood–brain barrier disruption cannot be distinguished from malignant tumors and needs to be carefully evaluated.

Characteristics of genomic breakpoints in TLS-CHOP translocations in liposarcomas suggest the involvement of Translin and topoisomerase II in the process of translocation

Fusion of TLS/FUS and CHOP gene by reciprocal translocation t(12;16)(q32;q16) is a common genetic event found in myxoid and round-cell liposarcomas. Characterization of this genetic event was performed by three methods, Southern blot, RT – PCR, and genomic long-distance PCR in nine myxoid and three round-cell liposarcomas. All but one tumors showed genetic alternations indicating the fusion of TLS/FUS and CHOP gene. Two novel types of fusion transcripts were found, of which one lacked exon 2 sequence of CHOP gene, and the other lacked 3′ half of exon 5 of TLS gene. The latter case was caused by a cryptic splicing site which was created by the genomic fusion. Detailed analyses genomic fusion points revealed several sequence characteristics surrounding the fusion points. Homology analyses of breakpoint sequences with known sequence motifs possibly involve in the process of translocation uncovered Translin binding sequences at both of TLS/FUS and CHOP breakpoints in two cases. Translocations were always associated with other genetic alterations, such as deletions, duplications, or insertions. Short direct repeats were almost always found at both ends of deleted or duplicated fragments some of which had apparently been created by joining of sequences that flank the rearrangement. Finally, consensus topoisomerase II cleavage sites were found at breakpoints in all cases analysed, suggesting a role of this enzyme in creating staggered ends at the breakpoint. These data suggested that sequence characteristics may play an important role to recruit several factors such as Translin and topoisomerase II in the process of chromosomal translation in liposarcomas.

A Case of Autoimmune Pancreatitis Associated with Sclerosing Cholangitis, Retroperitoneal Fibrosis and Sjögren’s Syndrome

We report a very rare case of autoimmune pancreatitis (AIP) associated with sclerosing cholangitis, retroperitoneal fibrosis and Sjögren’s syndrome. The patient had an enlarged pancreas, and autoantibodies were detected in the serum. Serum IgG and IgG4 concentrations were also elevated. Endoscopic retrograde cholangiopancreatography revealed an irregular narrowing of the main pancreatic duct from the head to the body and sclerotic change in the intrapancreatic common bile duct, which later extended to the intrahepatic bile ducts. In addition, histological examination of the liver revealed lymphocytic sclerosis around the bile ducts, similar to the histology in the pancreas of AIP. Retroperitoneal tumors were diagnosed as retroperitoneal fibrosis by histological examination. Serological and functional abnormalities suggestive of Sjögren’s syndrome were detected, and histological findings of the lip were compatible with Sjögren’s syndrome. Immunohistochemistry of each lesion disclosed that most of the infiltrating lymphocytes were T cells with similar levels of both CD4+ and CD8+ cells. Moreover, some of the infiltrating plasma cells were positive for anti-IgG4 monoclonal antibody. These diseases were dramatically improved by steroid therapy. Although the pathophysiology of AIP is still unclear, the present case suggests a common pathophysiological mechanism for AIP, sclerosing cholangitis, retroperitoneal fibrosis and Sjögren’s syndrome.

Apocrine adenocarcinoma of the eyelid with aggressive biological behavior: report of a case.

A case of apocrine adenocarcinoma of the eyelid that showed unusually aggressive biological behavior is reported. The patient was a 57‐year‐old man who complained of discomfort and excessive lacrimation of the left eye. A subcutaneous tumor measuring 2.5 cm was found at the medial canthus of the upper eyelid, and a plica‐like subconjunctival spread was noted in the lacrimal caruncle. Invasion into the extraocular muscles and metastasis to the cervical lymph nodes and bone were already present at the time of initial presentation. Histopathologically, the tumor showed features of poorly differentiated adenocarcinoma, and polygonal tumor cells had large, hyperchromatic nuclei with prominent nucleoli and abundant eosinophilic cytoplasm. The formation of ductal structures was found occasionally. The differentiation of the tumor cells towards the apocrine gland was corroborated by immunohistochemistry using monoclonal antibodies GCDFP‐15 and B72.3. The histogenesis and pathological differential diagnosis are discussed briefly, and the tumor was considered to have originated in the Moll’s gland in the eyelid. This case emphasizes that apocrine adenocarcinomas of the ocular region have the potential for aggressive biological behavior, including distant metastasis.

High ratio of IgG4-positive plasma cell infiltration in cutaneous plasmacytosis—is this a cutaneous manifestation of IgG4-related disease?

Cutaneous plasmacytosis is a rare condition affecting middle-aged individuals, characterized by multiple red-brown papules and plaques over the trunk. It has been reported mainly in Japan. The condition is accompanied by polyclonal hypergammaglobulinemia and superficial lymphadenopathy. Lung or retroperitoneal involvement occurs rarely. In the present study, 3 consecutive cases of cutaneous plasmacytosis were observed histologically to have abundant infiltration of IgG4-bearing plasma cells. All 3 were associated with superficial lymphadenopathy, one with interstitial lung involvement showing ground-glass opacity on computed tomography and the others with bone marrow plasmacytosis, showing histologic evidence of more IgG4-positive plasma cells. All 3 had polyclonal hypergammaglobulinemia, one had high serum concentration of IgG4, and all had elevated serum IL-6. The ratios of IgG4+ to IgG+ plasma cells were assessed using skin biopsy specimens with pemphigus (n = 7), discoid lupus erythematosus (n = 5), and morphea (n = 2) (mean ratios, 19%, 0%, and 0%, respectively); we noted the proportion of IgG4-positive plasma cells in cutaneous plasmacytosis (mean, 48%). IgG4-related sclerosing disease is a newly recognized systemic disorder characterized by lymphoplasmacytic infiltration and fibrosis and by a high serum IgG4 level and increased IgG4-positive plasma cells in the tissues. Skin manifestations of this disorder have not been described. Although cutaneous plasmacytosis could be a chronic allergic hypersensitivity reaction, our findings raise the possibility of a relationship in pathogenesis between cutaneous plasmacytosis and IgG4-related sclerosing disease.

The combination of mitotic and Ki-67 indices as a useful method for predicting short-term recurrence of meningiomas

BACKGROUND The most relevant factor in the progression-free survival (PFS) of patients with meningiomas is the malignant grade. However, using only the current World Health Organization (WHO) definition that does not consider precise quantitative indicators, an unequivocal diagnosis of the malignant grade is difficult. In our retrospective study of the PFS of meningioma patients, we focused on mitoses and the Ki-67 staining index of tumor specimens obtained at the initial surgery. METHODS AND RESULTS A total of 349 patients with intracranial meningioma, operated between 1978 and 2000, were followed for a mean of 7 years. According to the mitotic index (MI), we classified them into 3 groups. In Group A (n = 326), slide-mounted tumor samples exhibited no mitoses; in Group B (n = 15) there were fewer than 4 mitoses, and in Group C (n = 8) 4 or more mitoses were seen per 10 high-power fields (HPF). The estimated 5-year PFS rates in Groups A, B, and C were 93%, 10%, and 13% respectively. The mean PFS for Group A was 148 months; in Groups B and C the median PFS was 43 and 16 months, respectively. A Ki-67 staining index (SI) of less than 1% corresponded with no mitosis, while an SI exceeding 5% was indicative of the presence of mitoses. CONCLUSION In meningioma patients, no mitoses and/or a Ki-67 SI <1% signals a favorable outcome. An SI >5% or the presence of mitoses, even fewer than 4 in 10 HPF, is suggestive of a short PFS irrespective of other pathologic features. We suggest that in combination, assay of the Ki-67 SI and the MI represents a reliable, quantitative tool for predicting PFS in meningioma patients.

Distribution of collagen type IV in soft tissue tumors: An immunohistochemical study

The distribution of collagen type IV, one of the major constituents of basement membrane, was studied immunohistologically in a series of 103 soft tissue tumors including those of peripheral nerve origin, smooth muscle origin, striated muscle origin, fibrous tissue origin, fibrohistiocytic origin, adipose tissue origin, synovial tissue origin, and blood vessel origin, paragangliomas, alveolar soft part sarcomas, granular cell tumors, and epithelioid sarcomas. Intensely positive staining for collagen type IV was observed in neurilemomas, neurofibromas, malignant schwannomas, and blood vessel tumors. Weakly to moderately positive staining was seen in leiomyomas, angiomyomas, and leiomyosarcomas. In contrast, synovial, fibroblastic and fibrohistiocytic tumors, benign or malignant, were negative. In paragangliomas, granular cell tumors, and alveolar soft part sarcomas, positive staining was evident surrounding nests or clusters of tumor cells. In all tumors, staining for collagen type IV clearly illustrated the vascular pattern. Cancer 58:269–277, 1986.

A Novel Type of EWS-CHOP Fusion Gene in Two Cases of Myxoid Liposarcoma

Fusion genes consisting of TLS/FUS and CHOP or EWS and CHOP are characteristic markers for myxoid/round cell liposarcomas (MLS/RCLS). Several different structures of the fusion genes were reported in the case of the TLS/FUS-CHOP form, whereas only one type of structure has so far been found for the EWS-CHOP form, which consisted of exons 1 to 7 of the EWS and exons 2 to 4 of the CHOP gene. Here we describe a novel type of EWS-CHOP fusion gene in two cases of MLS/RCLS, which were found in a consecutive analysis of 21 cases. This fusion gene consisted of exons 1 to 10 of the EWS and exons 2 to 4 of the CHOP gene. The two cases with this fusion gene shared several clinical features, such as a large tumor mass, rapid and invasive growth, and local recurrence within 12 months after surgical resection. Histopathological findings also showed common features characterized by the diffuse proliferation of small spindle cells with a primitive mesenchymal appearance. The association of these clinical and histopathological features suggests a distinct biological property for this rare type of fusion product.

Degree of IgG4+ plasma cell infiltration in retroperitoneal fibrosis with or without multifocal fibrosclerosis

epithelial markers highlighted small clusters of chief cells trapped within the ASCLs. Transitional-type cells in the ASCL in the upper right gland showed some positivity for AE1 ⁄ AE3 (Figure 2E) and CAM5.2. Cyclin D1 immunohistochemistry showed nuclear staining of 30–40% of the cells in both the ASCLs and that of 20% of the cells in several chief cell nodules other than those with ASCLs. The MIB-1 labelling index was 10% in the ASCL of the lower right gland and 7% in that of the upper right gland, whereas MIB-1 staining was rarely found in the surrounding area. Several features associated with malignancy of the parathyroid gland were identified in the present case, including readily identifiable mitotic figures, coagulative tumour necrosis and macronucleoli present in many tumour cells. MIB-1 expression is higher in carcinoma than in adenoma or hyperplasia. MIB-1 indices in the ASCLs in the present case were similar to those in carcinoma. Although overexpression of cyclin D1 has been identified in parathyroid adenoma and carcinoma and is thought to be involved in the pathogenesis of some types of parathyroid neoplasia, it has also been detected in secondary hyperplasia. In the present case, overexpression of cyclin D1 was detected in the ASCLs as well as in other hyperplastic nodules. Vimentin has been shown to be positive only in stromal cells of normal, hyperplastic and adenomatous parathyroid glands. However, we identified glandular cells positive for vimentin in hyperplastic nodular lesions other than the ASCLs in the present case. Our preliminary immunohistochemistry of nine cases of secondary hyperparathyroidism with no ASCLs showed positive glandular cells in all cases. Since the introduction of antigen retrieval methods, more cell types, even cells of epithelial origin, have been reported to be positive for vimentin. The vimentin positivity of ASCLs may be compatible with a glandular cell origin of the lesions. The positivity of some transitional-type cells for epithelial markers in the present case also suggests an epithelial origin of the spindle cells. In the case reported by Alpers and Clark, the presence of similar transitional-type cells in the ASCLs was also described; they stated that the lesions were suggestive of parathyroid carcinoma, but there was insufficient evidence for this diagnosis. Secondary hyperparathyroidism is generally present in patients with uraemia. Neoplasia may emerge from nodular hyperplasia. Clonal analysis has suggested that in renal hyperparathyroidism, parathyroid glands initially grow diffusely and polyclonally, and that the cells within the nodules later become monoclonal and proliferate aggressively. It has been suggested that monoclonal tumours are more common than previously thought in both primary and secondary hyperparathyroidism. Although the cause of the ASCLs in the present case, and their malignant or benign nature, are uncertain at the present time, they may reflect malignant transformation with metaplastic changes.