Cancer Nests Research Articles

Expression of E-selectin on endothelial cells of small veins in human colorectal cancer.

E-selectin is an adhesion molecule of endothelial cells that binds to cancer cells mediated by sialyl Lewis A (sLea) or sialyl Lewis X (sLe(x)). It is suspected to be involved in hematogenous metastasis of tumors. Therefore, it is worth examining E-selectin expression in human colorectal cancer and its hepatic metastasis. In the present study, E-selectin was clearly revealed on the endothelial cells of small vessels adjacent to cancer nests both in primary and in metastatic nests in immunohistochemistry. In these tissues, E-selectin was observed on the endothelial cells lining the lumen of small vessels. Its expression adjacent to cancer nests appears to be induced through some stimuli by cancer cells, since its degree of expression is inversely correlated to the distance of the blood vessels from the cancer nests (p < 0.001). Endothelial cells adjacent to the metastatic lesion expressed E-selectin more extensively than those adjacent to the primary foci. This is also in line with the finding on serum E-selectin levels which were significantly elevated in the metastatic group as compared with the non-metastatic group. The serum E-selectin level may provide useful information in the diagnosis for hepatic metastasis of colorectal cancer, although the results are still tentative.

Expression of matrix metalloproteinase-3 in stage I and II squamous cell carcinoma of the oral cavity

Purpose: The object of this study was to evaluate the significance of matrix metalloproteinase-3 (MMP-3) in tumor invasion and metastasis of early squamous cell carcinoma (SCC) of the oral cavity. Materials and Methods: Surgical specimens from 65 patients with stage I and II SCC of the oral cavity were the subjects of this study. Tissue specimens were fixed in formalin and embedded in paraffin, and the sections were stained with monospecific antibodies against human MMP-3 by the avidin-biotin-peroxidase complex method. Results: Of the 65 patients, 30 (46.2%) tested positive for MMP-3. Immunore-activity revealed the expression of MMP-3 to be in the small cancer nests in the advancing front of invasion, but not in normal oral epithelium. MMP-3 expression was positively correlated with tumor size, depth of tumor invasion, diffuse invasive mode, and the high incidence of lymph node metastasis. Conclusion: MMP-3-containing tumors will invade adjacent normal tissues more aggressively, including lymphatic and blood vessels. Therefore, the examination of MMP-3 expression in biopsy specimens should provide information useful in predicting the malignant potential of early SCC of the oral cavity.

Portal vein embolization with lipiodol for treatment of HCC--an experimental study.

A suspension of iodized oil and anticancer agent was injected into the portal veins of 20 rats with hepatic carcinoma. Oil drops were seen in tumor cell lines, small blood vessels inside the cancer nest, the sinusoid, and the central veins. After injection of oil suspension through the portal vein the distal small vessels were embolized and necrotic changes of tumor cells and their subordinate normal liver cells were observed. The results obtained in this experiment provided a good anatomical and pathological basis for treating liver cancers with the portal vein embolization with chemotherapeutic agents.

Histopathological evaluation of response to pre-operative concurrent chemoradiotherapy for advanced squamous cell carcinoma of the thoracic esophagus

The histological features of tumor degeneration of 20 advanced squamous cell carcinomas of the thoracic esophagus after pre-operative concurrent chemo-radiotherapy were evaluated. All patients were staged and diagnosed microscopically before treatment. The i.v. continuous chemotherapy (Cisplatin and 5- Fluorouracil) and concurrent Co-60 therapy (total dose: 3000 cGy) were followed by subtotal esophagectomy around the 42nd day from the start of the treatment. The response to treatment was evaluated qualitatively and semiquantitatively on the basis of findings of degeneration and regression of tumor mass together with signs of regeneration of esophageal wall. This response was classified as complete (CR), partial 1 (PR1), partial 2 (PR2) and stable disease (SD). Of twenty patients, four (20%) were CR without microscopical evidence of cancer cells, four (20%) were PR1 with small cancer nests or single cancerous cells, nine (45%) were PR2 with diffuse cancer infiltration with different degree of cancer degeneration and three (15%) were SD with no appreciable changes of tumor mass. Generally, the regression of tumor mass was seen in 17 out of 20 patients. In the majority of them, decrease of mainly the endoluminal part of tumor mass, as compared to the pre-operative stage, was observed.

A RESECTED CASE OF ADVANCED ESOPHAGEAL CARCINOMA SHOWING A PROMINENT RESPONSE TO NEOADJUVANT CHEMOTHERAPY WITH 5-FU AND LEUCOVORIN

A 62-year-old man with advanced esophageal carcinoma which was suspected of direct invasion into the left atrium and descending aorta was confirmed to have Botallo's lymph nodes metastasis (M0N3A3 in Stage IV). So it was judged that operation was impossible and radiation was started. Mediastinitis developed when total radiation amounted to 10.5 Gy. Radiation therapy was withdrawn. Neoadjuvant chemotherapy with sustained i. v. drip infusion of 5-FU was started, and on the way 3 courses of Leucovorin 9mg daily for continuous 5 days were added. Total doses of 5-FU and Leucovorin came to 31, 500mg and 144mg, respectively. With the neoadjuvant chemotherapy, the size of the tumor decreased prominently (Pl0M0N0A0, stage 0). After the esophageal resection with reconstruction, the lesion of carcinoma almost disappeared microscopically. Only 3 small cancer nests in the lamina propria were found. Unfortunately this patient died of cardiorespiratory distress. It is though that sustained i. v. drip infusion of a low dose of 5-FU with Leucovorin regimen is safe and a promising neoadjuvant chemotherapy.

Gene expression of interstitial collagenase (matrix metalloproteinase 1) in gastrointestinal tract cancers.

Collagenolytic proteinases play an important pathological role in the invasion and metastasis of cancer cells. However, little is known about the role of interstitial collagenase (matrix metalloproteinase-1; MMP-1) in this process. To investigate the expression of the MMP-1 gene in cancer tissues, an in situ hybridization study was carried out in gastrointestinal tract cancers (one esophageal cancer, five gastric cancers, and four colorectal cancers), using a 35S-labeled MMP-1 cDNA probe. The MMP-1 gene was expressed in the stromal cells of fibrous tissue around cancer nests, especially at the margin of invasion and/or within the cancer nest; however, no definite expression within cancer cells was observed. Expression of the MMP-1 gene in the stromal cells was more common in well differentiated gastric adenocarcinoma than in poorly differentiated adenocarcinomas. These findings indicate that expression of the MMP-1 gene is greater in stromal cells that are closely associated with cancer cells, suggesting a pathophysiological role of MMP-1 in the invasion and metastasis of cancer cells.

A CASE OF BORRMANN 3 TYPE GASTRIC CANCER WITH REMARKABLY EFFECTIVE PREOPERATIVE CHEMOTHERAPY

A 68-year-old woman was successfully diagnosed as having a poorly defferentiated gastoric cancer of Borrmann 3 type preoperatively. The patient received preoperative chemotherapy with continuous infusion of 5FU 300 mg/m2/day from day 1 to 17, totally 6800mg/body and iv drip of CDDP 15 mg/m2/day from day 1 to 2, totally 50 mg/body; followed by total gastrectomy D3, splenectomy, and cholecystectomy (Stage IIIb). Histophathological examination of the primary tumor revealed that only a few cancer cell nests (por) remained in the mucosal layer. In all of the lymph nodes which were preoperatively suspected to be metastatic lesions, cancer nests have been completely destroyed. This case was judged to be in stage I a after chemotherapy, indicating a down staging.

唾液腺悪性腫ようの間質におけるＴｅｎａｓｃｉｎの免疫組織化学的研究

Tenascin (TN), an extracellular matrix component, is known to be an embryonic cancer antigen. This antigen is specifically found in the interstitial tissue of breast or lung cancer. This study immunohistochemically analyzed the expression and distribution of TN in the interstitial tissue of malignant salivary gland tumors, for which no detailed reports are available, and attempted to define the significance of TN. The subjects comprised 48 patients with malignant salivary gland tumors, 49 with benign salivary gland tumors, 8 with chronic sialoadenitis, and 20 with normal submandibular glands. In addition, another extracellular matrix component, fibronectin (FN), which has TNbinding properties, was also analyzed. In normal salivary glands, TN was detected in the basal layers of intercalated, striated and excretory ducts and not in serous or mucinous acinar cells, myoepithelial cells, or the stromal tissue. In chronic sialoadenitis, TN was detected in the same sites as in the normal submandibular gland in addition to the interstitial tissue surrounding the striated and excretory ducts. The presence of TN was demonstrated in the interstitial tissue, but not in the parenchyma, of pleomorphic adenomas in 26 of 30 patients (86.4%). For malignant salivary gland tumors, TN was detected in the interstitial tissue, but not in the parenchyma, in 45 of 48 patients (93.8%). These findings suggest that TN may be specific to the interstitium of malignant gland tumors. TN was diffusely distributed in the interstitium at the focal point of cancerous invasion and in the border area between cancer nests and normal tissue. Comparson of the appearance and distribution of TN and FN, suggested that TN may contribute to the proliferation and invasion of malignant salivary gland tumors. The higher the histological malignancy, the higher was the detection rate of TN in the interstitial tissue of adenoid cystic carcinomas and mucoepidermoid carcinomas, suggesting that TN may objectively reflect the histological malignancy of malignant salivary gland tumors. In addition, the rate of highly positive TN in the interstitium increased parallel to higher grades of malignancy, suggesting that TN may also be a useful indicator of the biological malignancy of malignant salivary gland tumors.

ヒト口腔へん平上皮癌における微小血管に関する免疫組織化学的検討

Thirty-three cases of oral squamous cell carcinoma (S. C. C.) were studied immunohistochemically, using an antibody against vascular endothelium (JC70A). The relationship between the distribution of microvessels and clinicopathological factors was also investigated.In healthy epithelium, crosssections and the course of microvessels had a regular appearance. However, in S. C. C., microvessels appeared to be irregular and their density was increased.In highly differentiated S. C. C., microvessels were localized around the cancer nests, but in poorly differentiated S. C. C., microvessels were scattered. The density of microvessels in highly-differentiated S. C. C. was higher than that in poorly differentiated S. C. C. However, no correlation between the density of tumor vessels and tumor proliferation. indicated by T classification and PCNA labelling Index, could be demonstrated.The relationship between tumor vessel density and the histological grade of the mode of invasion was determined. At the invasive edge of the tumor, tumor vessel density was higher in grades 4C and 4D than in other grades. The vessel density was also higher in tumors with lymphnode metastasis, than in those without lymph node metastasis.These results suggested that tumor invasion and metastasis may be related to the distribution of tumor vessels.

Distribution of S-100 protein-positive dendritic cells inside the cancer nest and expression of HLA-DR antigen and blood group antigen on the cancer cell in transitional cell carcinoma of the urinary bladder--in relation to tumor progression and prognosis

The distribution of S-100 protein positive dendritic cells (S100-DCs) inside the cancer nest and the expression of HLA-DR alpha antigen (HLA-DR) and blood group antigen (BGA) on cancer cells in 90 cases of transitional cell carcinoma (TCC) of the urinary bladder were immunohistochemically investigated in relation to the degree of malignancy and its prognosis. A dense infiltration of S100-DCs inside the cancer nest ("many", i.e. more than 10DCs/HPF) was detected in 47 (52%) out of 90 cases. The HLA-DR positive cancer cells (DR-CCs) were detected in 24 cases (27%), including in the 16 most dense cases ("many", i.e. more than 100DR-CCs/HPF). BGA positive cancer cells (BGA-CCs) were detected in 49 cases (54%) ("positive", i.e. more than 100BGA-CCs/HPF). In connection with the degree of malignancy and with the number of cases affected by S100-DCs infiltration. HLA-DR expression and BGA expression. A statistical analysis showed significant correlation between the number of cases affected by S100-DC and each clinicopathological factor including G, pT, ly, v, and showed also between that affected by BGA expression and each clinicopathological factor including G, pT, INF, but showed no significant correlation between that affected by HLA-DR and each clinicopathological factor. As regards the prognosis, the 10-year survival rates for all 90 cases were 60.4%. In the 10-year survival rate, S100-DCs "many'' (77.7%) and "few'' (39.0%), DR-CCs "many'' (85.7%) and "no'' (56.9%), DR-CCs "many'' and "few'' (43.8%), BGA-CCs "positive'' (74.3%) and BGA-CCs "negative'' (46.5%) were statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

頚胸境界部食道癌の合理的リンパ節郭清 下咽頭癌転移関連因子

Biopsy materials were studied immunohistologically in terms of factors responsible for neck metastasis. These materials were obtained from patients with hypopharyngeal or laryngeal carcinomas. A continuous expression of type IV collagen in the basement membrane that surrounds cancer nests may indicate that neck metastasis is negative and prophylactic neck dissection is not mandatory. Negative expression of type IV collagen, on the contrary, does indicate a positive neck metastasis and is a definite indication of neck dissection for any N classifications.Some metalloproteinases that may effect the expression of type IV collagen were also evaluated immunohistologically using monospecific monoclonal antibodies. These include type IV collagenase and cathepsin B, D and G. Their expression was observed in some cases, but a mutual relation between them and type IV collagen was not clearly demonstrated.

Scanning electron microscopic observations of the basal surface of the human oral mucosa and squamous cell carcinoma

The basal surface of epithelial cells in the normal oral mucosa and cancer lesions were investigated by scanning electron microscopy. The basal lamina and collagen fibers having been completely removed by strong alkali digestion, the true basal surfaces of the epithelium and cancer lesions were demonstrated in three dimensions. Visible on the outer surface of the nest of cancer cells was a flowerlike structure, presumably the connecting portion of the neighboring cancer nest.

Local control prediction by histologic grading of radiation effects with drill biopsy specimens for uterine cervical cancer

Purpose : Local control predictability by histologic grading for radiation effects was analyzed on 224 patients with cervical squamous cell carcinomas obtaining complete regression. Methods and Materials : The cervical specimens after radiation therapy were obtained by drill biopsy technic. Radiation effect was assessed with Shimosato's histologic classification for radiation effect. Results : The cancer tissues were altered by radiation to various degree from destruction of cancer nests with numerous viable cancer cells indicating grade 2a to scar tissues without viable or non-viable cancer cells indicating grade 4 at the end of treatment. Forty five percent of the patients had viable cancer cells remaining on the specimens at that time. The numbers of the grades 2a, 26, 3, and 4 in biopsy specimens were 36, 65, 39, and 84, respectively. The local control rates and 5-year survival rates were 53% and 28% for grades 2a, 75% and 51% for grade 2b, 95% and 74% for grade 3, and 92% and 76% for grade 4, respectively. The histologic grading was significantly associated with the local control and 5-year survival. Of 41 patients having remaining viable cancer cells, residual tumors disappeared in 33 patients (80%) and 8 (20%) still persisted to show grades 2a-b at 1 to 2 months after radiotherapy. Of the 8, all four patients without any salvage treatment, died of local recurrence. Conclusion : These results suggested that the remaining viable cancer cells in the specimens at 1 to 2 months after radiation therapy were highly associated with recurrence and that the histologic grading system was an indicator predictive for prognosis.

Distribution of S-100 protein-positive dendritic cells and expression of HLA-DR antigen in transitional cell carcinoma of the urinary bladder in relation to tumour progression and prognosis.

The distribution of S-100 protein positive dendritic cells (S100-DCs) in cancer nests and the expression of HLA-DR antigen on cancer cells in 90 patients with transitional cell carcinoma of the urinary bladder were studied immunohistochemically. A dense infiltrate of S100-DCs (more than 10 S100-DCs/high power field) was detected in 47 out of 90 cases, while in the remaining tumours the infiltrate was sparse. HLA-DR positive cancer cells (DR-CCs) were detected in 24 cases, including 16 with dense DR-CCs (more than 100 DR-CCs/high power field); no expression was observed in the remaining tumours. In terms of the numbers of S100-DCs infiltrating the following statistically significant differences were observed: tumour grading G1 > G3, depth of penetration pT0 > pT3; (p < 0.05), G2 > G3, lymphatic invasion - > + and venous invasion - > +; (p < 0.01). A multivariate analysis demonstrated that the most important factor affecting prognosis was distant organ and/or lymph node metastasis (p < 0.01) the number of S100-DCs, with a hazard ratio (HR) of 0.26 (p < 0.01), and the number of DR-CCs with HR of 0.18 (p < 0.05); these were statistically significant. S100-DCs and DR-CCs may be regarded as independent prognostic factors of tumour growth and progression.

Localization of E-cadherin adhesion molecules in human gingiva and gingival carcinoma.

Immunohistochemical investigations were carried out on the localization and expression of the Ca(2+)-dependent intercellular adhesion molecule E-cadherin in human gingiva and gingival carcinoma. Although E-cadherin did not appear in the parakeratinized layer of either clinically healthy or inflamed gingiva, it did appear strongly in the prickle layer and somewhat more weakly in the basal layer. Immunogold particles reactive to anti-E-cadherin monoclonal antibody in the electron microscopic findings were localized only in the vicinity of the desmosomes of the prickle and basal layers. In the case of gingival carcinoma, although E-cadherin was strongly expressed in the cells surrounding the keratinized region in the cancer nests, the expression decreased towards the marginal portion of the cancer nests. The distribution of E-cadherin in these cells may be dependent on the condition of the cancer cells that are potentially invasive. These findings suggest that cells of the parakeratinized layer of gingiva and cells of the marginal portion of the gingival carcinoma nests may easily detach or invade. In addition, the findings suggest that the gingival carcinoma used in this study tended to be invasive.

声門上癌間質における基底膜構成成分の発現

Fifteen supraglottic squamous-cell carcinomas were investigated for the immunohistochemical localization of the basement membrane components (BMCs), type IV collagen and laminin in the BM surrounding the cancer nest. Expression of the tumor supressor gene p53 and infection of huamn papillomavirus type 16 (HPV-16) were also examined in the cancer cells. A regular and continuous staining for BMCs was present, but p53 expression and HPV-16 infection were nondetectable, in normal suprragolottic epithelium. The distribution of BMCs was related to the lympho node metastasis (LNM) with a decreased immunostaining being evident in LMN-positive cancers. On the other hand, cancers showing suffiecient BMC deposition were poorly metastatic. Eight of 15 cancers (53%) exhibited elevated p53 expression and HPV-16E6 was detected in 4 of 15 (26%), one of which exhibited elevated p53 expression. Both the elevated p53 expression and the detection of HPV-16 E6 were found to correlate with poor distribution of BMCs surrounding the cancer nest. From the above, LMN may be more accurately diagnosed by these examinations.

Production of matrix metalloproteinase-2 and metalloproteinase-3 related to malignant behavior of esophageal carcinoma. A clinicopathologic study.

Matrix metalloproteinases (MMP) are a gene family of zinc enzymes capable of degrading almost all of the extracellular matrix macromolecules in vivo. Their enzymic activities are believed to be responsible for tumor invasion and metastasis. In this study, using peroxidase-antiperoxidase method, monospecific antisera against MMP-1 (tissue collagenase), MMP-2 (type IV collagenase/72-kilodalton [KD] gelatinase), and MMP-3 (stromelysin) were applied to 29 squamous cell carcinomas and normal epithelium of the esophagus to identify cells synthesizing and secreting these enzymes. Immunoreactivity of MMP-1, -2, and -3 was observed in small cancer nests of the deeply invasive or marginal portion of the tumor. Among the 29 patients studied, the presence of at least one MMP was observed in 17 (58.6%). All three enzymes were observed in six (20.6%) patients, MMP-2 and -3 in five (17.2%) patients, only MMP-2 in three (10.3%) patients, and MMP-3 alone in three (10.3%) patients. There was a good correlation among histologic stage and tumor invasion, lymph node metastasis, and MMP expression. In particular, expression of MMP-2 and -3 was closely related to lymph node metastasis and vascular invasion. These results suggest that MMP, especially MMP-2 and -3, play an important role in tumor invasion and metastasis and that analysis of MMP-2 and -3 production is useful for evaluation of malignant potential in esophageal carcinoma.

An analysis of proliferating cells in biopsy specimens from patients with small hepatocellular carcinoma.

The proliferation of neoplastic and nonneoplastic hepatocytes is caused by various humoral growth factors with autocrine and paracrine mechanisms, and the proliferative activity of both hepatocytes and nonhepatocytic cells contributes to neoplastic growth. The authors attempted to detect various kinds of proliferating cells immunohistochemically in small hepatocellular carcinoma (HCC) using a monoclonal antibody against DNA polymerase alpha. Most of the HCC cells that stained for this enzyme were small, had basophilic cytoplasm with poorly developed organelles, and aggregated to form clusters distributed randomly within cancer nests. Nonhepatocytic cells also were stained, including some endothelial cells, Kupffer's cells, macrophages, and lymphocytes. Fat-storing cells were not stained. The number of stained sinusoidal (capillary) cells decreased in this order: Kupffer's cells and macrophages, endothelial cells, and fat-storing cells. Nonhepatocytic cells, including lymphocytes, proliferated more actively in areas with actively growing HCC cells than in those with quiescent cancer cells. The relationship between stained HCC cells and stained sinusoidal cells was clearly defined; the correlation coefficient was 0.97. These findings suggest the possibility of a relationship between the proliferative activity of neoplastic hepatocytes and that of sinusoidal cells, including lymphocytes.

Immunohistological investigation of type IV collagen in the basement membrane surrounding the cancer nest (cancer nest membrane) of head and neck squamous cell carcinoma--its relation to frequency of cervical lymph node metastasis

Lymphoducts and blood vessels exist in the stroma, while none can be detected in the cancer nest itself within cancerous tissue. This explains why metastasis of carcinoma cannot occur without the escape of tumor cells through the basement membrane surrounding the cancer nest into the stroma. Accordingly, observation of the continuity of the basement membrane, what we call the cancer nest membrane, is essential for elucidating the first step of metastasis. Since type IV collagen is the most important structure composing the basement membrane, investigation of the immunohistological localization and continuity of type IV collagen is of value in predicting the metastatic aggressiveness of squamous cell carcinoma. We therefore studied biopsy tissues from the advancing lesion of head and neck squamous cell carcinoma in 95 untreated patients. The tissues were fixed in 85% ethanol and embedded in paraffin, and 5-um thin sections prepared were then immunohistochemically stained for type IV collagen by the ABC method for observation of the continuity status of the cancer nest membrane in relation to metastasis. The basement membranes of normal mucosal epithelium and normal interstitial capillaries were utilized as positive controls, and negative controls were obtained by using PBS in place of the primary antibodies for the immunohistochemical reaction. Membrane discontinuity (breaks or absence) correlated significantly with cervical lymph node metastasis, while intact membrane was associated with a low frequency of cervical lymph node metastasis. There was no obvious relation between the clinical T category and the continuity of the membrane; pN (+) carcinomas with membrane discontinuity included even T1 supraglottic and hypopharyngeal carcinomas, as well as T2 or higher oral mucosal carcinomas and T3 or higher glottic carcinomas, suggesting variation with tumor site. Hypopharyngeal and supraglottic carcinoma was associated with membrane discontinuity and a high incidence of cervical lymph node metastasis. On the other hand, glottic and oral carcinoma more often presented with intact membranes and had a lower incidence of metastasis, although carcinomas in these sites that did present with discontinuity of the membrane were associated with a high incidence of cervical metastasis. Therefore, observation of the continuity of the cancer nest membrane by the expression of type IV collagen may be useful in selecting better specific therapies and determining the necessity of prophylactic neck dissection. A correlation between the degree of tumor differentiation and the continuity of the membrane was also found; well-differentiated tumors with discontinuity of the membrane were frequently associated with cervical lymph node metastasis.(ABSTRACT TRUNCATED AT 400 WORDS)

口腔粘膜癌の化学療法効果と間質反応 特にｄｅｓｍｏｐｌａｓｔｉｃ ｒｅｓｐｏｎｓｅに関する検討

口腔粘膜癌の化学療法効果と間質反応 特にｄｅｓｍｏｐｌａｓｔｉｃ ｒｅｓｐｏｎｓｅに関する検討