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Murine choroid plexus cell lines were produced from choroid plexus carcinoma generated in transgenic mice harboring the viral oncogene simian virus 40 large tumor antigen under transcriptional control of an intronic enhancer region from the human immunoglobulin heavy chain (IgH) gene. Two morphologically distinct cell lines have been cloned. These established cell lines retained the characteristics of choroid plexus cells in that they expressed such choroid plexus cell marker or related proteins as transthyretin and alpha2-macroglobulin. They were tumorigenic in nude mice. In the cell lines, the muA and muB (HE2) motifs within the IgH intronic enhancer were active and we also demonstrated the existence of the proteins binding to these motifs, suggesting a potential link between the choroid plexus and immune systems. It is considered that these binding proteins act as trans-activators for the enhancer and may belong to the class of ETS-related proteins. These cell lines and xenografts should be useful materials for analyses of choroid plexus functions.

Sarcomatous transformation is found in approximately 5% of patients with intrahepatic cholangiocarcinoma. According to previous reports, sarcomatous cholangiocarcinomas are composed of spindle-shaped cells and/or multinucleated giant cells. Usually, vimentin is expressed by these sarcomatoid cells. We report a case of intrahepatic cholangiocarcinoma with an element of rhabdoid cells that occurred in a 61-year-old woman admitted for back pain. Various imaging techniques demonstrated multiple liver masses. Histologically, these tumours formed in both sarcomatous and ordinary tubular adenocarcinomatous areas. The sarcomatoid areas were occupied mainly by loosely arranged, eosinophilic rhabdoid cells, which expressed both keratin and vimentin. These findings suggest that rhabdoid cells may occur in an undifferentiated stage of cholangiocarcinoma and possess a strong tendency to metastasize.

We report here the establishment and characterization of a human melanoma cell line derived from the ascitic fluid of a patient with metastatic malignant melanoma with peritonitis carcinomatosa. This cell line was easily transplanted into nude mice. Flow cytometry and immunocytochemical analyses demonstrated that the cells expressed melanotransferrin and S-100 protein. Expression of cell adhesion and HLA molecules on the cells was also investigated. The results indicate that the cell line possesses some metastatic characteristics.

Immunoglobulin heavy-chain (IgH) gene expression is regulated largely by the IgH gene intronic enhancer (ENHiH), which is composed of multiple protein-binding motifs. These motifs are DNA elements that are important for the regulation of IgH gene transcription. It has been reported that the HE2 (mu B) and mu A motifs within the ENHiH affect B cell-specific gene expression. To examine the function of the HE2 and mu A elements in vivo, we established transgenic mouse lines. A deletion mutant of the human ENHiH that contains the HE2 and mu A motifs, but lacks the motifs corresponding to murine E5, E3, and octamer, functioned not only in B lymphocytes but also in choroid plexus cells, which secrete CSF. As a result, we obtained choroid plexus tumor-bearing transgenic mice and could establish choroid plexus carcinoma cell lines. In addition, using the luciferase assay, we confirmed at the cellular level that the HE2 motif shows a fair degree of enhancer activity in cultured choroid plexus carcinoma cells. These results suggest the existence of a trans-acting factor for the HE2 motif in choroid plexus cells. Actually, in this cultured cell line, the existence of a protein binding to the HE2 motif was demonstrated by a gel retardation assay. Due to the sequence homology between the HE2 motif and the Ets-binding sites, an Ets-related protein is a highly probable candidate for being the binding factor.

In the murine IgH gene intronic enhancer (ENHiH), two major functional domains were reported. One is the E4/octomer region and another includes the microA and microB motifs. In the human ENHiH, it was reported that the HE2, which corresponds to the murine microB, and E6 motifs play an important role in an enhancer activity and a tissue-specificity at cellular level. Here we examined the in vivo function of the E6, microA and HE2 motifs within the human ENHiH by using the transgenic mice technique. The microA and HE2 motifs together revealed almost the same enhancer function as the whole human ENHiH, but the E6 motif had lesser enhancer activity and tissue-specificity.

Background: A broad papillary proliferation resembling that in transitional cell carcinoma (TCC) of the urinary bladder was seen in 12 of 21 primary carcinomas of the Fallopian tube (PCFT)., Methods: According to their predominant histologic pattern (more than 50%), PCFT were classified into 9 TCC-predominant and 12 non-TCC-predominant tumors. The two groups were compared by clinicopathologic, histochemical, and immunohistochemical means., Results: TCC-predominant tumors were grossly solid and microscopically demonstrated more frequent tumor necrosis and spindled tumor cells than non-TCC-predominant tumors. Mucin histochemistry revealed a correlation between TCC-predominant tumor and sulfomucin-predominant secretion and between non-TCC-predominant tumor and sialomucin-predominant secretion. Immunohistochemical studies for cytokeratins, vimentin, epithelial membrane antigen (EMA), Leu-M1, carcinoembryonic antigen (CEA), and CA 125 were not useful for discrimination between the two groups. Both groups showed similar features in patient age, clinical stage, cytology of ascites or peritoneal washing, and serum CA 125 level. Despite the similarity in treatment (surgery and postoperative chemotherapy) between the two groups, TCC-predominant tumors tended to relapse later (mean, 31.2 months after diagnosis) than non-TCC-predominant tumors (mean, 14.4 months after diagnosis), resulting in a significant difference in the 2-year disease-free survival rate., Conclusions: TCC pattern and non-TCC pattern are considered to be worthy of distinction in PCFT.

Background: Malignant fibrous histiocytoma (MFH) of bone is a rare bone tumor, and its prognosis has been controversial., Methods: Thirty-four patients with MFH of bone were examined clinicopathologically for prognostic factors., Results: The most common skeletal site of the tumor was the femur (15 cases), followed by the pelvic bones (6 cases), tibia (5 cases), and fibula (5 cases). Of 29 patients available for follow-up, the 5-year survival rate of 17 who underwent adequate surgical treatment was 63%. The 5-year survival rate of the remaining 12 patients, including 5 with MFH of the pelvic bone who received inadequate or palliative surgery, was 17%. All six patients who received intensive chemotherapy combined with adequate surgical treatment were alive and well 5 years after the initial treatment. Histologically, the presence of desmoplasia and chronic inflammatory infiltration in the tumor tended to be prognostic indicators, although not to a statistically significant extent. Patients whose tumors contained wide areas of desmoplasia had a worse prognosis (5-year survival rate, 20%). In contrast, those with a prominent chronic inflammatory infiltrate had a 5-year survival rate of 78%., Conclusions: These histologic variables would be helpful for predicting the prognosis of MFH of bone. Adjuvant intensive chemotherapy combined with adequate initial surgery may effect a clinical cure.

Background: Gastric carcinoma is clinicopathologically divided into differentiated and undifferentiated types. The former is grossly protuberant and often causes hematogenous metastasis to the liver or lung, whereas the latter is mostly depressed or ulcerated from its early stage and rarely causes blood-borne metastasis. The purpose of this study is to clarify the microvascular architecture of early gastric carcinoma with reference to the histologic subtypes., Methods: A silicone rubber compound (Microfil) injection method with a methyl salicylate clearing technique was used in 32 resected early gastric carcinomas. The microvascular architecture was observed both in the carcinoma and its surrounding noncancerous tissue in each specimen under a stereomicroscope and light microscope., Results: Compared to the surrounding normal mucosa, the differentiated carcinomas (DC) mostly were hypervascular (24%) or normovascular (65%), whereas the undifferentiated carcinomas (UC) often were hypovascular (60%). Irregularity of tumor vessels (67%) and an arcade-like appearance (33%) was encountered frequently in UC, whereas hypervascularity of the surrounding noncancerous mucosa (29%) often was noticed in DC. Quantitative analysis, including vascular volume, mean vascular diameter, and cut section area, supported these differences between DC and UC., Conclusions: The results suggest that vascular structures of gastric carcinomas are characteristic with regard to their histologic subtypes; DC is normovascular or hypervascular, whereas UC is hypovascular.

A 62-year-old woman with a large mass in the hepatic hilus underwent surgery. Histologically the tumor was predominantly composed of spindle-shaped cells with nuclear palisading and cells that stained positively for S-100 protein. The diagnosis was benign schwannoma (neurilemoma). The presence of lymphoid cuffing with lymphoid follicles in the capsule and xanthomatous change differed from conventional soft parts schwannoma and closely resembled benign schwannoma in the gastrointestinal tract.

A rare case of a 71-year-old man with malignant oncocytoma is presented. The tumour was found in the left parotid region with enlarged lymph nodes in the neck. The resected parotid mass consisted of three discrete nodules, each histologically characterized by a uniform proliferation of oncocytic tumour cells. The patient underwent repeated operations for recurrences and metastases, and eventually died of acute pneumonia 18 months after the first admission. Metastases to the lymph nodes, ribs, spine and liver had been clinically pointed out. Immunohistochemically, the tumour cells were positive for alpha-1-antitrypsin, alpha-1-antichymotrypsin, lactoferrin, secretory component and carcinoembryonic antigen (CEA), while they were negative for S-100 protein and HHF35 (muscle specific actin). Ultrastructural pictures disclosed numerous mitochondria in the cytoplasm of the tumour cells, revealing neither myofibrils nor secretory granules. These findings therefore support the concept that this tumour is of a glandular epithelial origin.

Background and Methods: A univariate and multivariate analysis for the correlation between histomorphologic factors and prognosis was made using data from 1116 patients with soft tissue sarcoma, including 1005 cases available with complete histologic and follow-up data., Results: The overall 5-year survival rate was 43.6%. The univariate analysis using Kaplan-Meier survival curves showed that tumor differentiation, cellularity, nuclear atypia, cellular pleomorphism, mitotic activity, amount of fibrous stroma, extent of myxoid areas, extent of tumor necrosis, and histologic grading (determined by the estimated range of malignancy for each type of sarcoma using a reported guideline) were all significant prognostic factors in the overall soft tissue sarcoma group. By a multivariate analysis using a procedure based on the Weibull model to failure data, the histologic grading and extent of tumor necrosis were proved to be prognostically significant in the overall sarcoma group. However, after additional analysis on each histologic type of sarcoma, it was determined that both tumor necrosis and histologic grading were applicable in only two types: malignant fibrous histiocytoma and leiomyosarcoma. Liposarcoma, synovial sarcoma, and malignant schwannoma each also showed some determinable factor of prognostic significance., Conclusions: It was concluded that there seemed to be no single universal prognostic parameter that could be applied to each soft tissue sarcoma type. These results suggest that the predictive significance of the various histologic parameters should be based on each specific type of sarcoma.

Background: Despite perpetual efforts of investigators, the histogenesis of retinoblastoma is still in dispute and histologic classification satisfactorily predictive of prognosis does not seem to be in use., Methods: The authors studied 88 cases of retinoblastoma clinicopathologically and immunohistochemically, paying special attention to the presence of a "bipolar-like cell" element that would be used as one of the criteria for the diagnosis of differentiated retinoblastoma., Results: Twelve cases of retinoblastoma with the bipolar-like cell element in the absence of rosettes and 41 cases of the tumor with rosettes were classified as differentiated retinoblastomas. The other 35 cases without rosettes or bipolar-like cells were classified as undifferentiated tumors. Tumor cells forming rosettes usually had positive results for synaptophysin and neuron-specific enolase (NSE) and negative results for glial fibrillary acidic protein (GFAP) and S-100 protein; however, undifferentiated cells had negative results for these four antibodies. The bipolar-like cells had positive results for synaptophysin and NSE but negative results for GFAP and S-100 protein. Twelve tumors with bipolar-like cells that lacked rosettes showed no optic nerve invasion, and the patients had a significantly better prognosis (100% 5-year survival rate) than 35 patients with undifferentiated tumors (71% 5-year survival rate) (P < 0.01)., Conclusions: The findings support a neuronal origin of the tumor and indicate that, not only the rosettes symbolizing the photoreceptor differentiation, but also other neuronal elements, such as bipolar-like cells, can be used as criteria for histologic classification of retinoblastoma.

As has been indicated, signet-ring cell carcinoma often shows a three-layered pattern of mucus-containing cells in the mucosa, reproducing an organized differentiation in the normal mucosa. In 110 lesions of early stage signet-ring cell carcinoma of the stomach, the proportion between the area with the three-layered pattern and the non-layered area without such layered pattern was measured using a computer image analyzer. As the result, a positive correlation could be demonstrated between the extent of the non-layered area and the tumor size expressed in the largest diameter (r = 0.2777, P < 0.01). The incidence of submucosal invasion significantly increased when the non-layered area exceeded 50% of the total area of signet-ring cell carcinoma. The sites of submucosal invasion were almost always limited to within the non-layered area bearing another positive correlation between the area of submucosal invasion and that of non-layered intramucosal pattern (r = 0.4427, P < 0.01). Thus, it is indicated that the incidence of submucosal invasion in early signet-ring cell carcinoma was significantly related to a dissolution of the three-layered pattern of carcinoma within the mucosa. In addition, the presence or absence of fibrous and lymphoid stromal reactions to the carcinoma was evaluated in relation to the incidence of submucosal invasion.

Background: Despite recent advances in diagnosis and treatment, gastric carcinoma remains a major cause of death in the world., Methods: The clinicopathologic profile of 10,000 consecutive patients who underwent primary gastrectomy during 1962-1989 were reviewed and prognostic factors influencing survival in those with gastric carcinoma were analyzed in 7031 patients., Results: Incidence of gastrectomy for carcinoma has increased steadily and the rate of early carcinoma exceeded that of advanced carcinoma in the recent period of 1985-1989. Five-year and 10-year survival rates were 46.1% and 35.2% in 3868 patients with advanced carcinoma, and 88.8% and 77.3% in 3163 patients with early carcinoma, respectively. In patients with advanced carcinoma, significantly poorer survival rates were noticed for patients older than 70 years of age, those who underwent total gastrectomy, tumors involving the entire stomach or greater than 10 cm in diameter, a macroscopic diffusely infiltrative pattern, adenosquamous histologic type, positive surgical resection margins, or lymph node metastasis. None of the above poor prognostic features were identified in patients with early gastric carcinoma group except for those older than 70 years of age. Although lymph node metastases were present in 10% of early gastric carcinomas, this feature did not impart a poor prognosis. Patients with advanced carcinoma grossly resembling an early carcinoma had an intermediate prognosis, suggesting the existence of a developmentally midstage lesion between early and advanced carcinoma., Conclusions: The study illustrates that the most important role for clinicians treating with gastric carcinoma should be early detection and aggressive surgery for resectable tumors, followed by detailed pathologic examination.

To elucidate the precise origin and characteristics of the proliferating cells in malignant fibrous histiocytoma (MFH), the authors analyzed 33 MFH tumors, using immunohistochemical techniques with a panel of 12 antibodies. All three types of MFH cells (spindle cells, polygonal cells, and bizarre giant cells) stained positively for mesenchymal antigens (FU3 and vimentin) but did not stain for macrophage/histiocyte markers (HAM 56 and CD68). Therefore, the MFH cells may not represent true histiocytes, although they may be mesenchymal-derived cells behaving as "facultative histiocytes" with superficial resemblance to actual histiocytes. Normal histiocytes in the stroma tested positive for macrophage/histiocyte antigens; the most common cells were HAM 56-positive cells constituting 30-80% of nonneoplastic stromal cells, followed by those positive for CD68 (10-50%), Mac 387 (less than 2%), and S-100 protein (less than 1%). Our results indicate the presence of heterogeneity of "histiocytic" cells in MFH. Proliferating-cell nuclear antigen (PCNA) was expressed not only in the spindle and polygonal MFH cells but also in the bizarre giant cells. These findings suggest that all three types of MFH cells participate in the proliferative compartment of MFH. Uneven PCNA staining of the irregular nuclear segments of the bizarre giant cells may result in abnormal DNA synthesis, possibly contributing to the marked diversity of nuclear morphology in MFH. Touton-type and osteoclast-like giant cells did not stain for PCNA but stained positively for histiocytic markers. Therefore, these giant cells may lack proliferative activity and probably result from normal histiocytes fusing together.

A mapping study of cystectomy specimens in three cases of pure squamous cell carcinoma and 28 cases with transitional cell carcinoma with squamous differentiation is described, with an emphasis on the histogenesis of pure squamous cell carcinoma. Two of the three cases of pure squamous cell carcinoma had extensive benign keratinizing mucosa and an atypical squamous metaplastic mucosa contiguous with the tumour. These pure squamous cell carcinomas seemed to be derived from the squamous metaplasia. On the other hand, in all except one of the cases of transitional cell carcinoma with squamous differentiation, there was neither benign keratinizing nor atypical squamous metaplastic mucosa in the bladder. The quantitative amounts of both the transitional cell and squamous components differed from case to case in 28 cases with transitional cell carcinoma with squamous differentiation. Five of the 28 had a tumour composed predominantly of a squamous component with minute transitional cell components at the margin. In another two cases, transitional carcinoma in situ or satellite tumours of transitional cells were present adjacent to the main tumour which was composed of squamous cell carcinoma alone. We think these seven tumours originated as a result of extensive squamous differentiation in the transitional cell carcinomas. These features may indicate two forms of histogenesis of pure squamous cell carcinoma. The first is malignant transformation on the basis of squamous metaplasia of the bladder mucosa and the second is extensive squamous differentiation in a pre-existing transitional cell carcinoma.

Immunoglobulin heavy-chain (IgH) gene expression is regulated in a large part of the IgH gene intronic enhancer which is composed of certain protein-binding motifs. These motifs act as a DNA element which is important for the regulation of the IgH gene transcription. Two of these motifs, HE2 and E6 in the human IgH gene intronic enhancer, are considered to affect the B cell-specific gene expression. To examine the true function of the HE2 and E6 motifs in vivo, we established transgenic mouse lines. A 3'deletion mutant of the IgH gene intronic enhancer which includes an active HE2 motif showed almost the same degree of transcriptional activity and tissue-specificity as the whole IgH gene intronic enhancer. Still more, using the luciferase-assay, it was confirmed at cellular level that the HE2 motif plays an important role in the tissue-specific activity of the IgH gene intronic enhancer. On the other hand, the E6 motif was unable to sufficiently produce the B cell-specific expression in vivo and showed enhancer activity in some non-B cells. In transgenic mice, the IgH gene intronic enhancer functioned not only in B-lymphocytes but also in chorid plexus cells which are similar to glial cells. This suggests the existence of common gene expression control mechanisms between the immune system and the nervous system.

A nationwide multicenter joint study was undertaken to investigate the clinicopathologic characteristics of invasive ductal carcinoma of the breast with a predominant intraductal component, a diagnostic entity proposed in the histologic typing of breast tumors by the World Health Organization in 1981. A total of 368 tumors, of which 218 were studied pathologically between 1983 and 1987 and 150 between 1971 and 1977, were accumulated for the present study from seven medical institutes in Japan. The incidence of such types of tumor was higher in the latter period than in the former, as was that of pure intraductal carcinomas. Seventy of the 368 tumors displayed metastatic nodal involvement and nine tumor deaths were observed from 150 tumors followed up for over 10 years following radical mastectomy, the overall quantity of the extraductal stromal invasion clearly acting on lymph node metastases and patients' outcome. We consider a total stromal invasion of greater than 5 mm to be critical in the prognosis of patients with tumor of this type.

Fifty-four cases of undifferentiated neuroblastoma (stroma-poor neuroblastoma with undifferentiated histology) were studied immunohistochemically for the presence of S-100 protein-positive cells and extracellular matrix proteins (laminin, type IV collagen and fibronectin). In 30 of the 54 patients, the tumor had S-100 protein-positive cells in the peculiar stroma observed as thick fibrocellular septa (trabecular pattern) or delicate fibrovascular meshwork surrounding small nests of tumor cells (reticular pattern). The tumors were divided into four subgroups according to the stromal patterns: type A showing a predominant "reticular" pattern (14 cases); type B showing a predominant "trabecular" pattern (6 cases); type C showing both "reticular" and "trabecular" patterns (14 cases), and type D lacking either pattern but rich in vascular channels (20 cases). Clinicopathologically, the patients with S-100 protein-positive cells had a more favorable outcome (86.7% 2-year survival rate) than patients without these cells (12.0% 2-year survival rate). It is concluded that the existence of peculiar fibrovascular stroma containing S-100 protein-positive cells and extracellular matrix proteins is correlated with a favorable prognosis in undifferentiated neuroblastomas.

We report an extremely rare case of carcinoid tumor arising in a congenital choledochal cyst. The dilated choledochal cyst in a 66-year-old Japanese woman was surgically resected, after which the ovoid elevated tumor, measuring 1.5 x 1.5 cm, was detected in the proximal portion of the cyst. A carcinoid tumor was histologically confirmed. To the best of our knowledge, this is the first published case of carcinoid tumor in a choledochal cyst.

The clinicopathologic and immunohistochemical features in 120 cases of gastrointestinal stromal tumor (GIST) were reviewed. Excluding 24 cases of gastric schwannoma, 96 cases of GIST consisting of 62 benign tumors and 34 sarcoma (low grade, 17; high grade, 17), with 9 cases arising in the esophagus, 57 in the stomach, 28 in the small intestine, and 2 in the colon, were studied. All esophagus and colon tumors were benign and resembled a conventional leiomyoma histologically. However, the gastric and small intestine benign tumors mostly showed histologic features of cellular or epithelioid leiomyoma. Immunohistochemically, desmin caused a positive reaction in all esophagus and colon tumors, but only 26% of gastric and small intestine tumors. However, muscle-specific actin (HHF35) caused a positive reaction in most GIST (92%). The 10-year survival rates of the patients with gastric sarcoma and those with intestinal sarcoma were 74% and 17%, respectively. These results showed that histologic and immunohistochemical features were distinctly different, depending on the location in the gastrointestinal tract; that most GIST, excluding schwannoma, had smooth muscle differentiation; and that sarcomas had a more favorable prognosis when they occurred in the stomach rather than the intestine.

The histogenesis of malignant fibrous histiocytoma (MFH) is controversial. To elucidate the cellular origin and characteristics of this neoplasm, the authors analyzed cell lines grown from 17 patients (15 soft tissue MFH and 2 bone MFH) by using light and electron microscopy, immunocytochemistry, enzyme cytochemistry, and functional tests for receptors for the Fc portion of immunoglobulin (Fc receptors) and immunophagocytosis. Each culture exhibited a storiform/pleomorphic pattern with mixed cellular populations consisting of spindle cells, polygonal cells, and bizarre giant cells; these morphologic features corresponded to the histologic characteristics of the primary tumors. The cells in each MFH line displayed histiocytic functional markers such as lysosomal enzymes, Fc receptors and immunophagocytosis. However, these cells differed from monocyte-derived macrophages (histiocytes) in immunoreactivity; the MFH cells expressed a mesenchymal antigen (FU3) distributed among perivascular cells and fibroblasts but demonstrated no positive reactions with Leu-M1 (CD15) and Leu-M3 (CD14), which recognize the cells of the monocyte-macrophage lineage. In conclusion, these findings suggest that MFH is not a tumor of true histiocytes but of facultative histiocytes showing mesenchymal differentiation in vitro. Chromosomal analysis performed in one MFH line demonstrated abnormal karyotypes; the modal chromosome number was 58, with 5 marker chromosomes.

Ten cases of spindle cell haemangioendothelioma (SCH) were analysed clinicopathologically, including an immunohistochemical survey of seven cases and ultrastructural observations on one. There were seven females and three males, ranging from 16 to 76 years of age. All but one lesion developed on the extremities, predominantly on the hands and feet. Six of the ten patients presented multiple nodules or papules which gradually increased in size and number over a long duration. Among them, four patients had undergone operations twice or more, but no metastatic foci were recognized. Histologically, the lesions were composed of dilated vascular spaces and a proliferation of bland-appearing spindle cells and interspersed epithelioid endothelial cells. Ultrastructural and immunohistochemical studies demonstrated that the spindle cells were mainly made up of fibroblastic cells admixed with pericyte-like cells and macrophages. Smooth muscle cells and primitive mesenchymal cells were also present. The clinical and microscopic features suggest that SCH may be a benign vasoformative lesion of a heterochronological multicentric origin.

A total of 24 patients with endocrine neoplasms of the pancreas were clinicopathologically and immunohistochemically studied. They consisted of 18 patients with adenoma and 6 with carcinoma. Of the 24 patients, 13 developed attacks of hypoglycemia due to hyperinsulinemia, and 1 developed an uncontrollable duodenal ulcer caused by the hypersecretion of gastrin, however, the remaining 10 were asymptomatic. No prediction could be made as to the site of origin of the tumors. A clear difference was seen between adenoma and carcinoma in the size of the mass, the mean greatest diameter of the 18 adenoma cases being 1.7 cm, while that of the 6 carcinoma cases was 7.3 cm. One of the 13 insulinomas and a gastrinoma was malignant, while all 24 tumors were positive for neuron-specific enolase. The 13 insulinomas were diffusely positive for insulin and 5 were also shown to be focally immunoreactive for gastrin, with 3 also being immunoreactive for somatostatin and 2 for pancreatic polypeptide. The gastrinoma showed immunoreactivity for somatostatin, insulin, pancreatic polypeptide, and glucagon in addition to a positivity to gastrin. The above findings thus indicate the multiple hormone synthesis of endocrine neoplasms of the pancreas.

The histopathology of 12 patients with adenoma of the ampulla of Vater was examined to trace the adenoma-carcinoma sequence of the ampulla of Vater. Immunohistochemistry for carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 was also performed. Four large adenomas with mild dysplasia also had foci of moderate dysplasia while another one contained foci of severe dysplasia (intramucosal carcinoma). Immunohistochemically, adenomas of mild to moderate dysplasia had either linear CEA and CA19-9 immunoreactants at the apical portions, or fine granular immunoreactants in the cytoplasm of adenoma cells. In addition, adenomas of severe dysplasia (intramucosal carcinoma) showed a more diffuse or dense immunoreactivity for these two substances in the cytoplasm. These results are consistent with the adenoma-carcinoma sequence for the ampulla of Vater. The immunohistochemistry for CEA and CA19-9 was representative of the degree of dysplasia in the adenoma cells, but the relationship was not conclusive.

A total of 304 patients with pancreatoduodenal carcinoma were studied clinicopathologically and immunohistochemically in order to clarify features of carcinoma of four different sites of origin; carcinoma of the ampulla of Vater (Am), the distal common bile duct (DCBD), the head of the pancreas (PH), and the extra-ampullary duodenum (Du). The mean greatest diameter of 87 PH was 3.5 cm compared with 2.7 cm of 149 Am and 2.7 cm of DCBD. Histopathologically, 40% of Am were papillary adenocarcinoma, while about half of DCBD, PH and Du were tubular adenocarcinoma. PH invaded lymphatic (85%), vascular (62%), and perineural (95%) spaces and metastasized lymph nodes (72%) more frequently than Am (77%, 35%, 24%, 50%), DCBD (47%, 61%, 65%, 45%), and Du (76%, 29%, 35%, 65%), respectively. More than 50% of PH invaded the resected margins, whereas in only 2% of Am, the surgical margins were affected by malignant cells. Immunohistochemically, PH was more frequently positive for both carcinoembryonic antigen (CEA) (98%) and carbohydrate antigen (CA) 19-9 (91%) than Am (83%, 62%), DCBD (94%, 58%), and Du (56%, 11%), respectively. The stromal staining type of CEA and CA 19-9 was more frequently seen in PH (27%, 44%) than in Am (9%, 31%), DCBD (11%, 8%) and Du (0%, 0%), showing a more dedifferentiated nature of PH. The cumulative 3-year survival rate of 87 patients with PH (15%) was worse than that of 149 with Am (42%, P less than 0.001), of 51 with DCBD (25%) and of 17 with Du (58%, P less than 0.001). The survival curve of 87 with PH was worse than that of 51 with DCBD, of 149 with Am (P less than 0.001) and of 17 with Du (P less than 0.001). Cox regression analysis, using eleven profound prognostic variables, revealed that venous invasion, perineural infiltration, surgical margin, and histopathologic type were profound prognostic factors. Pancreatic carcinoma has a more dedifferentiated histopathologic nature, showing a more aggressive growth and fares worse than Am, DCBD, and Du.

A prostatic lesion, histologically identical to sclerosing adenosis of the breast, was found in five (1.9%) of 263 patients who underwent transurethral resection, open prostatic adenectomy, radical prostatectomy, or total cystoprostatectomy. This uncommon lesion was a localized proliferation of crowded small glands, small solid nests, and individual cells embedded in a cellular stroma, mimicking a small acinar prostatic adenocarcinoma. The proliferating glands were lined by a single layer of secretory cells surrounded by an eosinophilic membranous structure. Basal cells were disclosed in individual glands or as small nests and even individual cells with immunostainability for basal cell-specific cytokeratin (EAB903), S-100 protein, and muscle-specific actin (HHF35). These findings indicate the benign nature of the lesion with myoepithelial differentiation of the basal cells. In contrast, all 25 small acinar adenocarcinomas examined as controls lacked positive stains for the above three antibodies, verifying the usefulness of these antibodies to distinguish between this benign lesion from adenocarcinoma.

A total of eight patients with adenosquamous carcinoma of the pancreas were studied clinicopathologically. Histochemical and immunohistochemical studies were also done. The 8 patients were composed of 4 men and 4 women with a mean age of 56 years, which was 9 years younger than for other pancreatic carcinoma. The site of origin and size of the tumors were similar to those of usual pancreatic carcinoma. Histopathologically, all eight tumors showed an abrupt transition between adenocarcinoma and squamous cell carcinoma. Squamous cell carcinoma was located at the periphery of the tumors. Histochemistry and immunohistochemistry disclosed a different nature for both components. The cumulative 1-year survival rate of the 8 patients was 21.4%, compared to 42.1% of 72 with adenocarcinoma of the pancreas. The survival curve of the 8 patients with adenosquamous carcinoma was significantly less favorable than that of 36 patients with well-differentiated adenocarcinoma of the pancreas. These facts support the view that squamous cell carcinoma in adenosquamous carcinoma of the pancreas is squamous cell metaplasia of the pre-existing adenocarcinoma. The clinical course of adenosquamous carcinoma of the pancreas was unfavorable.

For 52 patients with depressed adenomas of the stomach, histopathologic studies were done on 56 tumors and for 43 of them, histochemical and immunohistochemical features were examined. In addition, nondepressed adenomas (n = 57) and the depressed type of early gastric adenocarcinomas of the well-differentiated variety (n = 44) were studied as the controls. Depressed adenomas in the majority (73%) involved the entire thickness of the mucous membrane of the stomach with tubules of atypical epithelium, presenting a severe grade in many of the cases (41%). Paneth's cells were found in cases of a depressed adenoma, in significantly higher percentages (61%) than in those with a nondepressed adenoma (P less than 0.01). The frequency of cases with argyrophil cells was also higher in depressed adenoma (63%) than in nondepressed adenoma (36%) or in cases of early gastric carcinoma (32%). Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were noticed in tumor cells, immunohistochemically in 28% of the cases with depressed adenoma, the frequency being intermediate between cases of a benign nondepressed adenoma (6% for both CEA and CA 19-9) and cases of early gastric carcinoma (71% for CEA and 66% for CA 19-9). No difference was noticed in lectin reactivity and mucin content between depressed and nondepressed adenomas, whereas tumor cells in the early depressed carcinoma had a higher lectin reactivity and less mucin content than those seen in the adenomas. It would thus appear that depressed adenoma is a benign neoplastic lesion; however, the malignant potential of this lesion is somewhat higher than the nondepressed counterpart, as indicated by the immunoreactivity to tumor markers and follow-up results reported by colleagues previously.

A review of 40 cases of obstructing colorectal carcinoma selected from 1,786 cases of surgically resected colorectal carcinomas was undertaken. The average age of the patients was 63 years, and there were 22 women and 18 men. Twenty-three lesions (58%) arose in the sigmoid colon and nine (23%) in the transverse colon, and obstructing rectal carcinomas were significantly rare. All of the obstructing tumors displayed a circumferential growth, 32 being examples of the annular constricting type. Obstructive colitis was caused by a combined lesion in only three cases. Microscopic characteristics of the obstructing carcinomas were as follows: 1) invasion of the whole thickness of the colorectal wall by the malignant tissue, 2) complete discontinuance of the muscularis propria in the affected area, 3) striking fibrous stromal reaction in the tumor, 4) upward rising, not descending, of both stumps of the discontinuous muscularis propria, 5) infiltrative growth of the tumor into the subserosa with scar-like fibrosis. It is indicated from the present study that obstructing carcinomas have features promising construction of the bowel lumen, but patients with such a tumor are not appreciably different in prognostic, histologic nor immunohistochemical aspects from those with a non-obstructing carcinoma.

One hundred and ninety patients with mammary ductal carcinoma were studied to evaluate the correlation of proportions of intraductal and invasive tumor growth to histologic and immunohistochemical features. Initially, attempts were made to divide the cases into 6 groups according to the proportion of extraductal invasive areas within the whole tumor. It has been found that ductal carcinoma could be divided, on this criterion, into 2 groups. One comprised tumors in which invasive areas made up less than 20% of the tumor, the other included those with invasive areas exceeding 20%. In the former, intraductal and invasive components exhibited a lower grade of nuclear and tumor component and a higher incidence of cells with CEA immune positivity. The latter manifested higher grades in both intraductal and invasive components and a lower incidence of CEA positive cells. Many of the latter tumors had a solid or comedo-like growing pattern of the intraductal component. There was a significant difference in the prognosis between the two categories. We conclude that like intraductal carcinomas, invasive ductal carcinomas with a predominant intraductal component should be considered a lower grade malignancy.

Three cases of tubular adenoma of the gallbladder with squamoid spindle cell metaplasia are reported. Two of the three patients, who were middle-aged Japanese, had a solitary polyp in the gallbladder, and the other had three polyps. All the lesions were detected incidentally by ultrasonography. The polyps were pedunculated with a fine or frail stalk, and ranged from 0.5 to 3.9 cm in diameter. Histologically, they were tubular adenomas accompanied by scattered foci composed of a compact collection of short-spindle or oval cells with mild atypia. These cells did not retain intercellular bridges, and lacked intracellular keratinization. Immunohistochemically, the spindle cells stained positively for high-molecular-weight cytokeratin (EAB 903, a marker of squamous cell differentiation), whereas adenoma cells lining the tubules were negative for this antigen. Therefore, the spindle cell component is considered to represent squamoid metaplasia of adenoma cells.

Soft tissue sarcomas are a heterogeneous group of malignant tumors with a wide range of clinical presentation, morphologic features and biologic behavior. During the past two decades, many acceptable new entities have been proposed, and the diagnosis and classification of these tumors have been modified. This paper reviews several current issues that are considered worthy of note for the histologic diagnosis of soft tissue sarcomas.

Clinicopathologic features of 145 Japanese patients with ampullary carcinoma were compared among three age groups. The 145 patients were divided into three groups by the patient's age at the time of operation; there were 24 patients in group I (younger) aged less than or equal to 50 years, 99 in group II (ordinary) aged 51-69, and 22 in group III (elderly) aged greater than or equal to 70. The three groups showed no significant difference in sex, icterus, duration of icterus, size of the tumor, year of operation, macroscopic type, histopathologic type, tumor margin, lymphatic permeation, venous invasion, or pancreatic invasion. The survival curve of group I was worse than those of groups II and III. Multivariate regression analysis using 11 prognostic variables failed to reveal that the age of the patient at the time of operation was an independent factor. The younger patients aged less than or equal to 50 fared worse than the elderly patients aged greater than or equal to 70, because the group I tumors included a significantly greater number of advanced ampullary carcinoma with more frequent perineural invasion than did the group III tumors.

Endoscopic biopsy specimens of the gastric mucosa from 13 patients who were found at follow-up examination to have gastric carcinoma were compared for abnormal histologic features, type of intestinal metaplasia, and presence of immunoreactive carcinoembryonic antigen (CEA), with specimens from 40 tumor-free controls. Villus-like changes and angular infolding, cytologic nuclear pleomorphism, distinct nuclear border, irregular thickness of the nuclear membrane, irregular chromatin clumping, prominent nucleoli, and distinct nucleoli were manifestations of the carcinoma group. Angular infolding, distinct nuclear border, irregular thickness of the nuclear membrane, and distinct nucleoli were also observed in the latent stage before detection of carcinoma. The individual features, however, lacked specificity. Histochemically, a IIB subtype of intestinal metaplasia, and immunoreactive CEA in the cytoplasm of foveolar epithelium appeared exclusively in the patients with carcinoma. These findings indicate that the gastric epithelium of patients with gastric carcinoma tends to be morphologically and histochemically abnormal even before the recognition of classical dysplasia. This can be described as abnormal epithelium and is believed to provide the soil on which gastric carcinoma develops.

Endoscopic biopsy specimens and surgically resected specimens in a collective series of 78 Japanese patients with ampullary tumor were retrospectively reviewed to investigate the clinical implications of endoscopic biopsy. Endoscopic biopsy specimens were classified into five groups based on the degree of epithelial atypia: group 1 (no atypia), group 2 (mild atypia), group 3 (moderate atypia or adenoma), group 4 (severe atypia or carcinoma in situ), and group 5 (invasive carcinoma). Final diagnosis of the 78 resected ampullary tumors was adenoma in five cases, carcinoma in 27 cases, and both adenoma and carcinoma in 46 cases. Biopsy accuracy of carcinoma (group 4 or 5) was 70% (51 of 73) overall in 73 carcinoma cases. Biopsy accuracy was 50% (7 of 14) in the intramural protruding type, 64% (21 of 33) in the exposed protruding type, and 88% (23 of 26) in the ulcerating type. The diagnostic accuracy of adenoma (group 3) was 80% (4 of 5) in five cases of ampullary adenoma. In 18 (25%) of the 73 carcinoma cases, biopsy diagnosis was adenoma (group 3), whereas carcinoma was found in the deeper layers of surgically resected specimens. Biopsy diagnosis of adenoma does not rule out the possibility of deeper carcinoma in ampullary tumors.

Six cases of Bednar tumor were analyzed clinicopathologically along with a review of 39 published cases. The findings were then compared with data on 44 cases of ordinary dermatofibrosarcoma protuberans (DFSP) obtained from our files. The clinical manifestations of the patients and the anatomic locations of the tumors were similar between the two categories, but the rate of recurrence was lower in cases of Bednar tumor. The histologic pattern of Bednar tumor was indistinguishable from ordinary DFSP except for scattered melanosome-containing cells. Ultrastructural and immunohistochemical examinations showed no evidence of neuroectodermal differentiation of dominant spindle-shaped cells in Bednar tumor, supporting a fibroblastic line of differentiation. The origin and pathogenesis of the melanosome-containing cells were considered. These cells failed to react with HMB-45, a melanoma-specific antibody, and the large majority of melanosomes present were mature or at Stage IV, plus a few immature ones at Stage II. These pigmented cells do not appear to be neoplastic, and cannot be used as proof to indicate that Bednar tumor is a neuroectodermal neoplasm.

This clinicopathologic study concerns 27 cases of "dedifferentiated" soft tissue sarcoma (DSTS), including 14 liposarcomas, six leiomyosarcomas, five chondrosarcomas, and two rhabdomyosarcomas. In addition, the authors conducted an immunohistochemical survey of 23 cases and an electron microscopic examination of three. The findings were compared with observations of 32 cases of de novo malignant fibrous histiocytoma (MFH). All tumors contained additional distinct anaplastic portions indistinguishable from MFH under conventional light microscopy, ultrastructurally, and in cases of immunoreactivity for alpha-1-antichymotrypsin and alpha-1-antitrypsin and on lectin histochemical findings for ricinus communis agglutinin and concanavalin agglutinin. The desmin reactivity present in anaplastic portions of 14 DSTS and in eight de novo MFH is taken to mean that myofibroblasts are present in these tumors. The anaplastic components of DSTS are presumed to represent the proliferation of another clone of undifferentiated mesenchymal cells that fail to differentiate along any specific lineage other than fibroblast-like cells, histiocyte-like cells, and myofibroblasts. Nineteen patients died of tumor and four are alive and well 1.6, 1.7, 2.1, and 5.2 years after the initial treatment, respectively.

Sixty-three gastrectomy specimens (21 with early intestinal type carcinoma, 21 with early diffuse carcinoma, and 21 with benign nonneoplastic lesions) were examined histochemically to determine the distribution of intestinal metaplasia (IM), particularly the sulphomucin-secreting type (Type IIB IM). The frequency and distribution of Type IIB IM were similar, irrespective of the disease, when age of the patient was matched and if the extension of the IM was similar. Type IIB IM was usually observed in the mucosa along the lesser curvature of the lower portion of the stomach, particularly in elderly patients and was mainly located in the deeper foveolae and intermingled with or transient to those in other types of IM. These findings suggest that a casual relationship between Type IIB IM and intestinal type carcinoma is dubious.

The authors examined the localization and behavior of beta-human chorionic gonadotropin (HCG)-positive cells in human gastric noncancerous mucosa and in gastric malignant tumors, using immunohistochemistry and the anti-beta-HCG antibody. The beta-HCG-positive cells were located mainly in the antral mucosa and were generally restricted to the neck portion of the pyloric glands, although a few were present in fundic glands of the gastric body. The beta-HCG-immunoreactive cells were found in gastric carcinomas in 53% of the 92 cases examined. These cells were observed more often in advanced carcinomas that were histologically poorly differentiated than in early carcinomas or in well-differentiated tumors, but this prevalence had no statistical significance. The presence of the beta-HCG-positive cells in the gastric carcinomas suggested no appreciable prognostic significance, even quantitatively. In the syncytiotrophoblast-like tumor cells seen in four gastric tumor samples with histologic features of a choriocarcinoma, immunoreactivity to the beta-HCG was striking. There was, however, no recognizable dominance in the number of beta-HCG-reactive cells in the noncancerous mucosa around the tumor.

We describe a female infant with obstructive jaundice due to inflammatory stenosis of the choledochus. It was surrounded and narrowed by a xanthogranulomatous lesion, extending from xanthogranulomatous cholecystitis (XGC). The obstructive jaundice was released by a cholecystectomy, resection of the choledochus, and hepaticojejunostomy. This is the first reported case of infantile XGC associated with obstructive jaundice.

Clinicopathologic findings and clinical follow-up data of 31 patients with non-icteric ampullary carcinoma (NIAC) and 111 patients with icteric ampullary carcinoma (IAC) were retrospectively compared. All of the IAC patients presented with obstructive jaundice. Twenty-three of the 31 NIAC patients developed abdominal pain and/or fever caused by cholangitis or pancreatitis, and the remaining eight patients were asymptomatic. The two groups were not significantly different in age, sex, size of the tumor, macroscopic type, lymph node metastasis, perineural invasion, lymphatic permeation, and venous invasion. Eighteen of the 31 NIACs (58%) were in stages I and II, whereas 25 of the 111 IACs (22%) were in stages I and II (p less than 0.01). Seventeen of the 31 NIACs (55%) were papillary adenocarcinoma, compared with 39 of 111 IACs (35%) (p less than 0.05). As to involvement of the biliary tract, the NIAC showed an intraluminal papillary growth in 14 cases (45%), whereas the IAC showed a periductal invasion in 58 cases (52%) (p less than 0.05). The cumulative 5-yr and 10-yr survival rates of 31 patients with NIAC were 57% and 57%, compared with 32% and 23% of 105 patients with IAC (p less than 0.05; p less than 0.01). The survival curve of the NIAC was significantly better than that of the IAC (p less than 0.01). Non-icteric presentation had no independent prognostic value, as determined by multivariate regression analysis. The NIAC fares better than the IAC, because the NIAC includes a greater number of early ampullary carcinoma and papillary adenocarcinoma. The detection of NIAC may therefore product an improvement in the clinical course of ampullary carcinoma.

Seventy-four cases of nasopharyngeal malignant neoplasms were analyzed immunohistochemically and classified into 16 lymphomas and 58 carcinomas. Eight lymphomas were of T-cell origin and eight were of B-cell origin. Although there were no significant differences in prognoses between patients with carcinoma and those with lymphoma, T-cell lymphomas resulted in a worse outcome. Five-year survival rates of T-cell and B-cell lymphoma were 12.5% and 75%, respectively. Polyclonal keratin and tissue polypeptide antigen were more sensitive and specific than other epithelial markers, and were positive in 97% (56 of 58) and 93% (54 of 58) of carcinomas, respectively. With regard to immunophenotypic analysis of malignant lymphomas, L26 to B-cells (88%) and UCHL1 to T-cells (100%) led to a satisfactory effect. Immunohistochemical investigations made possible differentiation of malignant lymphomas from a carcinoma and also aided in typing the latter.

We present a rare case of an osteosarcoma arising in a benign dermoid ovarian cyst. The cyst, removed intact from the right ovary of a 52-year-old Japanese woman, was unilocular, measured 10 x 9 x 8 cm, weighed 176 g, and contained yellow-brownish greasy material. From the inner surface of the cyst there protruded a subsessile solid mass, measuring 3.1 x 2.5 x 2.0 cm, with a variegated cut surface. Histologically, the cyst was an ordinary dermoid cyst, and the solid mass consisted of osteosarcoma with focal chondroblastic differentiation. Postoperative combination chemotherapy was prescribed and the patient remains alive and well 16 months postoperatively. This case is the third documented in the world literature.

Eighty-six cases of advanced gastric carcinoma simulating early gastric carcinoma were studied clinicopathologically. Cytophotometric DNA analysis was also performed in 33 cases. Most of these particular carcinomas were of the depressed type on gross inspection. Histologically, the tumors were of diffuse type in 60%. The rate of the carcinomas restricted to within the muscularis propria was 48% and high in comparison with those in conventional advanced gastric carcinomas. There were four main growth patterns: small invasion type (Type A, 43 cases), ulcer-connected type (Type B, 19 cases), vessel permeation type (Type C, six cases), and diffusely infiltrative type (Type D, 13 cases). There was a relationship between growth patterns, lymph node metastasis, and prognosis: Types A and B had a small percentage of lymph node metastasis and a good prognosis, whereas Types C and D a high percentage and a poor prognosis. DNA analysis revealed that two thirds of the examined cases showed a low ploidy pattern. The DNA ploidy patterns were concerned with the tumor growth pattern: high-ploidy cases were rarely seen in Types A and B yet were frequent in Types C and D. The 5-year survival rate was 73%, but results were poor in cases of tumors with blood vessel permeation, in those with lymph node metastasis, in those with the Type D or C growth patterns, and in those with high DNA ploidy pattern. Since these carcinomas can be understaged endoscopically and by gross examination, a precise study of the surgically excised tissues will aid in making an accurate prognosis.

A congenital primitive neuroectodermal tumor associated with epithelial and glial elements is described. This soft-tissue tumor present on the right temple of a newborn boy consisted mainly of small round cells of the primitive neuroepithelial type, occasionally forming rosettes. The other components were focal glandular structures producing mucin, and aggregates of epithelioid cells bearing clear cytoplasm, both being distributed throughout the entire tumor. Additional glandular and clear cell components were strongly positive for various epithelial markers, such as carcinoembryonic antigen, epithelial membrane antigen, and cytokeratin. Epithelioid cells were also positive for neuron-specific enolase and S100 protein. Glial differentiation was evidenced in some of the epithelioid cells by localization of cytoplasmic glial fibrillary acidic protein. These findings suggest that this tumor derives from a remnant of a neural crest, and the possibility of a special type of peripheral primitive neuroectodermal tumor is considered.