We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of “intraductal tubulopapillary neoplasms (ITPNs)” and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 men and 5 women with a mean age of 58 years. ITPNs were solid and nodular tumors obstructing dilated pancreatic ducts and did not contain any visible mucin. The tumor cells formed tubulopapillae and contained little cytoplasmic mucin. The tumors exhibited uniform high-grade atypia. Necrotic foci were frequently observed, and invasion was observed in some cases. The ITPNs were immunohistochemically positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. Molecular studies revealed abnormal expressions of TP53 and SMAD4 in 1 case, but aberrant expression of β-catenin was not observed. No mutations in KRAS and BRAF were observed in the 8 cases that were examined. Eight patients are alive without recurrence, 1 patient died of liver metastases, and 1 patient is alive but had a recurrence and underwent additional pancreatectomy. The mitotic count and Ki-67 labeling index were significantly associated with invasion. All the features of ITPN were distinct from those of other known intraductal pancreatic neoplasms, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and the intraductal variant of acinar cell carcinoma. Intraductal tubular carcinomas showed several features that were similar to those of ITPN, except for the tubulopapillary growth pattern. In conclusion, ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.

Background— A myocardial bridge (MB) that partially covers the course of the left anterior descending coronary artery (LAD) sometimes causes myocardial ischemia, primarily because of hemodynamic deterioration, but without atherosclerosis. However, the mechanism of occurrence of myocardial infarction (MI) as a result of an MB in patients with spontaneously developing atherosclerosis is unclear. Methods and Results— One hundred consecutive autopsied MI hearts either with MBs [MI(+)MB(+) group; n=46] or without MBs (n=54) were obtained, as were 200 normal hearts, 100 with MBs [MI(−)MB(+) group] and 100 without MBs. By microscopy on LADs that were consecutively cross-sectioned at 5-mm intervals, the extent and distribution of LAD atherosclerosis were investigated histomorphometrically in conjunction with the anatomic properties of the MB, such as its thickness, length, and location and the MB muscle index (MB thickness multiplied by MB length), according to MI and MB status. In the MI(+)MB(+) group, the MB showed a significantly greater thickness and greater MB muscle index (P<0.05) than in the MI(−)MB(+) group. The intima-media ratio (intimal area/medial area) within 1.0 cm of the left coronary ostium was also greater (P<0.05) in the MI(+)MB(+) group than in the other groups. In addition, in the MI(+)MB(+) group, the location of the segment that exhibited the greatest intima-media ratio in the LAD proximal to the MB correlated significantly (P<0.001) with the location of the MB entrance, and furthermore, atherosclerosis progression in the LAD proximal to the MB was largest at 2.0 cm from the MB entrance. Conclusions— In the proximal LAD with an MB, MB muscle index is associated with a shift of coronary disease more proximally, an effect that may increase the risk of MI.

BACKGROUND/AIMS:p53 plays an important role in the development of gastric carcinomas through its effect on apoptosis. Its use as a biomarker of tumorigenesis and progression in clinical tissue is currently under consideration. This project assessed its value in early and advanced stage gastric carcinomas.METHODOLOGY:The characteristics of positive staining for p53 was evaluated in 202 gastric adenocarcinomas classified into early stage (T1) (127 cases) and advanced stage (T2, 3 and 4) (75 cases) using the tumor-node-metastasis classification. Four subgroups (classified as p53 negative, +, ++ and +++ according to the level of positivity) were investigated for relationships with apoptosis (morphology) or cell proliferation (Ki-67).RESULTS:The mucosa of early stage and both mucosa and subserosa of advanced cancers were examined. p53-positive early stage cancers had more apoptosis but also more proliferation than p53-negatives (P<0.05), perhaps indicating conferral of a growth advantage. In advanced cancers, there was no correlation between apoptosis and extent of p53 positivity. p53 positivity had no correlation with cell proliferation in the mucosa and subserosa of these cancers.CONCLUSIONS:p53 may be useful as an indicator of development and progression in early stage gastric cancers but this is not the case for advanced stage gastric cancers.

We report a tumor in an 80-year-old man that was difficult to distinguish from other tumors, i.e., small cell carcinoma of the lung, PNET/Ewing tumor, malignant lymphoma, or malignant melanoma (amelanotic), and which was finally identified as cutaneous neuroendocrine carcinoma using immunohistochemical and ultrastructural methods. Autopsy did not show any tumors in the lungs, excluding the possibility of small cell carcinoma of the lung. Immunohistochemistry tests gave negative results for LCA, UCHL-1, CD3, and CD20, thereby excluding malignant lymphoma, and the negative results for S-100 protein and HMB-45 ruled out malignant melanoma. The possibility of PNET/Ewing sarcoma was also excluded because of negativity for CD99. In addition, the ultramicrostructure showed intercellular junctional complexes and neuroendocrine granules, indicating that the tumor had characteristics of both epithelial and neuroendocrine tissues. We therefore diagnosed the primary carcinoma of the skin as cutaneous neuroendocrine carcinoma.

To establish cytological features of pulmonary large cell neuroendocrine carcinoma (LCNEC), we evaluated the cytological characteristics of LCNEC. Samples from 25 histologically confirmed LCNECs (14 touch imprint (TI) and 11 curettage) were analyzed. The findings were compared with those for seven small cell lung carcinomas. Cytological findings of TIs were as follows: Tumor cells were medium- to large-sized, round or polygonal, and nuclear polymorphism was observed. Some of the tumor cells had clearly identified cytoplasms, but naked nuclei were frequently observed. Nuclei were round, oval, or polygonal, and possessed thin and smooth nuclear membranes. The nuclear chromatin pattern was finely or coarsely granular. One or two nucleoli were observed in the nuclei, but were inconspicuous in some cases. Tumor cells appeared in clusters, and rosette formation was observed, but single cells were frequently observed also. Necrotic background and nuclear streaking were frequently observed. In brush or curettage specimens, the number of cells observed on a glass was small, but the findings were almost the same as those for the TI samples. TI samples have characteristic features, such as a neuroendocrine morphologic pattern, large cell size, abundant cytoplasm, finely or coarsely granular chromatin of the nucleus, and prominent nucleoli, and the diagnosis of LCNEC is possible. In brush or curettage specimen, the LCNEC diagnosis may be possible if a sufficient number of tumor cells are obtained.

A 70-year-old man with a 2-year history of myelodysplastic syndrome (MDS), refractory anemia, was hospitalized because of pneumonia. He had received frequent transfusions because of anemia. The total amount of blood transfusions he had received during the 7 months before admission was 44 units. In the previous 6 months, he had intravenously received 500 mg of deferoxamine after every transfusion to prevent secondary hemochromatosis (total dose: 6,500 mg). On admission, a complete blood count showed a white blood cell count of 2.0x10 /L with 53% neutrophils, a hemoglobin level of 5.2 g/dL, and platelet count of 6x10/L. The serum ferritin was 1,532 ng/ml indicating an iron overload state. Although he received a series of antibiotics and fluconazole as empiric therapy, his pneumonia progressed and pleural effusion became evident. Frequent microbiological investigations, including cultures of blood, sputum, and pleural fluids, and serum levels of endotoxin and βD-glucan all yielded negative results. However, an intraventricular tumor mass was observed on echocardiogram on day 17 after admission, which had been undetectable 10 days before (Figure 1). Amphotericin B was started because of the suspicion of mucormycosis. However, he soon developed coma because of multiple cerebral infarctions on day 19, and died of cerebral hemorrhage on day 21. Autopsy revealed a large intraventricular thrombosis (Figure 2). Histopathologic findings of the thrombosis showed broad, irregularly-shaped, nonseptal hyphae with right-angled branching, which is characteristic of mucormycosis (Figure 3). Disseminated mucormycosis was also detected in abscesses in multiple organs, including the brain, lung, liver, spleen, thyroid gland, and kidney. Mucormycosis is an opportunistic infection caused by Mucorales zygomycetes, mostly due to the inhalation of spores. Treatment with the iron chelator deferoxamine has been reported to be one of the risk factors for developing mucormyocis in patients with iron overload. In human plasma or on the mucosal surfaces, the amount of free iron available for microbial growth is low; almost all of the iron is bound to iron-binding proteins such as transferrin and lactoferrin or is inaccessible in tissue stores. Micro-organisms compete for the iron in the host, usually by secreting siderophores that trap iron and deliver it to the micro-organism, thus enhancing their growth. Deferoxamine B mesylate (deferoxamine) is one of the siderophores produced by Streptomyces pilosus. Therefore, administration of deferoxamine is suggested to extract iron to support the growth of the micro-organism for mucormycosis and thus result in infection. Mucormycosis was also reported in patients with hematologic malignancies such as leukemia, lymphoma, and bone marrow transplant recipients, without these patients having received deferoxamine therapy. However, theses cases were reported to predominantly occur in the aplastic post-chemotherapy period. There are also some reports of mucormycosis in MDS patients not receiving deferoxamine. Therefore, we do not exactly know how much deferoxamine predisposed to mucormycosis in our case. However, caution should be taken to prevent mucormycosis in an immunocompromised host, especially those who are receiving deferoxamine for iron overload.

Background and Objectives: Selection of suitable treatment for early gastric cancers, such as endoscopic mucosal resection or the major surgical option of resection of the cancer together with a radical lymph node dissection, may be assisted by comparing the growth characteristics of the cancer with selected molecular characteristics. The results could be used to predict those cases that have a higher risk of developing secondary metastases. Methods: A total of 1,196 Japanese patients with early gastric cancers (648 mucosal cancers and 548 submucosal) were included in the selection of two groups: a metastatic group made up 57 cancers with lymph node metastasis (9 mucosal, 48 submucosal), and a nonmetastatic group of 61 cases (6 mucosal, 55 submucosal) without lymph node metastasis. Growth characteristics of the cancers (superficially spreading, penetrating or invasive, lymph node metastasis) were compared with immunohistochemical expression of single-stranded DNA (ssDNA) protein (apoptosis indicator), bcl-2 and p53 (apoptosis-associated), Ki-67 (cell proliferation), and E-cadherin (cell adhesion) proteins. Results: The lesions in the nonmetastatic group had higher levels of apoptosis and lower expression of bcl-2 than in the metastatic group, indicating an inhibitory role for apoptosis in malignant progression. Apoptosis was also higher in the superficial compared with the invasive lesions of both groups. The lesions in the metastatic group had higher p53 expression than that of the nonmetastatic group, whereas apoptosis in the metastatic group was lower than in the nonmetastatic group. An unproved explanation for this finding may be that, although increased, p53 was mutated and ineffective in promoting apoptotic control of metastatic progression. E-cadherin was decreased in the invasive lesions of both groups, indicating a greater ability of these cells to lose adhesion, to invade the submucosa, and to metastasize. Cell proliferation was highest in the superficial lesions of both metastatic and nonmetastatic groups. Conclusions: Early gastric cancers with low levels of apoptosis, increased bcl-2, and high levels of p53 expression are more likely to invade and metastasize. (C) 2003 Wiley-Liss, Inc.

Benign salivary gland tumors composed of purely squamous cells are quite unusual and are not included in the World Health Organization classification. We have seen two benign parotid gland tumors characterized by multicystic spaces with stratified squamous linings and focal solid epithelial nests. Seifert et al. recently described such a case as a choristoma; we, however, herein propose a new designation, keratocystoma, for this unique tumor group, because of its distinctive histological features. These tumors occurred in men aged 18 and 38 years with enlarging parotid gland tumors. Both had largely similar gross and histological features, with some variations. The epithelium lining of the cysts showed apparent keratinization through a parakeratotic or orthokeratotic pathway without forming a granular cell layer. Stratification of the epithelium was always regularly oriented from the outer basal to the inner keratotic cell layer. Focally, the outer layer had bud-like protrusions. In some areas, solid squamous cell islands surrounded by basement membrane were enclosed within the collagenous stroma. These cystic and solid structures were randomly distributed, showing no definite lobular architecture. All of the tumor cells had uniform, bland nuclei and abundant eosinophilic cytoplasm. Scattered mitotic figures were observed, limited to the outer epithelial layer, and showed no abnormal patterns. Transformation from the parotid ductal epithelium to the tumor cells is evident. Foci of foreign-body reactions against keratin materials were present. Immunoreactivities for cytokeratins reconfirmed the nature of squamous differentiation of the tumor cells. Ki-67-positive cells were confined along the outer basal layer of the tumor epithelium. Tests for α-smooth muscle actin and S-100 protein were completely negative. Both patients had no evidence of recurrence 3 and 2 years after subtotal parotidectomy, respectively, without any additional therapy. We believe that this lesion represents a benign cystic neoplasm rather than a malignant tumor or pseudoneoplastic metaplastic condition. It is important to recognize that this peculiar benign tumor does originate from the salivary gland.

We present a new cell line, EJ, established from an invasive endometrioid adenocarcinoma of the uterine corpus in a 56-year-old patient. The cells show rapid growth in culture with a doubling time of 16 h and high migration activity. Monolayer-cultured cells were polygonal in shape showing a tendency to pile up without contact inhibition. Subcutaneous transplantation of the EJ cells into nude mice formed solid tumors that were histologically diagnosed as adenocarcinoma, whereas no metastasis was observed. Cultured EJ cells produced tissue polypeptide antigen (TPA). Genetic and molecular analyses revealed high telomerase activity but not estrogen receptor α expression. Using the DNA sequencing technique, we have screened EJ cells for p53 mutation in exon 5 to 8 but no mutation of p53 was observed. This cell line appears to represent the development of a more malignant clone with divergent receptor function and growth behavior, and provides us with an interesting new tool for the study of tumorigenesis in the human endometrium.

Secondary pulmonary alveolar proteinosis (PAP) is one of the complications of hematologic malignancy and immunosuppressive diseases. We encountered four cases of myelodysplastic syndrome (MDS) associated with PAP detected on autopsy. They consisted of two refractory anemia (RA) and two patients with refractory anemia with excess blasts in transformation (RAEBt) at the time of MDS diagnosis, but all of them developed leukemic phase and were resistant to chemotherapy at the time of pulmonary episodes. Of the four MDS patients, two also had pulmonary aspergillosis. Previously, 69 patients with PAP associated with hematologic disorders have been reported, but there have been only seven cases with MDS, including our four patients. Of the 69 reported cases of PAP in hematologic malignancies, 24/63 (38%) informative patients with infection had fungal infections of the lung; 2/7 (29%) MDS cases had fungal infection. We should, therefore, pay careful attention to this possibility in cases of MDS with lung complications, including PAP, especially in patients in the leukemic phase of MDS.

背景:卵巣の輪状細管を伴う性索腫瘍 (Sex cord tumor with annular tubules (SCTAT)) の1例において免疫染色および捺印細胞診を行ったので報告する.症例:63歳女性. 2経妊, 2経産にて自覚症状はなく, 健康診断の腹部エコー検査で下腹部腫瘤を指摘された. Peutz-Jeghers症候群の徴候はない. 右卵巣摘出手術が施行され, 9×7×6cmの多房性嚢胞がみられ, 一部に充実性肥厚部を認めた. 肥厚部からのスタンプ標本では多数の腫瘍細胞が採取され, 乳頭状ないし腺腔様構造がみられた. 腫瘍細胞は淡明な胞体内に多糖類と考えられるPAS陽性の穎粒を有していた. 腫瘍の一部には腸管上皮に類似する異所性成分が認められ, 胞体内にAlcianblueに染まる粘液を有しCEAとCAI9-9が陽性であった. 他の大部分の上皮成分ではAFPが陽性であった.結論:異所性成分の存在やAFPの陽性所見はSertoli-Leydigcelltumorlこは高頻度に認められるため, 本症例はSertoli-Leydig cell tumorの性格を有するSCTATと考えられた.

We investigated the effect of expression of survivin, an apoptosis inhibiting protein, on cellular proliferation and apoptosis in gastric cancer and assessed its relation to the pathological characteristics of gastric cancer. Resected gastric cancer specimens from 42 patients (intestinal type; 21 cases and diffuse type; 21 cases) were evaluated. There were no significant differences in the clinicopathologic factors between the two groups. Survivin mRNA expression was measured using real-time reverse transcription-polymerase chain reaction, and survivin protein expression was evaluated by immunohistochemical staining. The Ki-67 index was adopted for cell proliferation scoring, and the ss-DNA positive rate as an apoptotic index. The survivin mRNA expression inversely correlated with the apoptotic index (p<0.05). Survivin mRNA expression (p<0.001) and survivin protein expression (p<0.001) were significantly higher in the diffuse type than the intestinal type. In conclusion, gastric cancer avoids cellular death by survivin expression and this tendency was more conspicuous in diffuse type gastric cancer.

Hybrid carcinomas of the salivary gland are a recently defined and rare tumor entity, consisting of two histologically distinct types of carcinoma within the same topographic area. In this study, we examined nine such cases, which mainly arose in the parotid gland (seven cases), with an additional one each from submandibular and lacrimal glands, and analyzed their clinicopathologic profiles, including immunohistochemical features and p53 gene alterations. The prevalence of hybrid carcinomas was 0.4% among the 1863 cases of parotid gland tumors in our series. The nine patients comprised five men and four women, ranging in age from 40 to 81 years (mean, 62 y). Tumor size ranged from 2 to 10 cm (mean, 4.2 cm). Of the seven patients who were followed up, two were alive with disease and five were alive with no evidence of disease, although the follow-up period was short. Three cases had cervical lymph nodal metastases. The combinations of carcinoma components in our hybrid carcinomas were as follows: epithelial–myoepithelial carcinoma and basal cell adenocarcinoma in two cases, epithelial–myoepithelial carcinoma and squamous cell carcinoma in one case, salivary duct carcinoma and adenoid cystic carcinoma in two cases, myoepithelial carcinoma and salivary duct carcinoma in one, acinic cell carcinoma and salivary duct carcinoma in one, and squamous cell carcinoma and salivary duct carcinoma in two. Although the proportion of each carcinoma component in a tumor mass varied from case to case, the minor component always represented ≥ 10% of the area. Differences in cellular composition were studied by immunohistochemistry and electron microscopy. The Ki-67–labeling index apparently differed between the two carcinoma elements in five cases. Diffusely positive p53 immunoreactivity was observed in four cases, restricted to the more aggressive component in each pair. Furthermore, p53 gene alteration analysis of these p53-positive cases revealed that all and three cases demonstrated loss of heterozygosity at p53 microsatellite loci and p53 gene point mutations, respectively, which were detected only in the p53-immunoreactive carcinoma component. Therefore, there is the possibility that such molecular-genetic events take an integral part for inducing the transformation from histologically lower to higher grade tumor during the hybrid carcinoma genesis of the salivary glands.

背景:皮膚原発のアポクリン癌はまれで, さまざまな抗体を用いることにより組織学的診断が可能であるが, 細胞所見の報告は少ない.われわれは腋窩部原発アポクリン癌の2例を経験し, その細胞学的特徴を検討した.症例:症例1は49歳男性で5年前に左腋窩部腫瘍摘出術を受けたが, 局所再発をきたした.吸引細胞診ではほとんどが孤立散在性で, 一部に上皮性細胞集塊が含まれていた.腫瘍細胞は細胞質が厚くて広く, 断頭分泌を認めた.組織学的には充実性, 索状および腺管状構造を示し, 腫瘍細胞の細胞質は広く好酸性で, 断頭分泌, ジアスターゼ抵抗性PAS陽性顆粒が認められた.GCDFP-15が陽性であった.症例2は53歳の男性で, 15年前に左腋窩部腫瘤の診断を受け, 摘出術が施行された.リンパ節の擦過細胞診では比較的重積性の少ない上皮性細胞集塊が主体で, 腫瘍細胞は大型で広い細胞質, 円形から卵円形の偏在核と明瞭な核小体を持ち, 断頭分泌が認められた.組織学的には潰瘍を形成し, 腺管形成を伴い皮下脂肪織まで浸潤していた.細胞質は広く好酸性で断頭分泌が認められ, ジアスターゼ抵抗性PAS陽性顆粒を含んでいた.GCDFP-15が陽性であった.結論:腋窩部に発生するアポクリン癌は汗腺あるいは副乳由来のアポクリン癌や転移性腺癌が鑑別となる.皮膚原発アポクリン癌は細胞診でも特徴的な像を保持しており, 詳細な検討によって推定診断が可能であると考えられた.

目的. CDDP耐性肺癌培養細胞とその親株の蛋白の2次元電気泳動像からその耐性に関与すると見られる蛋白を検出し, 臨床症例における影響を検討した. 方法. 肺癌培養細胞H69とPC14のCDDP耐性株とその親株での2次元電気泳動像を比較し明らかに発現量の変化した蛋白を検出した. 1994年10月～1998年9月に外科的切除され2次元電気泳動による肺癌蛋白解析が施行された80症例を対象にこの蛋白発現と臨床病理学的緒因子および予後との関係を検討した. 結論. CDDP耐性株で顕著に発現低下する分子量44.0kDaの分子を検出した. この分子はN末端アミノ酸配列解析よりカルシウム結合性蛋白Reticulocalbin-1と相同な蛋白であった. この蛋白発現と臨床病理学的緒因子との関係に有意なものはなかった. しかし術後の白金製剤による全身化学療法施行症例にかぎりReticulocalbin-1相同蛋白発現例が低発現例に比べ有意に予後良好であった. Reticulocalbin-1相同蛋白分子が白金製剤の薬剤耐性機構に何らかの関与をしている可能性が示唆された.

BACKGROUND:Intracytoplasmic lumina have been recently recognized as a characteristic histologic feature of ependymoma. However, the cytologic diagnostic usefulness has not been discussed. We encountered two imprint cytology cases of spinal cord ependymomas in which there were intracytoplasmic lumina in the tumor cells.CASES:Two women had spinal cord tumors on magnetic resonance imaging. Imprint cytology study was carried out on the resected tumors. The cytologic specimen of the first case, aged 52, showed tumor clusters consisting of elongated epithelioid cells, a few of which also had intracytoplasmic lumina. Histologically, tumor cells formed ependymal rosettes and pseudoperivascular rosettes. There were a few tumor cells with intracytoplasmic lumina. The cytologic specimen of the second patient, aged 37, had scattered and isolated tumor cells with intracytoplasmic lumina resembling signet-ring cells and paired tumor cells forming small, glandlike structures. Histologically, the tumor was composed mainly of signet-ring-like cells containing intracytoplasmic lumina.CONCLUSION:Intracytoplasmic lumina were observed in the imprint cytologic specimens of spinal cord ependymoma. The diagnosis of ependymomas can be made cytologically when intracytoplasmic lumina are found since no other primary neuroepithelial tumors of the central nervous system possess such a characteristic feature.