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A case of cystitis occurring after administration of nivolumab, an anti-programmed death-1 antibody, which was considered to be an immune-related adverse event, is reported. A 62-year-old man with pulmonary squamous cell carcinoma (T4N0M1a Stage IV) was being treated with nivolumab as fourth-line chemotherapy. He was hospitalized for a fever and diarrhea after 3 courses. Fasting and antibiotic medication reduced the fever and alleviated the diarrhea. He then developed cystitis with no evidence of infection. Cystoscopy showed diffused redness and erosion of the bladder mucosa; urine cytology was negative. Imaging examinations showed no abnormalities. Urinary tract pain and hematuria due to nivolumab were diagnosed by exclusion following a bladder biopsy. Since symptomatic treatment was unsuccessful, steroid pulse therapy was given, which resolved the patient’s signs and symptoms. The patient was then switched to maintenance prednisolone and tapered gradually. The 4th course of nivolumab was then resumed with concomitant administration of steroid, and it was possible to continue administration of nivolumab without progression of cystitis.

Gastric inverted hyperplastic polyp (IHP) is a rare type of gastric polyp, and is characterized by downward growth of the hyperplastic mucosal components into the submucosa. To the best of our knowledge, 16 gastric IHP cases have been described in the English literature, but the pathogenesis has not been established. We report the clinical and pathological findings of four gastric IHP cases. The lesions were mainly composed of hyperplastic foveolar-type glands with focal cystic dilatation. Pyloric type glands, endocrine cells, acinic cell metaplasia, and smooth muscle bundles were also seen as components of the polyp. Two cases (cases 1 and 4) coexisted with multifocal gastritis cystica profunda (GCP) and gastric adenocarcinoma. Case 4 furthermore exhibited an intermediate form between IHP and GCP. We suggest that IHP may be GCP associated with exaggeratedly hyperplastic and metaplastic changes. In case 4, the coexisting gastric carcinoma was mainly located in the submucosa, whilst the mucosal component was minimal. Five out of twenty reported gastric IHP cases, including our cases, coexisted with gastric adenocarcinoma. These facts would lead us to further investigate the relation between gastric IHP and carcinoma.

To clarify whether scattered endocrine cells in pancreatic ductal adenocarcinoma are neoplastic or not, we immunohistochemically studied 29 cases of invasive pancreatic ductal adenocarcinomas, 17 with metastases, for chromogranin A, insulin, glucagon, pancreatic polypeptide, serotonin, gastrin, laminin, and Ki-67. Endocrine cells were found in primary sites in 24 cases (82.3%), where endocrine cells showed at least a visibly close location to adjacent islet cells. Although endocrine cells in neoplastic glands were within the neoplastic basement membrane, endocrine cells were not seen in invasive sites beyond the pancreas where islets were not present. Endocrine cells in neoplastic glands were reactive for two or three of the islet hormones in all cases, and different types of hormonal reactivity was recognized in the same neoplastic gland or the same cluster of neoplastic glands in 22 (91.7%) cases, thus suggesting a close relation with islets. Ki-67 did not stain any endocrine cells in ten of the adenocarcinomas studied. In three (10.3%) cases, endocrine cells were found in the intraductal extensions. They may have pre-existed in non-neoplastic ducts. In 17 cases with metastatic sites, all but one had no endocrine cells in the metastases. Serotonin-positive cells were found in one metastatic lymph node in one case. We concluded that most endocrine cells seen in ductal adenocarcinomas of the pancreas are non-neoplastic and are derived from the surrounding islets. Some neoplastic endocrine cells may exist, though their frequency is low.

CD34 is a marker of haematopoietic progenitor cells, stromal precursors, vascular endothelial cells, and a variety of stromal tumour cells. This immunohistochemical study examined the CD34 expression of glomerular mesangial cells in normal and diseased glomeruli and compared it with the staining patterns of alpha-smooth muscle actin (ASMA), as a transformed mesangial cell marker, and CD31, as an endothelial cell marker. In addition, the CD34 and ASMA expression of mesangial cells in various glomerulonephritis and the relationship of the immunostaining intensity to the severity of IgA nephropathy were semiquantitatively evaluated. In normal glomeruli, all cell types were negative for CD34, but in glomeruli in mesangial proliferative glomerulonephritis, CD34 was expressed exclusively in mesangial cells, corresponding to ASMA expression. The dendritic and scattered staining pattern, the mesangial location of positive signals, and the enhanced expression were clearly different from CD31 expression in diseased glomeruli. In comparison with normal controls, the grade of immunostaining for CD34 (CD34 INDEX) in mesangial proliferative glomerular diseases was higher than that of ASMA (ASMA INDEX). With the severity of glomerulonephritis, the CD34 INDEX gradually increased. These studies indicate that CD34 is a useful marker of mesangial transformation and that immunohistochemical examination with the anti-CD34 antibody is useful for the diagnosis and stage determination of glomerular diseases.

We report a case of a 17-year-old man with a spindle cell tumor in the occipital subcutaneous tissue. The enucleated tumor, measuring 2.5 x 2.0 x 1.0 cm, had a broad-bean shape and well circumscribed border and was localized to the subcutis without dermal involvement. Microscopically, the tumor was composed of uniform spindle cells showing interlacing bundle formation and a herringbone pattern. The neoplastic cells were separated by collagen fibers in parallel fashion, the amount of which varied with different areas in the tumor. Mitotic figures were eight mitoses per 50 high-power fields in number. The neoplastic cells were positive for vimentin, Factor-XIIIa, alpha-smooth muscle actin and CD34, but negative for desmin, calponin, high molecular weight caldesmon, smooth muscle myosin heavy chain, collagen type IV, laminin and S-100 protein. These immunohistochemical results indicated that the neoplastic cells showed differentiation toward fibroblasts/myofibroblasts/dendritic interstitial cells. Although more than 50% of the neoplastic cells were positive for CD34, the present tumor should be diagnosed as well differentiated fibrosarcoma, adult type, rather than extrapleural solitary fibrous tumor and fibrosarcomatous areas of dermatofibrosarcoma protuberans, on the basis of routine microscopic findings mentioned above.

An immunohistochemical study of nine cases of chondroid syringomas/mixed tumors of the skin was performed to elucidate the nature of the so-called neoplastic myoepithelial cells (NMEC) in tumor tissues. These nine tumors contained NMEC of considerable variability in number from one tumor to another. These NMEC were classified into three types: (i) hyaline cells (plasmacytoid cells); (ii) spindle NMEC; and (iii) polyhedral cells. They showed different immunostaining patterns, as the following describes. Cytokeratin 14 was positive in most of the spindle NMEC and a large number of the polyhedral cells, and in a small number of the hyaline cells. Concerning low molecular weight cytokeratins, most of the hyaline cells showed immunoreactivity, whereas they were negative in many of the spindle NMEC and were expressed only in a small number of the polyhedral cells. alpha-Smooth muscle actin and muscle-specific actin were positive in the spindle NMEC but negative in any of the hyaline cells and polyhedral cells. These findings strongly indicate that the hyaline cells and the spindle NMEC are of the simple epithelial and myoepithelial types, respectively. The findings also suggest that the polyhedral cells show differentiation toward basal cells of the sweat gland dermal ducts or myoepithelial cells.

To investigate the pathogenesis of congenital hydrocephalus the brains of HTX rats aged between 16 days and 4 weeks and the brains of normal Wistar rats of the same ages were examined. In the fetal HTX rat brains, the lateral ventricles were symmetrically dilated from 20 days of gestation. The neuroepithelium bordering the ventricles showed thinning with cellular disarrangement and deformity. Similar neuroepithelial abnormalities were also found in the lateral ventricles of the HTX rat brain with no macroscopic signs of hydrocephalus at 20 days of gestation. The neuroepithelium showed flattening of the cells, widening of the intercellular spaces, formation of microvilli on the detached lateral cell surfaces, and frequent macrophage infiltration. On the other hand, the neuroepithelial cells of the third ventricle and the aqueduct were affected less severely or showed no significant abnormalities. Immunohistochemically, most of the neuroepithelium and ependyma of the lateral ventricles were positive for vimentin in both prenatal and postnatal hydrocephalic HTX rats, while a small number or none of those in normal control rats were positive. These morphological changes suggested that preferential involvement of the lateral ventricular neuroepithelium might be closely associated with the pathogenesis of congenital hydrocephalus in HTX rats.

肺の大細胞神経内分泌癌の1剖検例を経験したので報告する. 症例は62歳, 男性. 労作時呼吸困難, 胸部痛を主訴に近医受診. 右上肺野に異常陰影を指摘され, 当院紹介となり, 気管支鏡下擦過細胞診が施行された. 壊死を背景に多数の腫瘍細胞が認められ, 孤立散在性のものが多いが, 胞巣状, ロゼット状, インディアンファイル状に配列する像もみられた. 核は卵円形で, 中等大～大型であった. クロマチンは繊細あるいは粗顆粒状で増加しており, 核小体の目立つ細胞も認められた. 大型の腫瘍細胞が混在しているものの小細胞癌 (中間細胞型) が疑われた. 以後, 化学療法を受けたが, 肺炎を合併し, 亡くなり, 病理解剖が施行された. 組織学的に腫瘍はTravisらの提唱する肺の大細胞神経内分泌癌の典型像を呈していた. 本疾患の鑑別診断には小細胞癌や低分化扁平上皮癌, 腺癌, 大細胞癌などが考えられるが, 細胞の詳細な観察に加え, 積極的に特殊染色や免疫組織染色を行い, 総合的に判定することが重要と考えられる.

Our report concerns gastric carcinoid tumors in a man and his younger sister who had no endocrine symptoms. The tumors in both cases were multiple, located in the corpus, and showed no significant differences in light microscopic and immunohistochemical examination. In electron microscopic observation, the endocrine granules of tumor cells were roughly classified into four types: granules with fine granular content with low electron density, irregularly striped granules with medium electron density, concentrically laminated or regularly striped granules, or smaller and almost uniformly high electron-dense granules in which it was difficult to recognize the internal structure. From the sequential morphological changes of the granules, we have considered that each type of granule reflects various stages of granulogenesis, although the possibility that they are distinct and contain different hormones or chemical mediators is not absolutely ruled out.

To elucidate sinusoidal cell structure and function under normal conditions and their behavior in diseased settings, an understanding of their developmental aspects is needed. At day 10 of gestation in mice and rats or at 5 weeks of gestation in humans, the hepatic cords grow into the mesenchymal tissue of the septum transversum, and the primitive sinusoidlike structure is simultaneously observed between the liver cell cords. In the margin of the growing liver primordium, mesenchymal cells in the septum transversum are trapped in the subendothelial space. These subendothelial cells are at the early stages of organogenesis and become progenitors of the Ito cells. By days 12-14 of gestation in mice and rats or 8 weeks of gestation in humans, the basic structure of the sinusoids has developed. Embryonic hepatic sinusoids are usually lined by a continuous endothelium without basement membranes, and an incompletely fenestrated sinusoid appears at the middle gestational stage. In the late gestational stages, the Ito cells exhibit myofibroblastlike features in humans, mice, and rats. In association with this event, perisinusoidal reticular networks are gradually intensified. After birth until days 4-5 in mice and rats, the sinusoidal and perisinusoidal structures are almost completely formed, although slight morphological differences from those in adult livers still exist. What happens to sinusoidal endothelial cells and Ito cells in hepatic fibrosis-cirrhosis of the adult may be a deviated or uncontrolled occurrence of what goes on during the fetal period, i.e., a continuous nonfenestrated sinusoidal lining in the early embryonic stage and a myofibroblastlike transformation of Ito cells in late fetal life.

We report one rare case of superficial angiomyxoma of the right inguinal region, in a 67-year-old man. The tumor, measuring 4.5 x 4.0 x 3.0 cm, had a finger-like shape, was composed of a well circumscribed conglomerate of multiple myxomatous nodules and was located partially in the dermis and partially in the subcutaneous tissue. Microscopically, in contrast to previously reported cases, the tumor was composed mainly of oval plump stromal cells with an amphophilic cytoplasm. Spindle-shaped stromal cells were scattered throughout the tumor. The tumor border was not infiltrative and was well defined by thick hyalized collagen bundles. Neither hyperchromasia nor pleomorphism was apparent. No mitotic figures were detected in the specimens prepared. Small to medium-sized blood vessels showed a scattered distribution, but large vessels, seen frequently in aggressive angiomyxoma, were absent. Moreover, no plexiform capillary pattern was evident. These findings were diagnostic of superficial angiomyxoma. Although this disease entity is considered as including cutaneous focal mucinosis, follicular fibroma, trichofolliculoma and trichogenic adnexal tumor, we propose that these tumors should be excluded.

腎臓の複雑な器官形成機序の解明に，従来の形態学的観察に加え，免疫組織化学的観察法や分子生物学的技法が導入され，機能蛋白や産生細胞の同定や局在，およびその蛋白やmRNAの発現の調節機序など新しい知見が数多く得られてい る。本稿では腎臓の発生・分化に関する最近の免疫組織学的および分子生物学的研究のうち，特に細胞内骨格，細胞外マトリックス，接着分子，サイトカインに関するものを自験例を含め，文献的に整理した。その結果，腎臓の正常発生における細胞内骨格，細胞外マトリックス，接着分子とそれぞれの調節にあずかるサイトカインの役割，機能的意義や相互関係の重要性があきらかになり，さらに各種腎疾患の病態の解明にも，腎臓の発生のメカニズムが重要な手がかりとなることが期待される。

松果体細胞腫は非常にまれな腫瘍である.われわれは最近その1例を経験し, 細胞・病理組織所見に加え細胞増殖能についても検討したので報告する.症例は40歳, 男性.平成4年9月頃より閉塞性水頭症出現.CT, MRIでは松果体部に径2.5cm大の腫瘍を認め, 12月腫瘍摘出術施行.捺印細胞診では多数の腫瘍細胞がシート状, 集籏性に認められた.細胞は小型で均一, 胞体はやや乏しく薄く細胞境界は比較的明瞭.核は類円形～ 卵円形でクロマチンは微細顆粒状.小型の核小体を認めるものもある.細胞集塊の中にロゼット様構造もみられた.組織学的には類円形核と弱好酸性胞体をもつ腫瘍細胞が充実性胞巣状に増殖しており, 一部ではpineocytomatous rosetteが認められた.免疫組織学的にはSynaptophysinが細胞質に顆粒状に陽性.一部の細胞質や細胞突起内でNeurofilament, GFAP, S-100蛋白が陽性.電顕的には細胞内小器官の乏しい未熟な細胞から小器官が比較的よく発達しannulate lamellaeの目立つ細胞もみられた.一部ではシナプス様構造も認められた.BrdU標識率は約3%, PCNA陽性細胞は約5%であり, 本例では細胞増殖能は通常の低悪性脳腫瘍ほど低くはないものと考えられた.

甲状腺髄様癌は比較的まれな腫瘍である. われわれは好酸性大型細胞からなり組織像が褐色細胞腫と類似した1例を経験したので, その細胞病理学所見を中心に免疫組織学的および電顕的所見と細胞増殖能について報告する. 症例は65歳, 女性. CEA, カルシトニン高値を指摘され精査加療のため来院. 甲状腺左葉に被膜形成のない境界明瞭な1.5×1.3cm大の腫瘍を認めた. 捺印細胞では, 顆粒状の豊富な胞体をもつ腫瘍細胞が多数散在性に, 一部集籏性に認められた. 細胞, 核ともに大小不同が著明であった. 組織学的には, 豊富な好酸性胞体をもつ多形性の大型細胞が充実性密に, あるいは索状, 胞巣状に増殖, 核分裂像が散見された. グリメリウス染色では胞体内に多数の好銀顆粒がみられた. 免疫組織学的にはカルシトニン, CEA, NSE, ケラチン陽性. 電顕的には, 細胞内小器官はよく発達し, ミトコンドリアが豊富であった. 200～500nm大の類円形の分泌顆粒を多数認めた. PCNA陽性細胞は約50%であり甲状腺未分化癌と高分化型の乳頭癌や濾胞癌の中間であった. 褐色細胞腫に類似した甲状腺髄様癌であったが, その鑑別にはカルシトニンの免疫染色が有用と考えられた.

The juxtaglomerular cell tumor (JGCT) of the kidney is a rare neoplasm which commonly secretes renin. This tumor often occurs in teenagers. This paper documents the 14th adult-onset (over 30-years-old) case with a giant JGCT which measured 9.0 x 8.0 x 7.5 cm. Histologically, this tumor was composed of both vascular and tubular components. Immunohistochemically, the vascular component reacted with renin, cytokeratin 7, ulex europaeus agglutinin-1, vascular endothelial growth factor (VEGF) and Flk-1 (VEGF-R2), whereas the tubular component was positive for renin, epithelial membrane antigen (EMA), cytokeratin 7, alpha-1-antitrypsin, VEGF and Flk-1. This finding suggests that both vascular and tubular components of JGCT may promote neoplastic proliferation via an autocrine mechanism through the action of VEGF.

Signet-ring cell carcinoma (SRCC) of the prostate is a very rare neoplasm and there have been only 38 cases reported to date. Here the 39th case of prostatic SRCC containing a small amount of neutral mucin, prostatic specific antigen (PSA) and prostatic specific acid phosphatase (PSAP) in the signet-ring cells is reported. It was also found that some intracytoplasmic lumina were derived from the shallow or deep invagination of luminal membranes of cancer cells that formed the neoplastic glands. Using immunohistochemistry, a combination of monoclonal antibodies against cytokeratins 7 and 20 as well as PSA and PSAP may be useful in differentiating prostatic primary SRCC from metastatic SRCC originating in the gastrointestinal tract.

Ito cells play a major role in various types of liver fibrosis in humans and experimental animals through initial myofibroblastic transformation. In granulation tissue following liver cell necrosis, the transformed Ito cells are large and star-shaped, and are easily identified by strong immunoreactivity for α-smooth muscle actin (ASMA), and characteristic electron-microscopic findings such as a well-developed rough endoplasmic reticulum, a large Golgi complex, bundles of numerous microfilaments with dense bodies beneath the cell membrane, and irregular cytoplasmic processes. These cells are closely associated with activated Kupffer cells, macrophages, lymphocytes, and neutrophils. In the fully developed stage they actively synthesize and secrete components of the extracellular matrix, resulting in the formation of the loose young fibrous tissue. With the progression of fibrosis, the transformed Ito cells become spindle-shaped and are arranged in parallel with dense collagen fibers. They lose both the well-developed rough endoplasmic reticulum and the large Golgi complex, but there is a more significant increase in subplasmalemmal microfilaments. This type of transformed cell, positive for ASMA, may not participate in the production of extracellular matrix components, but does participate in the contraction of old fibrotic tissue. On the other hand, portal fibroblasts show no significant changes in any type of fibrosis. The myofibroblastic transformation of Ito cells is seen not only in fibrosis, but also in the late stage of fetal liver development, when the perisinusoidal reticular fibers are more abundant than in normal adult livers. These findings suggest that the myofibroblastic transformation of Ito cells, the most important event in fibrosis, is a recapitulation of a normal developmental process.

BACKGROUND In order to elucidate the significance of myofibroblasts in invasive growth of colorectal adenocarcinomas, we examined the number of myofibroblasts at the tumor border of colorectal adenocarcinomas. METHOD A total of 91 invasive colorectal adenocarcinomas were examined immunohistochemically using anti-alpha-smooth muscle actin (ASMA) and high-molecular-weight caldesmon (h-CD) antibodies; 25 carcinomas confined to the submucosa (sm carcinomas), 40 carcinomas confined to the muscularis propria (mp carcinomas) and 26 carcinomas invading the subserosa or adventitia (ss carcinomas). We considered ASMA-positive and h-CD-negative stromal cells as myofibroblasts. RESULTS Twenty-seven (67%) of the 40 mp carcinomas and 25 (96%) of the 26 ss carcinomas had a small number of myofibroblasts at the tumor border facing the muscularis propria. CONCLUSIONS Although direct evidence is lacking, there is a possibility that the further immediately vertical and radial invasion of carcinoma cells into the subserosa or adventitia is associated with a smaller number of myofibroblasts at the tumor border facing the muscularis propria in mp carcinomas, resulting in a low incidence of mp and a high incidence of ss carcinomas in the colorectum.