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Reclassification of endocervical atypical immature metaplasia (AIM) into reactive changes and neoplastic lesion is often challenging. We aimed to accurately reclassify AIM on hematoxylin and eosin (HE)-stained sections without auxiliary immunohistochemistry (IHC). A total of 133 AIM diagnosed by punch biopsy were reclassified by IHC for p16 and Ki-67 into high-grade squamous intraepithelial lesion (HSIL) or negative for intraepithelial lesion or malignancy or low-grade squamous intraepithelial lesion (NILM/LSIL) as a reference. Nuclear features significantly associated with HSIL on HE-stained sections were extracted by multivariate logistic regression analysis. Propensity score (PS) of HSIL was calculated in each case and cut-off was determined by receiver operation characteristic (ROC) curve analysis. As a result, AIM was reclassified into 104 NILM/LSIL and 29 HSIL by IHC. Compared with reference diagnosis, accuracy of pathologists' subjective diagnosis was 54.9% (kappa coefficient, 0.208). Three nuclear features on HE-stained sections, ie, nuclear enlargement with anisokaryosis, nuclear hyperchromasia, and mitosis, were significantly associated with HSIL. The ROC curve analyses revealed that PS and number of nuclear features were significant predictors of HSIL. Diagnostic accuracy of PS-based diagnosis was 76.7% (kappa, 0.447). When AIM with 2 or more of the 3 nuclear features was diagnosed with HSIL, diagnostic accuracy was 77.4% (kappa, 0.448). Nuclear feature-based diagnosis significantly improved diagnostic accuracy on HE-stained sections compared with subjective diagnosis and may be useful when IHC is not available. However, a considerable proportion of AIM would still remain misdiagnosed and IHC for p16 and Ki-67 should be mandatory for accurate reclassification.

Introduction Patients with esophageal cancers including carcinosarcoma sometimes have underlying liver cirrhosis because of a history of heavy drinking. It is definitely required to determine the appropriate surgical strategy and to manage the patients promptly when performing esophagectomy for the esophageal carcinosarcoma coexisting with alcoholic liver cirrhosis. Presentation of case A 56-year-old male patient with a history of chest pain and difficulty swallowing was admitted to our hospital. He had a history of drinking 250 g of alcohol per day. Endoscopy revealed an irregular protruding tumor on the left wall of the lower-third thoracic esophagus. Computed tomography showed a tumor lesion in the lower-third thoracic esophagus; the images also showed irregularities on the surface of the liver, suggestive of coexisting alcoholic liver cirrhosis. The preoperative diagnosis was T3N2M0, Stage III esophageal leiomyosarcoma. In consideration of the underlying alcoholic liver cirrhosis, a staged operation was planned for this patient as a curative treatment. The patient had an uneventful postoperative clinical course and was discharged on the 47th day after the first surgery. Final histopathological diagnosis was T2N0M0, Stage II esophageal carcinosarcoma. The patient is alive without recurrence three years after surgery. Discussion This is the first report of long-term survival case of esophageal carcinosarcoma with alcoholic liver cirrhosis that was treated successfully by staged operation. Conclusions Despite coexisting with alcoholic liver cirrhosis, staged operation could reduce the surgical invasiveness, so that very good short-term outcome and long-term survival was obtained in the patient with esophageal carcinosarcoma., Highlights • Patients with esophageal carcinosarcoma sometimes have underlying liver cirrhosis because of a history of heavy drinking. • Postoperative severe complications often occur after esophagectomy in patients with liver cirrhosis. • Staged operation could reduce the surgical invasiveness and manage these patients.

背景 : 多発性骨髄腫 (骨髄腫) において腫瘍細胞が体腔液中に出現することはまれであるが, 多数の腫瘍細胞を胸水中に認めた骨髄腫の 2 例を経験したので報告する.症例 : 症例 1 : 54 歳, 男性. 両側上顎洞, 背部腫瘤にて発症した IgG 型骨髄腫. 胸水中に好塩基性の細胞質と核周明庭を認める, 類円形の成熟型の骨髄腫細胞が多数出現し, 形質芽球型の骨髄腫細胞が混在していた. 症例 2 : 53 歳, 男性. IgA 型骨髄腫の再発後に左胸水が認められた. 好塩基性の細胞質と核周明庭を認める, 類円形の骨髄腫細胞が多数出現していた. 明瞭な核小体を認め, 核の大小不同, 核型不整を認める細胞や, 2 核を含む多核細胞も混在していた.結論 : 骨髄腫の中で胸水中に腫瘍細胞が出現するのはまれであるが, Papanicolaou 染色標本で核クロマチンの性状や核小体の観察を行い, Giemsa 染色標本で好塩基性の細胞質や核周明庭など骨髄腫細胞としての特徴的な所見を確認することで, 診断精度の向上につながると考えた.

We report here a case of idiopathic CD4(+) T-lymphocytopenia (ICL) associated with Epstein-Barr virus (EBV)(+) lymphoproliferative disorder (LPD) terminating in Burkitt lymphoma (BL). A 33-year-old Japanese male was admitted to the hospital showing severe CD4(+) lymphocytopenia and neutropenia that was diagnosed as ICL in 1993. Twenty months after the onset of disease, right cervical lymphadenopathy was detected. Biopsy of the specimen showed reactive lymph node hyperplasia and interfollicular B-cell hyperplasia. Ninety-one months later, polypoid tumors were resected from the bilateral nasal cavities and were diagnosed as BL. Immunohistological studies suggested the reactive nature of the initial lymph node biopsy specimen. Polymerase chain reaction (PCR) analyses of immunoglobulin heavy-chain gene (IgH) demonstrated a polyclonal pattern in the initial lymph node lesion. However, the subsequent BL demonstrated a clonal band in the PCR assay for the IgH gene. As demonstrated in human immunodeficiency virus (HIV)-patients, clonal expansion of EBV infected B-cells in the initial lymph node lesion may progress to BL in this patient. The present case did not associate with severe opportunistic infections during the course of disease. EBV(+) BL may be the first manifestation of severe immunodeficiency of the ICL in this patient.

Küttner's tumor (KT) is a benign tumor-like lesion of the salivary gland that mimics neoplasm clinically because of presentation as a hard mass. Recently, the histomorphological and immunohistochemical findings of this lesion have been analyzed, and differential diagnostic problems relating to salivary gland lymphoma have been discussed. However, currently there is little information on the cytological findings of those lesions. We present cytological findings from five such cases using fine-needle aspiration cytology (FNAC). FNAC of this lesion may present a diagnostic challenge to the cytologist as lesions share some cytologic features with inflammatory process containing numerous lymphoid cells. Smears obtained from two cases contained moderate to large numbers of lymphoid cells without definite cytological atypia, scattered ductal structures, and acinar cell clusters. The remaining three cases showed low cellularity probably attributable to fibrosis that made it difficult to aspirate the cellular element. FNAC findings of scattered ductal structures surrounded by collagens and infiltrated by a mixed population of lymphoid cells, not specific for KT, are highly suggestive of the diagnosis with the appropriate clinical findings. However, a portion of cytological specimens of KT containing relatively large numbers of lymphoid cells should be differentiated from malignant lymphoma arising from the submandibular gland.

Idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hyperimmunoglobulinemia is considered identical to multicentric Castleman's disease (MCD) reported in western countries. Clinically, both IPL and MCD are characterized by multicentric lymphadenopathy, prominent polyclonal hypergammaglobulinemia, elevated erythrocyte sedimentation rate, elevated serum interleukin-6 concentration, bone marrow plasmacytosis, and various abnormal laboratory data such as anemia and positive autoantibodies. However, IPL has a significantly better 5-year survival rate than that of MCD. Moreover, none of the present 16 cases developed Kaposi's sarcoma or B-cell lymphoma. Histologically, the interfollicular area contains a sheet of polytypic mature plasma cells in both IPL and MCD. In MCD, the majority of lymphoid follicles had hyaline-vascular germinal centers. However, lymphoid follicles of IPL usually exhibit a hyperplastic germinal center. Immunostaining also demonstrated a normal/ reactive follicular dendritic cell network pattern in the germinal center of IPL. Moreover, there were no human herpes virus-8-positive cells detected by immunohistochemistry. The overall clinicopathologic and immunohistochemical findings of our 16 cases suggest that IPL is distinct from MCD reported in Western countries.

We present 3 patients with a sclerosing variant of follicular lymphoma that arose from the submandibular gland and resembled "Kiittner tumor." All 3 patients developed a painless unilateral tumor in the submandibular region. Histologically, all 3 lesions were categorized as follicular lymphoma grade 2. The neoplastic follicles were found to be separated by thick connective tissue, and periductal chronic inflammation with periductal fibrosis and duct ectasia was found in the residual atrophic gland. Immunohistochemistry revealed that all of the lesions contained a monoclonal tumor cell population. The immunophenotyopes of the lymphoma cells were CD 10+, CD 20+, CD 79a+, BCL-6+, CD 3-, CD 5-, CD 21-, CD 23-, CD 43-, CD 45RO-, BCL-2-, and Cyclin DI -. Two of the 3 patients exhibited clonal bands for the IgH gene by polymerase chain reaction assay. "Kiittner tumor," which is a common fibrosing, chronic inflammatory lesion of the submandibular gland, is sometimes diagnosed as a malignant tumor. This study indicates that this sclerosing variant of follicular lymphoma should be added to the list of different diagnoses for “Kuittner tumor.”

Dihydrolipoamide succinyltransferase (DLST) is a subunit enzyme of the α‐ketoglutarate dehydrogenase complex of the Krebs cycle. While studying how the DLST genotype contributes to the pathogenesis of Alzheimer9s disease (AD), we found a novel mRNA that is transcribed starting from intron 7 in the DLST gene. The novel mRNA level in the brain of AD patients was significantly lower than that of controls. The truncated gene product (designated MIRTD) localized to the intermembrane space of mitochondria. To investigate the function of MIRTD, we established human neuroblastoma SH‐SY5Y cells expressing a maxizyme, a kind of ribozyme, that specifically digests the MIRTD mRNA. The expression of the maxizyme specifically eliminated the MIRTD protein and the resultant MIRTD‐deficient cells exhibited a marked decrease in the amounts of subunits of complexes I and IV of the mitochondrial respiratory chain, resulting in a decline of activity. A pulse‐label experiment revealed that the loss of the subunits is a post‐translational event. Thus, the DLST gene is bifunctional and MIRTD transcribed from the gene contributes to the biogenesis of the mitochondrial respiratory complexes.

To clarify the clinicopathological features of progressive transformation of germinal center (PTGC) unrelated to nodular lymphocyte predominant Hodgkin's lymphoma in Japanese patients, we reviewed 42 cases and compared the results with those of the United States and Germany. Our results were similar to theirs, with male predominance (M/F ratio, 3:1) and the presentation of a solitary asymptomatic enlarged lymph node in the head and neck area as the common features. However, in Japan, PTGC occurs more frequently in elderly patients. In this study, 12 (29%) of the patients with PTGC were aged 60 years or more. Thirteen patients (31%) with lymphadenopathy in the neck and head area had developed localized chronic inflammation (chronic sialoadenitis=4, chronic tonsillitis=3, infectious epidermal cyst=2) or an autoimmune disorder (hyperthyroidism=2 and bronchial asthma=2). None of the patients developed a malignant lymphoma during the follow-up period of 5 to 238 months (median 27 months). Histologically, in a single longitudinal section of the lymph node, the PTGC occupied up to 5% of the total follicles in 22 patients, 5-10% in 10, 10-20% in 7, and more than 20% in 3. In 5 (12%) patients, an association with prominent marginal zone hyperplasia was also noted. This study also indicates that nodal involvement by various low-grade B-cell lymphomas exhibiting marginal zone distribution patterns should be considered as a differential diagnosis of PTGC. Moreover, in Japan, PTGC is thought to be involved in the etiology of florid reactive follicular hyperplasia in elderly patients.

Summary We report on a case of Riedel's thyroiditis containing cytologically atypically appearing B-cells. The patient was a 60-year-old Japanese female, who had a well-demarcated tumor that showed extensive growth from the right thyroid lobe into perithyroidal soft tissues. Histologically, the lesion consisted of two components. The central tumor-like portion of the mass showed spindle cells intermixed with abundant collagen fibers. In addition, scattered B-cells with large nuclei and multiple small, but conspicuous nucleoli were also present. At the periphery of the nodule, numerous plasma cells and small lymphocytes, as well as occasional B-immunoblasts and plasmablasts were growing between non-neoplastic thyroid follicles. An infiltration of thyroid follicles by B-cells also resulted in lymphoepithelial-like lesions. The specimen obtained from an enlarged cervical lymph node occurring 14 months later contained numerous mature plasma cells showing a sheet-like arrangement with occasional immature plasma cells and immunoblasts in the interfollicular area and medullary cords. The polyclonal nature of B-cells was demonstrated immunohistochemically and by polymerase chain reaction in both the thyroid gland and the lymph node lesion.

Nodal marginal zone B-cell lymphoma (NMZBL) occasionally represents prominent plasma cell differentiation. Recently, primary lymph node plasmacytoma has been suggested to represent an extremely plasmacytic differentiation of NMZBL. We here report a case of NMZBL showing histological features resembling plasmacytoma arising from a plasma cell variant of localized Castleman's disease (PCLCD). The patient was a 69-year-old Japanese female with a 20-year history of a right inguinal mass. Histologically, a prominent proliferation of plasma cells occupied the interfollicular area of the central portion of the lymph node, whereas centrocyte-like (CCL) cells were the main cellular component in the peripheral portion of the lymph node. Although most of the plasma cells were mature 'Marshalko-type', occasional atypical forms with enlarged nuclei were also present. The majority of the lymphoid follicles had atrophic or regressive germinal centers. A few lymphoid follicles were colonized by CCL cells. Immunohistochemistry study revealed that both plasma cells and some CCL cells had a monotypic intracytoplasmic lambda light chain. When monoclonal plasma cell infiltration is observed in PCLCD, the light chains are mostly restricted to the lambda chain. This case suggests that some plasma cell-containing tumors arising from PCLCD may represent a variant of NMZBL.

An absence of germinal centers is one of the histological characteristics of angioimmunoblastic T-cell lymphoma (AITL). We report here 10 unusual cases of AITL with hyperplastic germinal centers. The clinical presentation of each patient was characterized by generalized lymphadenopathy, constitutional symptoms and polyclonal hypergammaglobulinemia. The initial biopsy findings of each patient were similar and were characterized by hyperplastic germinal centers with ill-defined borders and a proliferation of high endothelial venules (HEV). In the paracortical area there was a mixed infiltrate including irregularly shaped clusters or small nests of clear cells in all cases. Moreover, the clear cells invaded the lymphoid follicles, resulting in expansion of the germinal centers, except for one case. Immunohistochemistry revealed that the tumor cells, including clear cells, were CD4-expressing T cells. Some of the atypical lymphocytes were also Bcl-6-positive. A majority of the follicular dendritic cell networks showed a normal/reactive or an expanded/disrupted pattern in all cases. Moreover, three lesions possessed a few large irregularly shaped proliferations of follicular dendritic cells around the HEV Four cases progressed to AITL within a few years. The present 10 cases probably represent an early stage of AITL preceding follicular dendritic cell hyperplasia. Detection of clear cells, Bcl-6-positive atypical T lymphocytes, and foci of irregularly shaped proliferation of follicular dendritic cells appears to be critical for early diagnosis and treatment of AITL with hyperplastic follicles.

To clarify how Alzheimer disease pathology develops in the brains of nondemented subjects, we examined the interrelations among the amounts and morphology of Abeta deposition, neurofibrillary pathology, and apolipoprotein E (ApoE) genotype in the frontal association cortex of 101 autopsy brains from patients aged between 40 to 83. Senile plaque density correlated well with the logarithmic data of insoluble Abeta measured by enzyme immunoassay (EIA). The amounts of Abeta42-ETA increased dramatically in the late preclinical stage, whereas the AP42+ plaque density increased in the early preclinical stage. Neurofibrillary pathology appeared only in the areas with severe Abeta deposition and in subjects aged over 70. The ApoE epsilon4 allele enhanced the Abeta3 deposition in presenile subjects. Plaque-associated glial Abeta was prominent in subjects with mild to moderate Abeta deposition. The morphology of cerebral Abeta deposition changed from diffuse plaques with small amounts of Abeta in each plaque in the early preclinical stage to primitive/neuritic plaques with larger amounts of Abeta in each plaque in the late preclinical stage. Our findings suggest that the prevention of Abeta deposition in the late preclinical stage can be a rational therapeutic target, especially in elderly people with ApoE epsilon4 allele.

To learn more about the process of amyloid beta-protein (Abeta) deposition in the brain, human prefrontal cortices were fractionated by sucrose density gradient centrifugation, and the Abeta content in each fraction was quantified by a two-site enzyme-linked immunosorbent assay. The fractionation protocol revealed two pools of insoluble Abeta. One corresponded to a low-density membrane domain; the other was primarily composed of extracellular Abeta deposits in those cases in which Abeta accumulated to significant levels. Abeta42 levels in the low-density membrane domain were proportional to the extent of total Abeta42 accumulation, which is known to correlate well with overall amyloid burden. In PDAPP mice that form senile plaques and accumulate Abeta in a similar manner to aging humans, Abeta42 accumulation in the low-density membrane domain also increased as Abeta deposition progressed with aging. These observations indicate that the Abeta42 associated with low-density membrane domains is tightly coupled with the process of extracellular Abeta deposition.

We previously noted that some aged human cortical specimens containing very low or negligible levels of amyloid beta-protein (As) by enzyme immunoassay (EIA) provided prominent signals at 6 approximately 8 kd on the Western blot, probably representing sodium dodecyl sulfate (SDS)-stable Abeta dimer. Re-examination of the specificity of the EIA revealed that BAN50- and BNT77-based EIA, most commonly used for the quantitation of Abeta, capture SDS-dissociable Abeta but not SDS-stable Abeta dimer. Thus, all cortical specimens in which the levels of Abeta were below the detection limits of EIA were subjected to Western blot analysis. A fraction of such specimens contained SDS-stable dimer at 6 approximately 8 kd, but not SDS-dissociable A(beta) monomer at approximately 4 kd, as judged from the blot. This A(beta) dimer is unlikely to be generated after death, because (i) specimens with very short postmortem delay contained the A(beta) dimer, and (ii) until 12 hours postmortem, such SDS-stable A(beta) dimer is detected only faintly in PDAPP transgenic mice. The presence of A(beta) dimer in the cortex may characterize the accumulation of A(beta) in the human brain, which takes much longer than that in PDAPP transgenic mice.

Families bearing mutations in the presenilin 1 (PS1) gene develop Alzheimer’s disease. Previous studies have shown that the Alzheimer-associated mutations in PS1 increase production of amyloid β protein (Aβ 1–42 ). We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3β (GSK-3β). Deletion studies show that both tau and GSK-3β bind to the same region of PS1, residues 250–298, whereas the binding domain on tau is the microtubule-binding repeat region. The ability of PS1 to bring tau and GSK-3β into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3β. Mutations in PS1 that cause Alzheimer’s disease increase the ability of PS1 to bind GSK-3β and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3β with mutant PS1 leads to increased phosphorylation of tau.

We report here a case of mucosa-associated lymphoid tissue (MALT)-type lymphoma arising from the minor salivary gland of the oral cavity exhibiting tumor-forming amyloidosis. The patient was a 64-year-old Japanese woman who presented with 4-year history of a left soft palate mass. Despite multiple and multifocal recurrences including the lip, soft palate, tongue, oral base and vocal code and soft palate, the tumor remained localized in the upper aerodigestive tract, and the patient did not develop multiple myeloma during the course of disease. Histologically, the majority of the lesion was occupied by amyloid deposition. Only the periphery of the lesion contained numerous plasmacytoid cells, along with occasional centrocyte-like cells. In addition, lymphoepithelial lesion and follicular colonization were noted. The present case indicates that primary minor salivary gland MALT-type lymphoma appears to be the cause of tumor-forming amyloidosis of the upper aerodigestive tract including the larynx.

Four autopsied brains from mentally normal patients aged 43–49 who had cerebral β amyloid deposition were examined. Three patients had breast cancer, and in one of these cases it was associated with brain metastasis and brain radiation therapy. One other case had pulmonary small cell carcinoma. In two patients, small β amyloid deposits were only found in the frontal cortex. In another two patients, β amyloid deposits were found in many cortical areas and the density of plaques was higher than in the former two patients. No β amyloid deposition was found in the cerebella, basal ganglia, or brain stem in any of the four patients. When examined with end-specific antisera for the C-terminal of amyloid β protein (Aβ), Aβ42 was predominant in the diffuse plaques and immunoreactions for Aβ40 varied among the patients. The N-terminal of Aβ was truncated in a subset of plaques. Tau- and phosphorylated tau-reactive fine neurites were only found in the entorhinal cortex of Case 3. The apoE genotype of these four patients were 3/4, 3/4, 4/4 and 3/3, and therefore, the e4 allele frequency (50%) was as high as that in AD. Three out of four patients had at least one e4 allele, a risk factor of AD. There is a possibility that these subjects might develop AD when in their seventies. It may take 30 years from the beginning of Aβ deposition to the clinical manifestation of dementia.

We report a 79-year-old male patient with urothelial cancer who underwent total cystectomy with ureterostomy 10 years earlier and right nephroureterectomy 3 years and 9 months earlier. The patient had chest complaint with posterior mediastinal tumor for 7 years and its slow growth rate suggested that the mediastinal tumor was benign but metastatic materials could not be ruled out because cytology of pleural effusion demonstrated atypical cells. He died from the progression of urothelial cancer and autopsy demonstrated that metastatic urothelial cancer was involved in the mediastinal benign neurilemmoma.

We examined immunohistochemically 123 autopsy brains from patients aged between 30 to 59, who died as a result of malignant neoplasms. Using antiserum to amyloid beta protein (A beta), we found that cerebral A beta deposits began in the subjects' fifth decade; its prevalence was 0%, 9.8% and 21.5% in the fourth, fifth and sixth decades, respectively. The major form of A beta deposition was diffuse-type plaques, although one third of the brains with A beta deposition showed amyloid angiopathy. Subpial A beta deposition is frequently associated with amyloid angiopathy. The prevalence of cerebral A beta deposits was about two times higher in the patients who had received brain radiation therapy (27.8%) compared to non-radiated patients (14.8%). Amyloid angiopathy was much more prominent (P0.05) with radiation therapy (22.2%) than without (8.0%). We found that cerebral A beta-deposition is dependent on aging, even in patients with malignant tumors and at beginning in their forties, and that brain radiation therapy is a possible risk factor of A beta deposition, especially in the form of amyloid angiopathy.

We examined by immunohistochemicistry the carboxyl (C)-terminus extent of the amyloid beta protein (Aβ) that constitutes senile plaques and amyloid angiopathy in the brains of non-demented and Alzheimer's disease (AD) subjects. We developed two antisera, which selectively recognized free C-termini of Aβ: BC40 for Aβ40; and BC42 for Aβ42. BC42 labeled various types of senile plaques as well as reference Aβ antiserum, whereas only some parts of the senile plaques were positive with BC40: i.e., all of the plaque cores and some diffuse and primitive plaques. In the brains of non-demented middle-aged subjects, a majority of BC42-positive diffuse plaques were also positive with BC40, but with less intensity than that shown with BC42. The ratio of BC40-negative plaques increased with increasing plaque density. Amyloid in the meningeal vessels showed much greater immnnoreactivity with BC40 than with BC42. Some extracellular neurofibrillary tangles were positive with both BC40 and BC42, although most of them and a...

A 60-year-old man with renal cell carcinoma and metastases to the right 7th rib and L2 vertebra (T2N0M1, OSS) was treated with interferon-alpha and the uracil and tegafur combination following nephrectomy. One and a half years later on bone scintigraphy, the abnormal accumulation had disappeared at the L2 vertebra and weakened in its intensity at the right 7th rib. Plain X-ray revealed that the metastatic lesion at the right 7th rib had decreased in size and had been replaced by calcification. The right 7th rib was removed surgically and step-sectioned pathological specimens revealed necrosis with no viable cancer cells.

An autopsy case of pleural malignant mesothelioma was reported with histopathologically and ultrastructurally. The patient was 51 year-old female. She was admitted to Gunma Cancer Center Hospital because of respiratory disturbance. She died of respiratory failure caused by marked pleural and abdominal effusion and cachechitic change six months after the admission. Autopsy findings showed multiple metastases : lungs, pericardium, mediastinum, diaphragma, abdominal serous menbrane, lymph nodes. Histologically, the tumor was diffuse type malignant mesothelioma of biphagic pattern. Immunohisto-chemistry showed positive reaction for keratin, vimentin, and EMA, but negative for CEA. Ultrastructural findings showed the charcterictics of mesothelial cells. In order to make accurate pathological diagnosis, we should use immunohisto-chimistry and electronmicroscopy.

One autopsy case of a latent paraganglioma of the urinary bladder is reported. The patient, a 46-year-old woman, died as a result of the ventricular septal defect. Paragangliomas consisting of seven tumors were present in the urinary bladder. The largest one in seven tumors was three millimeters in diameter and six similar tumors were noticed in the muscle layer around the tumor. Some multicentric tumors have been reported in cases of multiple endocrine neoplasia (MEN) and often associated with anomalies. Although the present case does not belong to MEN, this is the seventh report of a multicentric paraganglioma of the urinary bladder.

One autopsy case of a neonate with herpes simplex virus type 1 (HSV-1) is reported. In this case, isolation from skin lesions and typing of the causative virus were performed virologically, and HSV-1 was identified as the causative virus. At autopsy coagulative necrosis was seen in the liver and adrenal glands. Numerous intranuclear inclusions were found in the vicinity of the necrotic lesions. Immunohistochemical study showed the same result as the virological study. Electron microscopically viral particles were seen in the necrotic tissue of the liver.

Hepatic angiomyolipoma (AML) may demonstrate a marked histologic diversity and is frequently misdiagnosed. HMB45 is a promising marker for this tumor and is expected to facilitate the recognition of some AMLs with unusual morphology. We report on a case of hepatic AML exhibiting histologic features that were similar to inflammatory pseudotumor (IPT) or to IPT-like follicular dendritic cell (FDC) tumor of the liver. The patient was a 21-year-old Japanese woman with a mass in the left lobe of the liver (70 x 73 mm). There were no clinical features of tuberous sclerosis. Histologically, numerous inflammatory cells, including small lymphocytes, plasma cells, and histiocytes, showed diffuse infiltration throughout the lesion. However, the present case also shared some of the morphologic findings of hepatic AML, including clusters of smooth muscle cells with clear cytoplasm, a few scattered adipose cells, and thick-walled blood vessels. Moreover, the smooth muscle cells consisted of spindle-shaped cells or larger, more rounded cells with either clear cytoplasm or eosinophilic epithelioid cell features positive for vimentin, muscle-specific actin, and smooth muscle actin. HMB45 immunostaining confirmed the diagnosis of AML. The present case indicates that IPT or IPT-like FDC tumor should be added to the list of differential diagnoses for AML of the liver.

To clarify the clinicopathologic and immunohistochemical features of dermatopathic lymphadenopathy not associated with mycosis fungoides among Japanese, 19 patients were studied. Seventy-four percent of the patients were more than 50 years old (median; 63 years, mean 61 years). Systemic symptoms such as fever were recorded in 68% and multicentric lymphadenopathy was noted in 83% of patients. An association of autoimmune disease or positivity of autoantibodies was recorded in 6 patients. Five patients showed cutaneous hypersensitivity reactions to a drug. Histologically, in addition to the dermatopathic lymphadenopathy, numerous immunoblasts were observed in 2 cases and sheet-like proliferation of mature plasma cells in 3 cases. Various atypical or malignant lymphoproliferative disorders exhibiting immunologic abnormalities such as angioimmunoblastic T-cell lymphoma or autoimmune disease-associated lymphadenopathy frequently occur in middle-aged and elderly patients. At least some of the patients with dermatopathic lymphadenopathy should be clinicopathologically differentiated from these lymphoproliferative disorders.

Three cases of Epstein-Barr virus (EBV)-related lymphoproliferative disorders in elderly patients showing autoimmune disease-associated lymphadenopathy-like clinicopathological findings have been reported. Clinically, they were characterized by systemic lymphadenopathy, "B" symptoms, polyclonal hypergammaglobulinemia, elevated serum LDH and transient presence of various autoantibodies, and absence of atypical lymphocytosis in peripheral blood. One case was associated with idiopathic thrombocytopenic purpura. The clinical course was self-limiting. Histologically, they exhibited numerous lymphoid follicles with hyperplastic germinal centers and atypical interfollicular widening with prominent vascular proliferation. In the paracortical area, there was a mixed infiltrate comprising small to medium-sized lymphocytes and plasma cells, and variable numbers of eosinophils and T- and B-immunoblasts. In situ hybridization demonstrated a varying number of EBV-infected lymphocytes in the germinal center as well as in the interfollicular area. Polymerase chain reaction demonstrated that neither clonal rearrangement of T-cell receptor gamma-gene nor immunoglobulin heavy-chain rearrangement was detected in two of the cases examined. Although acute EBV infection rarely occurs in older adults, EBV related to reactive lymphoproliferative disorder should be added to the differential diagnosis of autoimmune disease-associated lymphadenopathy and node-based peripheral T-cell lymphoma in elderly patients.

We present a case of a classical Hodgkin lymphoma occurring in clusters of marginal zone B-lymphocytes (MZBLs). Most lymphoid follicles possessed hyperplastic germinal centers, while a portion of the follicles exhibited a progressive transformation of the germinal center (PTGC). Clusters of MZBLs showed a perifollicular distribution. The classic Reed-Sternberg cells were found in clusters of MZBLs. A portion of the Reed-Sternberg cells were CD15+, CD20+, CD30+, CD79a+, fascin+, vimentin+, EMA-, and bcl-2-. Some Reed-Sternberg cells were surrounded by CD3+ CD45RO+ CD57-rosettes. In situ hybridization studies demonstrated strong expression of EBER in classic Reed-Sternberg cells and their variants. The overall morphological, immunohistological, and EBV findings confirmed that the present case is a classical Hodgkin lymphoma. The MZBLs were CD20+, CD79a+, sIgM+/-, sIgD-, CD5-, CD21-, CD43-, CD45RO-, and Bcl-2-. Some MZBLs had polytypic intracytoplasmic immunoglobulin. Problems arising in the differential diagnosis between lymphocyte-predominant Hodgkin lymphoma and PTGC have been described. An occasional association between MZBLs clusters and PTGC has been reported previously. This case suggests that classical Hodgkin lymphoma should be added to the differential diagnosis of PTGC.

It has been reported that chronic lymphocytic leukemia (CLL) often occurs concomitantly with other malignant neoplasms. However, because CLL is rare in Japan, there are only a limited number of reports of the occurrence of malignant neoplasia in Japanese patients with CLL. We report here the simultaneous occurrence of rectal cancer and CLL in a 57-year-old man. Because the clinical stage of CLL was Rai system I, we decided, in accordance with the National Cancer Institute-Sponsored Working Group guidelines, to monitor him without therapy for CLL until evidence of disease progression, and we performed abdominoperineal resection of the rectum for the cancer. The small rectal tumor was associated with aggressive lymphangiosis carcinomatosa, and multiple nodal metastases were observed in the pool of CLL cells. He died of rectal cancer 7 months after the operation, and autopsy revealed extensive metastases of the cancer. Cellular and humoral immunity is often impaired in patients with CLL, and the defective immunity in this patient may have had an etiological role in the development and rapid progression of the cancer. In the follow-up of CLL patients, we must always be aware of the possible existence of a second malignant disease. Particular attention should be paid to those with defective immunity, and screening should be performed, especially for pulmonary and gastrointestinal malignancies.

Nodal marginal zone B-cell lymphomas (NMZBL) occasionally represent prominent plasma cell differentiation. Recently, we presented a patient with NMZBL who exhibited histological features that resembled plasmacytoma arising from a localized plasma cell variant of Castleman's disease. To further clarify the clinicopathological, immunohistochemical, and genotypical findings, we studied seven such patients. Clinically, these patients were characterized by localized disease and an indolent clinical course with a slowly growing bulky mass in the affected lymph node. Only one patient exhibited paraproteinemia. Histologically, the lesions were characterized by numerous evenly distributed germinal centers in extensive sheets of plasma cells. Various numbers of centrocyte-like (CCL) cells arranged in a marginal zone distribution pattern occupied the peripheral region of the lymph node. The majority of the lymphoid follicles had atrophic or regressive germinal centers. A few lymphoid follicles were colonized by CCL cells. Immunohistochemistry showed that all of the lesions contained a monoclonal plasma cell population. In three tumors, a number of the CCL cells had a similar light chain restriction pattern to that observed in plasma cells. Two of the four patients evaluated exhibited clonal bands for the IgH gene by polymerase chain reaction assay. Moreover, the presence of surface IgM+, IgD- and CD27+ CCL- cells suggests that these tumors are derived from memory B-lymphocytes.

To clarify the cellular composition of subacute thyroiditis, histologic and immunohistochemical studies were performed. Histologically, the lesion presented a patchy distribution of non-caseous granulomas comprising colloid, small lymphocytes, neutrophils, macrophages with or without epithelioid features, and multinucleated giant cells of foreign body type. In addition, numerous plasmacytoid monocytes were closely associated with the granulomas. The giant cells were CD68+, thyroglobulin- and cytokeratin-. Usually, small lymphocytes in the granulomas are CD3+, CD8+, CD45RO+ cytotoxic T-cells. In the non-granulomatous lesion, the follicles were often infiltrated by CD8+ T-lymphocytes, plasmacytoid monocytes and histiocytes, resulting in disrupted basement membrane and rupture of the follicles. Lymphoid follicles with or without active germinal centers were not observed. Moreover, no residual follicular dendritic cell networks were detected by CD23 and CAN.42 immunostains. In the interfollicular area, scattered plasma cells were observed among infiltrating cells. Neither human herpes virus 8 nor EBER-positive cells were detected in the six patients. The findings of our study suggest that cellular immune response may play an important role in the pathogenesis of subacute thyroiditis.

We report a case of primary pulmonary low-grade marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)-type with prominent sclerosis, which morphologically resembled pulmonary hyalinizing granuloma (PHG) or inflammatory pseudotumor (IPT) of the lung. The patient, a 66-year-old Japanese female with a history of Sjogren's syndrome and primary biliary cirrhosis, presented with a lower left lobe mass 6.8 cm in diameter. Histologically, the lesion is characterized by dense bundles of collagen with scattered plasma cells, mature small lymphocytes, and histiocytes among the collagen bundles. Only the peripheral area of the nodule contained dense lymphoplasmacytoid and histiocytoid infiltrates. A few centrocyte-like cells were obscured by the numerous plasma cells and plasmacytoid cells. In addition, lymphoepithelial lesions and colonalized lymphoid follicles were identified by immunohistochemistry alone. Although PHG and IPT are unlikely to be confused with pulmonary MALT-type lymphomas, the present case suggests that MALT-type lymphoma should be added to the list of differential diagnoses for PHG and IPT.

A completely infarcted lymph node should alert the pathologist to the high possibility of malignant lymphoma. The lymph node lesion of infectious mononucleosis (IM) shows marked histologic diversity and occasionally may be confused with malignant lymphoma. We report a rare case of IM showing extensive lymph node infarction whose lymph node lesion was similar to lymph node infarction associated with maligant lymphoma. This case describes a 32-year-old Japanese man who had signs and symptoms consistent with IM, which he was later proven serologically to have, but whose cervical lymph node showed extensive lymph node infarction with a thin area of granulation tissue beneath the capsule. The infarcted tissue contained numerous eosinophilic ghosts of large lymphoid cells. The thin granulation tissue was composed of numerous small lymphocytes, plasma cells, and histiocytes, in addition to large lymhoid cells including immunoblasts and granulocytes. CD20, CD3, and CD45RO imunostains revealed the mixed Bnd T-cell nature of the ghosts of large lymphoid cells in the infarcted tissue as well as viable large cells in the granulation tissue. The patient was free from disease after 50 months' follow-up.

Adult-onset Still's disease (AOSD) is known to be a cause of fever of unknown origin. We describe the clinicopathologic, immunohistologic, and genotypic features of 3 patients with lymph node lesions from AOSD, which posed a serious diagnostic difficulty from peripheral T-cell lymphomas. The patients were 22-, 26-, and 63-year-old Japanese women. At the onset of disease, all patients had multicentric lymphadenopathy in association with clinical and laboratory findings suggestive of a malignant lymphoma. None of the patients developed malignant lymphomas during the follow-up period. Histologically, the lesions were characterized by paracortical hyperplasia with prominent vascular proliferation. In the paracortical area, there was a mixed infiltrate including small-to-medium-sized lymphocytes, variable numbers of eosinophils, plasma cells, and B immunoblasts. Polymerase chain reaction analysis demonstrated that neither clonal rearrangement of the T-cell receptor y-chain gene nor immunoglobulin heavy-chain rearrangement was detected in any patient. Although AOSD appears to be a rare systemic inflammatory disorder, the lymph node lesion should be added to the differential consideration of benign lymph node lesions simulating node-based peripheral T-cell lymphoma.

A minority of centroblastic and centroblastic/centrocytic cell lymphomas are accompanied by a prominent epithelioid cell response and were suggested to be a distinct variant of B-cell lymphoma of germinal center cell origin. To confirm the clinicopathologic significance of these mainly large B-cell lymphomas with an epithelioid cell response (LBCL-ER), we reviewed 50 patients with LBCL-ER and compared the results with those of 167 other diffuse large B-cell lymphomas (DLBCL) and 94 follicular lymphomas (FL) without epithelioid response. The patients with LBCL-ER showed a higher age distribution (median 71, P =.03), a female predominance (M:F = 18:32, P =.001) and less frequent involvement of extranodal sites >1 (P =.004) compared with those with DLBCL, and presented with a bulky mass of the affected lymph nodes in 54% of cases. They were also older (P =.0006) and more associated with the aggressive clinical factors such as serum LDH level and International Prognostic Index score than those with FL. Histologically, nine cases (18%) partially showed a follicular growth pattern, and the others (82%) were occupied by a diffuse growth pattern. The epithelioid cells were accumulated in large demarcated masses, partially imparting a lymphoepithelioid (Lennert) lymphoma-like appearance to some portions of the lesions in every case. Immunohistochemically, LBCR-ER was positive for CD20 in every case, CD10 in 43% of the cases, and BCL-2 in 56%. None of the tumor cells in the 40 cases tested expressed CD5 antigen. Immunostaining also often highlighted the remnants of the follicular dendritic cell network. The BCL-2 gene rearrangement was detected in only 19% of the cases examined. The survival curve of the cases of LBCL-ER was almost identical with that of DLBCL and was significantly inferior to that of FL. The centroblastic and centroblastic/centrocytic lymphoma with an epithelioid cell response may be regarded as the morphologic variant of DLBCL preferentially arising in the aged population and reflecting the disease progression of FL.

OBJECTIVE. We examined retrospectively the MR imaging findings in eight patients with mucinous carcinoma of the breast to better describe the imaging characteristics of this disease.CONCLUSION. The MR imaging findings in mucinous carcinomas include dynamic curves of the gradually enhancing type and a very high signal intensity on T2-weighted images compared with other histologic types of invasive ductal carcinoma. These findings appear to be useful for diagnosis.

Deposition of amyloid ss-protein (Ass), a hallmark of Alzheimer's disease, occurs to some extent in the brains of most elderly individuals. We sought to learn when Ass deposition begins and how deposition is affected by apolipoprotein E allele epsilon4, a strong risk factor for late-onset Alzheimer's disease. Using an improved extraction protocol and specific enzyme-linked immunosorbent assay, we quantified the levels of Ass40 and Ass42 in the insoluble fractions of brains from 105 autopsy cases, aged 22 to 81 years at death, who showed no signs of dementia. Ass40 and Ass42 were detected in the insoluble fractions from all of the brains examined; low levels were even found in the brains of patients as young as 20 to 30 years of age. The incidence of significant Ass accumulation increased age-dependently, with Ass42 levels beginning to rise steeply in some patients in their late 40's, accompanied by much smaller increases in Ass40 levels. The presence of the apolipoprotein E epsilon4 allele was found to significantly enhance the accumulation of Ass42 and, to a lesser extent, that of Ass40. These findings strongly suggest that the presence of epsilon4 allele results in an earlier onset of Ass42 accumulation in the brain.

To clarify whether senile plaques disappear, we examined amyloid beta protein (A beta) deposits in non-demented subjects, and found novel diffuse plaques associated with astroglial A beta. Formalin-fixed paraffin-embedded sections from cortical areas were immunolabeled with a panel of A beta antibodies, and astroglial and microglial markers. Cerebral A beta deposition was primarily found as diffuse plaques (DP) in these subjects. A subset of DP was associated with clusters of intensely A beta-positive small granules. The clusters, which were located just adjacent to astroglial nucleus, had the characteristics of lipofuscin granules and, therefore, were quite different from "small stellate deposits". Substantial amounts of A beta-positive granules were found inside astrocytes by dual labeling of A beta and glial fibrillary acid protein, and the majority of astroglial A beta immunoreactivity was located on lipofuscin granules. A beta-positive granules lacked immunoreactivity with antisera for the N-terminal region of A beta. These peculiar DP showed a much weaker staining than ordinary DP. The DP associated with astroglial A beta were found in about one third of the subjects, although the density varied widely among individuals. From these findings, we propose that DP, which are associated with the N-terminal truncated A beta in astrocytes, represent the disappearing stage of senile plaques.

The present study was undertaken to investigate the relationship of microglial activation to amyloid beta protein (A beta) deposition, particularly at the early stage. Using single and double immunostaining methods with a panel of microglia markers and antibodies against A beta and amyloid beta protein precursor (APP), we examined the cerebrum and cerebella of both Alzheimer's disease (AD) and non-demented subjects obtained at autopsy. In nondemented, middle-aged subjects that had small amounts of cerebral A beta deposits, approximately 70% of the diffuse plaques contained ramified microglia. However, no evidence of microglial activation was found in diffuse plaques in any of the non-demented subjects. Dual immunostaining of sections of cerebral cortex using antibodies against A beta and major histocompatibility complex class II antigen showed that in AD subjects, approximately 20% of total diffuse plaques contained a few, activated microglia. Most of these plaques were defined as a transitional from between diffuse and primitive plaques. Both primitive and classic plaques in the cerebral cortex of AD subjects consistently contained clusters of activated microglia. Subpial A beta deposits without neuritic changes lacked microglial activation. In the cerebellum, all of the diffuse plaques lacked microglial activation, and activated microglia in the compact plaques were not as hypertrophic as those in cerebral primitive/classic plaques. Our findings indicate that microglial reactions are absent in the early stages of A beta deposition, and it occurs during the transition from diffuse to primitive plaques, when amounts of A beta deposits and the degree of neuritic changes increase.

The immunophenotype of perivascular cells (PC) in temporal lobe tissues obtained at autopsy in 48 patients (aged 41–88 years) was characterized using light and electron microscopic immunocytochemistry with a variety of antibodies. In all cases studied, PC bearing CD11 c (Ki-M1 P) and CD68 (KP1) were distributed throughout the temporal cortex. In addition to Ki-M1P and KP1, the monoclonal antibodies against major histocompatibility complex (MHC) class II antigen (Ag) (LN-3, CR3.43), anti-leucocyte common antigen (LCA), LN-5, Mac 387 were all found in PC with variable immunoreactivity. In contrast, LN-1 and OPD4 were not found in PC, although the former showed nearly constant staining of resting microglia. Semiquantitative analysis disclosed differences in the numbers of cells labeled with the markers in the 21 normal brains (KI-M1P > KP1 » LCA, LN-3, LN-5 » Mac 387). Ultrastructurally, immunoreactivity for Ki-M1P, KP1, and LN-3 was observed in PC with cytoplasm containing dense lysosomal bodies. In brains from patients with Alzheimer's type dementia, PC were seen in the wall of β-amyloid protein-positive small vessels. However, there was no definite alteration of anti-genicity in PC from AD brains compared with those from normal brains. The immunophenotype of PC was similar to that of macrophages, which were observed in the perivascular spaces and the leptomeninges in some normal and diseased brains. In contrast with PC, however, macrophages showed high incidence of labeling for some mac-rophage markers LN-5 and Mac 387. These findings demonstrate that PC may be a normal constituent of the adult human brain with a variable expression of monocyte/ macrophages markers and MHC class II Ag and that PC could be distinguished from resting microglia by their morphology and by their immunophenotype.

The localization of apolipoprotein E (ApoE) has been examined immunohistochemically in the autopsied brains of middle-aged and old-aged control subjects, with and without amyloid beta protein (A beta) deposits, and of Alzheimer's disease patients. Senile plaques were consistently labeled with ApoE antiserum even in the very early stage of senile plaque formation seen in the fifth decade. In the cerebellar molecular layer, small dots of ApoE immunoreactivity, which were prominent in the Alzheimer's disease subjects, were observed in addition to immunoreactivity in diffuse plaques. ApoE antisera labeled all of the extracellular neurofibrillary tangles (NFT), whereas only a small minority of extracellular NFT were positive for A beta. A punctate pattern of ApoE immunoreactivity was seen at the media of the meningeal vessels lacking amyloid, when senile plaques were present in the nearby cortex. In the early stage of amyloid angiopathy, the distribution of ApoE immunoreactivity was much more extensive than that of A beta positivity. These findings suggest that ApoE accumulates in the early stage of senile plaque formation and, furthermore, that ApoE accumulation precedes A beta deposition in extracellular NFT and amyloid angiopathy.

Twenty-five patients with renal cell carcinoma were treated with a lipophilic macromolecular drug, poly(stylene-co-maleic acid)-conjugated neocarzinostatin (SMANCS) dissolved in lipid contrast medium (Lipiodol). The drug was injected by catheterizing the renal artery and another feeding artery in 24 patients, and in the common hepatic artery in 1 patient with metastases to the liver after a radical nephrectomy. The procedure of selective arterial administration of 3-20 mg/mL of SMANCS/Lipiodol was simple to perform and was required once every two to three weeks. Total dose of SMANCS for each patient varied from 3 to 57 mg. Both SMANCS and Lipiodol accumulated more selectively in tumor than in any other tissue and remained in the neovasculature and extracapillary space for a long time. CT pattern of the remaining oil contrast medium in the tumor was characterized by the high-density area localized mainly in the periphery of the tumor around the central necrosis. When hyperviscosity Lipiodol (Lipiodol HV) was used as lipid contrast medium, it remained more persistently in the tumor and disappeared more slowly than Lipiodol. Moreover, the pronounced anticancer effect was recognized when SMANCS/Lipiodol HV was administered compared with only SMANCS/Lipiodol. Severe side effects, such as myelosuppression, unendurable pain, paralytic ileus, etc., were not observed. This targeting chemotherapy may be of great significance for advanced renal cell carcinoma.