Yoko Iwasa

High incidence of allelic loss on chromosome 5 and inactivation of p15^{INK4B} and p16^{INK4A} tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules, a consequence of Fenton-like reaction, that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. In order to find common genetic alterations in this oxystress-induced carcinogenesis model, RCCs were produced in F1 hybrid rats between Wistar and Long-Evans strains and genomes were screened for loss of heterozygosity (LOH) with microsatellite polymorphic markers by PCR. Five consecutive markers on chromosome 5 (D5Mgh5, D5Mit9, D5Mgh6, D5Mit11 and D5Mit6) showed LOH in ≥40% of the RCCs. As possible candidate tumor suppressor genes on chromosome 5, p15INK4B and p16INK4A were investigated for genetic alteration and aberrant methylation by Southern blot, PCR/SSCP/sequencing and methylation-specific PCR. Genetic alteration (homozygous or hemizygous deletion with or without point mutation) or aberrant methylation were found in 30.7 and 53.8% of the RCC cases, respectively, which was proportionally associated with the histological nuclear grade and metastatic activity. Our data suggest that inactivation of p15 and p16 genes could be one of the major pathways responsible for oxystress-induced carcinogenesis.

Expression of stress-response and cell proliferation genes in renal cell carcinoma induced by oxidative stress.

Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. In search of genes specifically involved in oxystress-induced carcinogenesis, we have applied a modified fluorescent differential display technique to the tumors and an established cell line as well as their non-neoplastic counterparts. We screened approximately 84,000 products. Reverse Northern blotting confirmed differential expression of 20 transcripts, which showed either significant increase, decrease or lack of expression in the RCCs. Five cDNA clones encoded novel products of unknown function. Fifteen cDNA clones were identified by homology search, which included annexin II, Y-box binding protein, ribosomal proteins, heat shock proteins, DNA polymerase, nonmuscle caldesmon (increased); protein tyrosine phosphatase (decreased); selenoprotein P, stromal cell-derived factor 1, intestinal trefoil protein, nicotinamide adenine dinucleotide, reduced form (NADH) dehydrogenase, and insulin-like growth factor binding protein 7 (deleted). Most of the identified genes were associated with stress-response or cellular proliferation. These results suggest that multiple, interactive genetic pathways are involved in carcinogenesis induced by oxidative stress.

Primary hepatic carcinoid tumor with metachronous lymph node metastasis after long-term follow up.

A case of hepatic carcinoid tumor occurring in a 71‐year‐old man is reported. The tumor was diagnosed initially as a hepatocellular carcinoma, and was then shown after resection histologically to be a carcinoid tumor. The tumor cells formed small nests and trabeculae separated by fibrous septa and were positive for Grimelius staining. Immunohistochemically, most of the tumor cells stained positive with chromogranin A and neuron‐specific enolase. After a follow up for 5 years and 7 months, the patient developed tumors in lymph nodes between the remnant liver and the lesser curvature of the stomach with no tumors in other organs. Histologically, the tumor cells in the lymph nodes demonstrated a pattern of the immunostainings consistent with carcinoid tumor. After lymphadenectomy, the patient is free from recurrence in the regional lymph nodes for more than 1 year. This case is con‐sidered to be a primary hepatic carcinoid tumor with metachronous lymph node metastasis.

Rabies virus dissemination in neural tissues of autopsy cases due to rabies imported into Japan from the Philippines: immunohistochemistry.

Two Japanese men, 65 and 69 years old, developed rabies in Japan around 2–3 months after dog‐bite exposure in the Philippines. Laboratory diagnosis of rabies was made following the detection of rabies virus genome on reverse transcription–polymerase chain reaction from saliva, and on immunohistochemistry of a nuchal skin punch biopsy in one case. The patients died 9 and 19 days after clinical onset. At autopsy, no macroscopic changes in the CNS were observed. Histopathology indicated that eosinophilic and cytoplasmic inclusion bodies, Negri bodies, were seen in neuronal cells of the CNS. Inflammatory cell reactions were scarce, and no apoptosis in the CNS was detected. Immunohistochemistry demonstrated that rabies virus nucleoprotein (N) and phosphoprotein (P) were disseminated to all neural tissues and cells in the body with a similar pattern in both cases. Interestingly, there were no differences of localization between N and P antigen in the brain, but the N antigen was located at the peripheral nerve sheaths and the P antigen was localized in axons. These data indicate that rabies virus dissemination in all neural tissues causes disease development and death. Immunohistochemistry for rabies is a powerful tool to understand the pathogenesis of rabies.

MR imaging of müllerian mucinous borderline tumors arising from endometriotic cysts.

This report describes MR findings of müllerian mucinous borderline tumors, pathologically proven to have arisen from endometriotic cysts, in three patients. They were unilocular or paucilocular masses with mural nodules. Cystic components showed hyperintensity on both T1- and T2-weighted images, simulating clear cell or endometrioid carcinomas arising from endometriotic cysts. Mural nodules showed prominent high signal intensity on T2-weighted images. Correlation with pathologic findings suggests that this hyperintensity reflects intraluminal mucinous material and stromal edema.

Sclerosing peritonitis associated with luteinized thecoma of the ovary

A unique case of bilateral Iuteinized the comas of the ovary associated with sclerosing peritonitis is reported and the clinical and pathological features of this and previously reported cases are reviewed. The patient, 52 years of age, presented with abdominal distension and diarrhea. Pelvic imaging studies revealed bilateral ovarian tumors with ascltes. Total abdominal hysterectomy and bilateral salpingo‐oophorectomy with adhesiotomy of the small bowel were performed. Histologically, the ovarian tumor was composed of closely packed spindle to round‐shaped cells, and within the spindle cell population, lutein‐like cells were scattered singly or in clusters. Mitotic counts of spindle cells revealed 12 mitotic figures (MF) per 10 high‐power fields (HPF) in one part of the left ovarian tumor, but other areas of the tumor showed less than 3 MF/10 HPF on average. The lesion from the resected small bowel showed prominent fibrosis confined to the serosa with no evidence of metastasis from the ovarian tumor. The patient has undergone adhesiotomy with parttal resection of the small bowel seven times since the first laparotomy because of the recurrent small bowel obstruction. The patient has survived with complications due to short bowel syndrome for 7 years after the initial surgery and so far no recurrence or metastasis of the ovarian tumor has been Identified. The case reported here also supports the idea that lutefnlzed thecoma of the ovary associated with sclerosing peritonitis may be a distinct clinicopathologic entity, in terms of the unique association and of the unique features of thecoma; that is, bilateral, hormonally inactive and apparently benign in spite of its highly mitotic activity. Additional attention should be paid to the patients quality of life, which is often degraded by peritoneal flbrosis and small bowel obstruction.

Sacral chordoma in early childhood: clinicopathological and immunohistochemical study.

ABSTRACT Two cases of sacral chordoma in a 7-year, 9-month-old boy and a 3-year, 4-month-old boy are presented. In addition to the typical histology of conventional chordoma, both tumors showed the less differentiated sarcomatoid appearance of atypical chordoma in the major portion. Immunohistochemically, in both cases neoplastic cells in areas of conventional as well as atypical chordoma were positive for keratins (CAM 5.2, AE1 and AE3), epithelial membrane antigen, vimentin, S-100 protein, carcinoembryonic antigen, and glial fibrillary acidic protein. Both patients underwent resection of the tumor and chemotherapy. In comparison with conventional chordomas in adults, however, these two tumors showed more aggressive clinical course and were less amenable to therapeutic control. The older boy died of multiple metastasis 1 year after initial diagnosis. At the last follow-up, 15 months after initial diagnosis, the younger boy was alive, but with recurrent and metastatic disease of the left parasacral area and chest wall. Our studies of these two cases and the reported cases suggest that sacral chordoma in children has distinctive clinicopathologic features denoting a highly aggressive tumor and that it should be treated as such.

Salivary duct carcinoma: A clinicopathologic study of three cases with a review of the literature

Three cases of salivary duct carcinoma are presented. They occurred in a 60 year old man, a 66 year old man and a 57 year old woman. All of the lesions were located In the parotid gland. The tumor size ranged from 3 to 5 cm across the largest diameter. Facial paralysis was observed in two cases. Histologically, intreductal and invasive adenocarcinoma showing papillary, cribriform, and solid patterns with comede like necrosis was observed. lmmunohistochemically, the tumor cells were positive for keratin and epithelial membrane antigen. No myoepithelial cells were demonstrated within the tumor by staining for S‐100 protein, α‐smooth muscle actin or muscle specific actin. Ultrastncturally, intracytoplasmic lumina with microvilli, a moderate number of mltochrondria, lysosomes, and tight junctions were found. Regional lymph node metastasis was observed in one case, and distant metastasis developed in two cases. All of me patients were treated with adjuvant postoperative irradiation. One patient died of disease at 11 months after the initial diagnosis, another was alive with disease at 8 months, and the third patient was alive without disease at 2 years and 3 months. Salivary duct carcinoma should be ditterentiated from low‐grade salivary gland carcinomas using morphologic and clinical criteria because of its poor prognosis even with aggressive therapy.

Fine‐needle aspiration cytology of malignant hemangiopericytoma of the salivary gland: A case report

A 79‐yr‐old woman presented with a 5‐yr history of swelling of the left cheek. The fine‐needle aspiration (FNA) smear showed a spindle‐cell neoplasm with capillaries and benign endothelial cells. The spindle cells possessed pleomorphic, hyperchromatic elongated nuclei and a moderate amount of ill‐defined cytoplasm. They also showed papillary arcades surrounded and encased by relatively small ovoid to short spindle cells. Subsequent surgical excision confirmed the presence of malignant hemangiopericytoma (HP). Immunohistochemical studies on the histologic section using vimentin were strongly positive, consistent with HP. To the best of our knowledge, this is the second published report of FNA cellular features of malignant HP of the salivary gland. Besides delineating the FNA cellular features of HP of the salivary gland, the present case illustrates the value of using immunohistochemical approaches. Diagn. Cytopathol. 1999;21:398–401.

Cytology of three cases of salivary duct carcinoma

背景:唾液導管癌 (Salivary duct carcinoma) は比較的まれな高悪性唾液腺腫瘍である. 耳下腺に発生した唾液導管癌3例の穿刺吸引細胞像を報告する.症例:症例1;49歳, 男性.左耳下腺腫瘍. 穿刺吸引細胞像では, 壊死物質とともに結合性が強く節状構造を示す上皮性大細胞集団を認めた. 細胞は多辺形から円柱形の豊富で厚い細胞質を有し, まれにintracytoplasmiclumina (ICL) を認めた. 核は遍在傾向を示し円形から楕円形で細顆粒状のクロマチンを有し, 腫大した核小体を認めた. 症例2;76歳, 男性. 左耳下腺腫瘍. 細胞像では壊死物質を背景に結合性が低下した充実性の上皮性細胞集団を認めた. 細胞の細胞質は厚く, 核細胞質比は高く, 核の配列不整や核小体の腫大が目立った. 症例3;66歳, 男性. 右耳下腺腫瘍. 細胞像ではきれいな背景中に結合性の低下した上皮性集塊が少量認められた. 腫瘍細胞は多辺形で顆粒状の細胞質を有し, 変性のため核が濃縮状で核細胞質比が低かった.結論:唾液導管癌の細胞診断では, 典型的な細胞像とともに症例間の細胞像の差異や壊死による細胞像の変化も念頭におくことが重要と考えられた.