Laminin-5 gamma 2 chain expression correlates with unfavorable prognosis in colon carcinomas.

Expression of the gamma 2 chain at the invasive front of different tumors has indicated an important role for laminin-5 in cell migration during tumor invasion and tissue remodeling. As there is considerable need for reliable invasion and prognostic markers we evaluated the correlation of laminin-5 gamma 2 chain expression with clinicopathologic parameters and patient survival in 93 primary colon carcinomas. Epithelial cells of normal mucosa were consistently negative for staining. In contrast, positive cytoplasmic staining was observed in 89 tumors (96%). Twenty-four (26%) cases were scored as sparse, 34 (37%) as moderate, and 31 (33%) as frequent gamma 2 chain expression. There was a significant association of laminin-5 gamma 2 chain expression and local invasiveness of colon carcinomas according to Dukes stage (A-C) (p=0.001) and tumor budding (p<0.001). A statistical significance could also be noted in decreasing tumor differentiation (p<0.001) and correlation to tumor size (p=0.032). No correlation was observed to tumor site. Univariate analysis identified laminin-5 (p=0.010), tumor differentiation (p=0.006) and Dukes grade (p<0.001) as significant variables in predicting prognosis. However, by multivariate analyses, this study could not demonstrate that laminin-5 gamma 2 chain expression is an independent predictive factor for survival. The results indicate that laminin-5 gamma 2 chain expression is up-regulated during the progression of human colon cancer and that it plays a role in the aggressiveness of these tumors. Demonstration of laminin-5 gamma 2 chain positivity also facilitates detection of individual cells or minor cell clusters invading the surrounding stroma. Figures on http://www.esacp.org/acp/2001/22-4/lenander.htm.

Ulcerative colitis and colorectal carcinoma: DNA-profile, laminin-5 gamma2 chain and cyclin A expression as early markers for risk assessment.

BACKGROUND: Ulcerative colitis patients are at increased risk for developing colorectal carcinomas. Despite expensive surveillance programmes, clinical practice reflects an uncertainty in individual risk assessment. The aim of the study was to evaluate independent cellular features with possible predictive value. METHODS: Two patient groups were selected: group A comprised 8 patients with ulcerative colitis-associated colorectal carcinomas, group B comprised 16 ulcerative colitis patients with risk factors (duration of disease, extent of inflammation, epithelial dysplasias). A total of 683 paraffin-embedded mucosal biopsies were retrospectively evaluated for inflammatory activity, grade of dysplasia, ploidy status, laminin-5 gamma2 chain and cyclin A expression. RESULTS: Mild or moderate inflammatory activity was present in 78% of all biopsies, low- or high-grade dysplasia in 5.5%. There was no difference in inflammatory activity and dysplasia between patient groups. In group A, 75% of the biopsies exhibited aneuploid DNA distribution patterns. Group B showed mainly proliferative-diploid cell populations (85% / P = 0.006). Laminin-5 gamma2 chain was expressed in 13% of all biopsies, with a higher frequency in group A (P = 0.002). Cyclin A expression was found in 98% of all biopsies, with a higher number of immunopositive cells in group A biopsies (P = 0.014). CONCLUSIONS: Combined nuclear DNA assessment, laminin-5 gamma2 chain and cyclin A expression may help to identify ulcerative colitis patients with an increased risk for cancer development.

Prognostic significance of free gastrointestinal tumor cells in peritoneal lavage detected by immunocytochemistry and polymerase chain reaction.

AIMS: The aim of our study was to identify tumor cells in peritoneal lavage comparatively with immunocytochemistry (ICC) and half-nested reverse transcriptase-polymerase chain reaction (RT-PCR) using carcinoembryonic antigen (CEA) as marker and to evaluate their prognostic significance. PATIENTS AND METHODS: In 75 patients who underwent surgery for a carcinoma of the colorectum (n=49), stomach (n=17) or pancreas (n=9) and 13 patients with an abdominal aortic aneurysm (control group) the abdomen was irrigated with saline solution immediately after laparotomy. Cells were separated by Ficoll-density centrifugation and divided into 2 equal volumes for ICC and RT-PCR. For ICC cells were spun onto slides by cytospin centrifugation and stained with a monoclonal antibody (mab) against CEA using the APAAP method. For RT-PCR total RNA was extracted from the cells, transcribed into cDNA and amplified with CEA-specific primers. Lavages of 13 patients with an abdominal aortic aneurysm and blood samples of 6 healthy donors served as controls. RESULTS: Immunostained tumor cells were found in peritoneal lavage in 23% (17/75) of all patients, whereas 63% (47/75) of patients gave a positive result by RT-PCR analysis. In the control group (n=13) no patient presented with tumor cells in ICC, however 5 of 13 (38%) showed amplified CEA-mRNA by RT-PCR, and so did one of six blood samples. Using ICC technique, we found significant correlations between detection rates and pT-, pN-, pM-categories as well as tumor stage. On the contrary, by RT-PCR significant correlations were observed only between pT- and pM-categories and detection rates. Detection of tumor cells in peritoneal lavage with both techniques was associated with poor prognosis. Moreover, these tumor cells are an independent prognostic factor and may have an influence on the development of peritoneal carcinomatosis. CONCLUSION: ICC is a useful method for detection of tumor cells in peritoneal lavage. In contrast, half-nested RT-PCR cannot be recommended, as the detection rates are unproportionally high, obviously as a result of CEA-mRNA expression in nontumor cells.

p53 autoantibodies in sera of patients with a colorectal cancer and their association to p53 protein concentration and p53 immunohistochemistry in tumor tissue.

We evaluated p53 autoantibodies (p53-Ab) as a preoperative tumor marker and as a prognosis marker. We also investigated whether p53-Ab production is dependent on p53 protein overexpression in tumor tissue or on tumor volume. Serum samples of patients with a colorectal cancer (n = 130) and of healthy controls (n = 44) were examined for p53-Ab using an ELISA kit. P53 protein expression in tumor tissue was demonstrated immunohistochemically and quantified by ELISA. Tumor volume was calculated and patients' survival computed using the Kaplan-Meier method. p53-Ab were detected in the serum from 15% of patients; all controls were negative. There was a significant correlation between p53-Ab production and positive immunostaining or p53 protein concentration in tumor tissue. p53-Ab were detected at a higher percentage of patients with a tumor volume of 10 cm3 or greater than in those with a smaller tumor. No difference in patients' prognosis was found between the p53-Ab positive and negative groups. Because of their low sensitivity (15%) p53-Ab are not suitable as a preoperative tumor marker. However, their high specificity (100%) and their potential for early diagnosis of a tumor relapse makes them valuable for postoperative monitoring during follow-up in p53-Ab positive patients. Furthermore, their detection can be used as a simple serological test for early detection of p53 alterations.

[J-pouch. Selection of patients and how to avoid malfunctions]. / Ileumpouch - Indikationen, Vermeidung von Fehlschlägen.

J-pouch. Selection of patients and how to avoid malfunctions.Indications for a total proctocolectomy with ileal pouch-anal anastomosis are given in patients with a familial adenomatous polyposis (FAP) and in patients with an ulcerative colitis under certain circumstances: therapy-refractory ulcerative colitis, side effects from conservative treatment, malignant transformation and emergency situations, i. e. toxic megacolon or massive bleeding. The preparation follows along anatomic layers and includes in cases of malignant transformation a radical lymph node dissection of the dependent area. When mobilizing the rectum the branches of the hypogastric nerve have to be observed with caution. A total anorectal mucosectomy is discussed controversely. In many centers the transitional zone is preserved due to a better discrimination. The pouch and the pouch-anal anstomosis should be protected by a loop ileostomy.

[Significance of lymph nodes in tumor surgery. Value of minimally invasive staging]. / Die Bedeutung der Lymphknoten in der Tumorchirurgie. Stellenwert des minimal-invasiven Stagings.

Malignant tumors require an exact staging in order to initiate individual tumor related therapeutic concepts to avoid unnecessary explorative laparotomy and to compare different treatment regimes. The assessment of the lymph node status with regard to tumor involvement using any of the actual imaging methods is quite unsatisfactory. For the improvement of the pretherapeutic tumor staging including N-classification the diagnostic laparoscopy and laparoscopic sonography are presently being evaluated. Both methods should be carried out according to a standardized investigation record. When limited to the pure diagnostic aspect, the morbidity is approx. 2%. Low patient figures with different tumor entities, insufficient information on the simultaneous occurrence of lymph node and distant metastases and/or of a peritoneal carcinomatosis as well as on the extent of the lymphadenectomy and histopathologic outcomes restrict the signifying value of many studies. It seems to be only clear that, when using the laparoscopic sonography, the sensitivity of the evidence of lymph node metastases increases in comparison with the sole laparoscopy. Definite recommendations based upon the outcomes with the required evidence, can presently neither be made with regard to the use of the method in general nor for the laparoscopic lymph node staging in particular. The use with regard to a lymph node assessment from today's point of view seems to be appropriate above all in case of: Suspect of an advanced tumor stage (existence of M1 lymphomas) For the indication in case of justified application of multimodal therapeutic concepts (exact tumor staging/N-classification). Beyond this, the laparoscopy for lymph node staging should only be used in conjunction with prospective randomized studies. Sufficient experience in the field of laparoscopic surgery and sonography as well as compliance with the rules of action for the prevention of tumor cell conveyance should be demanded.

[Cooperative procedures between endoscopy, laparoscopy. intervention and laparotomy in palliation]. / Kooperatives Vorgehen zwischen Endoskopie, Laparoskopie, Intervention und Laparotomie in der Palliation.

Within the framework of interdisciplinary palliative treatment strategies for gastrointestinal neoplasms, surgical therapeutic options are of essential importance. They are dominated by the reconstruction of the gastrointestinal passage, ensuring drainage of secretion and the alleviation of pain. Conventional, minimal-invasive and endoscopic procedures are employed individually or in a combined way, integrating all conservative therapies. In many cases, an unnecessary laparotomy with its high morbidity, mortality and prolonged hospitalisation can thus be avoided. This paper describes and discusses current surgical and endoscopic techniques for the palliative treatment of patients suffering from advanced gastrointestinal malignant tumours.

[Diagnosis and therapy of non-occlusive mesenteric ischemia (NOMI)]. / Diagnostik und Therapie der nicht-okklusiven mesenterialen Ischämie (NOMI).

Pathophysiologically, the non-occlusive mesenteric ischemia (NOMI) results from reduced blood supply to the intestine, caused by "low cardiac output syndrome", or the use of certain drugs leading to intestinal vasoconstriction and stasis of the microcirculation. Regardless of the aetiopathogenesis, the patient's prognosis crucially depends on rapid diagnosis and initiation of adequate medical or surgical intervention. In a 10-year retrospective chart analysis (1989 to 1998) we identified a total of 62 patients that demonstrated classical features of NOMI. The investigation focused on patients' history, risk factors, clinical symptoms, diagnostic procedures and patient's clinical outcome. The most important associated risk factors and concomitant diseases were reduced cardiac output (caused by preexisting heart failure), renal diseases, diabetes and the use of some specific drugs (digitalis, furosemide, ergotamine). Except for leucocytosis, elevated serum lactate and an increased CK/CK-MB level, all laboratory findings were unspecific. Using abdominal ultrasound and plain abdominal x-ray, 80% of the cases showed positive signs of ileus, subileus and free intraabdominal fluid. The angiographic diagnostics (mesentericography) of non-occlusive mesenteric ischemia showed the typical signs of peripheral vasoconstriction in 90% of the cases. Fifty three patients (86%) presenting with peritoneal signs underwent operative bowel exploration. Necrotic bowel had to be resected in 37 cases (60%). The overall letality was 58%. The progress made in better understanding the pathophysiology of NOMI has led to differential treatment of the disease. Close cooperation between surgeons and radiologists, coupled with early diagnosis and prompt treatment are necessary to optimize the clinical outcome.

[Ulcerative colitis-associated colorectal carcinoma. DNA ploidy as indicator of impending malignant transformation?]. / Das Colitis ulcerosa-assoziierte kolorektale Karzinom. DNS-Ploidie als Indikator einer drohenden malignen Transformation?

The onset of a malignant transformation in long-standing ulcerative colitis is difficult to predict. The value of the clinical and histomorphological parameters in current use is limited. It was thus aim of the present study to investigate the value of DNA-ploidy for the early detection of a malignant transformation in long-standing ulcerative colitis. This retrospective study comprised 20 patients with long-standing ulcerative colitis. The average observation time was 7.3 years (range: four to twelve years). All patients took part in a surveillance program and had between four and seven colonoscopies within a minimum period of time of five years. At these instances mucosal biopsies were taken in a standardized manner at eight different locations throughout the colon. These paraffin-embedded specimens (n = 542) were analyzed histomorphologically and DNA-cytometrically. During the observation time five patients developed an ulcerative colitis-associated colorectal carcinoma (UCA). In these patients epithelial dysplasias were not more common than in the remaining 15 cases. The vast majority of the specimen of the patients with UCA showed distinct DNA-cytometrical alterations, i.e. they were aneuploid. Such aneuploid mucosal cell populations were distributed over the whole colon, irrespectively of the later site of the carcinoma. These aneuploid lesions were found in one case eleven years, in an average seven years prior to the final diagnosis of a UCA. In contrast, the colon epithelium of the patients without UCA showed only proliferative-diploid DNA-distribution patterns during the observation time. In summary, affected patients had multiple highly aneuploid lesions of the colon mucosa at an average of seven years prior to the final diagnosis of UCA. These lesions came from macroscopically chronic inflamed tissue, and where histomorphologically without signs of dysplastic transformation. DNA-cytometrical investigations could thus be of additional predictive value for the individual risk assessment as regards an impending malignant transformation.

Expression of p53 and mdm2 mRNA and protein in colorectal carcinomas.

The aim of our study was to investigate the expression of p53 and mdm2 mRNA and protein in colorectal adenocarcinoma. For the detection of mRNA, 60 fresh frozen human tumour samples and 12 samples of corresponding normal tissue were examined. After total RNA extraction, reverse transcription (RT) was performed followed by cDNA amplification with specific primers using RT-polymerase chain reaction (PCR). Immunohistochemical detection of protein was examined in 81 formalin-fixed and paraffin-embedded human tumour specimens as well as 15 samples of adjacent normal colorectal tissue. p53 mRNA was detected in 80% (48/60) of the tumours and in 67% (8/12) of normal tissue samples; 87% (52/60) of tumours had mdm2 mRNA in contrast to only 17% (2/12) of normal tissue specimens. Nuclear p53 protein expression was observed in 52% (42/81) of the tumour specimens and in none of the 15 normal specimens, whereas mdm2 protein was found in the nucleus (31%, 25/81) and also in the cytoplasm (86%, 70/81) of tumour samples. In normal tissue, mdm2 protein expression was only observed in the cytoplasm (13%, 2/15) and not in the nucleus. There was a significant correlation between coexpression of p53 and mdm2 protein and the occurrence of lymph node metastases (P = 0.03) as well as between p53 protein expression and the occurrence of distant metastases (P = 0.007). Additionally, significant associations were found between p53 mRNA and p53 protein, p53 mRNA and mdm2 mRNA or protein, and also between mdm2 mRNA and mdm2 protein expression, supporting the existence of a regulatory mechanism involving p53 and mdm2.

Assessment of the proliferation index in gastric carcinomas with the monoclonal antibody MIB 1.

Our study aimed to reveal whether the proliferation index of tumor cells, calculated with the monoclonal antibody (mAb) MIB1, is of prognostic relevance in patients with a gastric carcinoma and shows any correlation to well-known clinicopathological factors (TNM categories, stage, grade, Laurén type). We examined formalin-fixed, paraffin-embedded tissue blocks of samples from 94 patients, who underwent surgery for an adenocarcinoma of the stomach between 1988 and 1991. Specimens were immunohistochemically stained using the mAb MIB1 in combination with the alkaline-phosphatase/anti-(alkaline phosphatase) technique. The proliferation index (PI) was estimated in various areas of interest (tumor center and periphery and in lymph node metastases of compartments I and II), by always counting 200 tumor cells in three different high-power fields per specimen, and calculated as the percentage of MIB1-positive tumor cell nuclei relative to all tumor cell nuclei in the area examined. The total PI in the primary tumor was 47.2% and slightly higher in the center (49.1%) compared to the periphery (44.7%). Surprisingly in lymph node metastases the PI was lower than in the primary tumor (compartment I: 39.5%, compartment II: 33.6%). Tumors with distant metastases revealed a higher proliferative activity (55.1%) than tumors without (44.3%). The PI increased significantly from well to poorly differentiated carcinomas (P < 0.01), whereas the intestinal Laurén type showed a lower PI than the diffuse type. No difference in survival was found between patients with a median PI or less and those with a PI above the median (47.2%). Our results show that the proliferation index in gastric carcinomas has no prognostic relevance and therefore is of low clinical value.

Prognostic relevance of occult tumor cells in lymph nodes of colorectal carcinomas: an immunohistochemical study.

PURPOSE: Whereas lymph node metastases in colorectal carcinoma are an important prognostic factor, the prognostic relevance of occult tumor cells in lymph nodes is not elucidated at present. Therefore, our study intended to assess the rate of patients with occult tumor cells in histopathologically negative lymph nodes. Furthermore, we tried to evaluate an eventual influence of these occult tumor cells on patients' prognoses. METHODS: For examination, we used paraffin blocks of lymph nodes, tumor-negative by conventional histopathology, from 49 patients with colorectal carcinoma (Stage I-III) after a curative (R0) tumor resection in 1987. After preparation of tissue blocks using the serial sectioning technique, the specimens were stained with the alkaline phosphatase, antialkaline phosphatase method and two monoclonal antibodies (AE1/AE3 and Ber-EP4). RESULTS: In 13 of 49 patients (26.5 percent), we disclosed tumor cells, mostly located in subcapsular sinuses as single cells or in groups. There was a good correlation between the detection rate and N category, tumor stage, and grading. Moreover, 33 percent of patients in Stage I/II with occult tumor cells (N0+) developed a local relapse and/or distant metastases in contrast to 12 percent of patients without tumor cells (N0-). With a median follow-up of 84 months, we found no difference in disease-free survival between the tumor cell negative and positive groups in Stage I/II patients. CONCLUSION: The results show that occult tumor cells might increase the risk for development of a local tumor relapse and/or distant metastases but do not influence patients' prognoses at all.

[A technic of MRT-guided abdominal drainage with an open low-field magnet. Its feasibility and the initial results]. / Technik der MRT-gesteuerten abdominellen Drainage an einem offenen Niederfeldmagneten. Durchführbarkeit und erste Ergebnisse.

PURPOSE: To test the practicality of MRT-aided drainage using an open low-field magnet and to report on the early clinical results. METHODS: So far seven patients have been treated (four subphrenic abscesses, two psoas abscesses and one pancreatic pseudocyst). The planning of the approach and catheter insertion were carried out under MRT control (Magnetom Open, 0.2 T). Subsequent treatment was controlled by CT and fluoroscopy. Initial puncture was carried out with a non-magnetic 18 gauge Chiba needle. The drainage catheter was introduced by Seldinger's technique in six cases and with a trocar in one patient. RESULTS: In all seven patients drainage could be started successfully. The design of the magnet and coils permitted adequate accessibility of the patient. There were no problems in visualising the puncture needle. Controlling the position of the catheter by MRT was, however, difficult. CONCLUSION: The first two steps in abscess drainage (planning the approach and inserting the catheter) can be carried out under MRT control. For further catheter control and observing the course of the disease we presently prefer CT or fluoroscopy.

[Tumor cell dissemination in bone marrow and peritoneal cavity. An immunocytochemical study of patients with stomach or colorectal carcinoma]. / Tumorzelldissemination in das knochenmark und in die peritonealhoehle. Eine immunzytochemische untersuchung an patienten mit einem magen; oder kolerektalen karzinom.

The tumor spread and the radicality of surgical resection are the most important facts in a patient's prognosis. In spite of curative tumor resection many patients die from metastases or local tumor recurrence. One possible reason is early dissemination of tumor cells which cannot be detected with clinical methods of examination. For this reason the aim of our study was to examine both bone marrow and peritoneal lavage for disseminated tumor cells with an immunocytochemical technique in patients with a gastrointestinal carcinoma. We also wanted to find out whether there was any correlation between the incidence of tumor cell detection and the TNM classification, staging and tumor grading and whether disseminated tumor cells have any prognostic significance. Our study included 54 patients who underwent surgery in our clinic for a carcinoma of the stomach (20 patients) or the colorectum (34 patients) from November 1993 to December 1994. At the beginning of the operation bone marrow had been taken from the iliac spine, and the abdomen was irrigated with 1000 ml saline solution immediately after laparotomy or laparoscopy. After cell separation with Ficoll density centrifugation 5 x 10(5) cells were applied per slide by a cytospin technique. For detection of the tumor cells we used the APAAP technique and the following monoclonal antibodies: KL1, CK2, anti-CEA, 17-1A (bone marrow) and Ber-EP4, B72.3, anti-CEA and 17-1A (peritoneal lavage). Altogether 77% of all patients had tumor cells in the bone marrow and 69% in peritoneal lavage fluid. It was possible to detect tumor cells in bone marrow (67%) and peritoneal lavage fluid (25%) even of patients with T1 tumors. The percentage increased with depth of wall infiltration. There was a marked difference in bone marrow aspirates between patients with lymph-node-negative tumors (N0) and those with lymph-node-positive tumors (N+): 65% had tumor cells in N0 and 85% in N+ stages. This trend was also seen in patients with (M1) and without (M0) metastases, in both bone marrow aspirates and peritoneal lavage fluid. In bone marrow there was a good correlation of tumor cells with staging, but in peritoneal lavage fluid this was not so. Finally, we detected tumor cells more often in bone marrow and peritoneal lavage fluid of patients with poorly differentiated tumors (G3) or diffuse Lauren type than in patients with moderately differentiated tumors (G2) or intestinal Lauren type. After a median follow-up period of 12.5 months patients with disseminated tumor cells had a lower survival rate than patients without tumor cells.

Association of immunohistochemical p53 tumor suppressor gene protein overexpression with prognosis in highly proliferative human mammary adenocarcinomas.

An increasing body of evidence suggests that in addition to conventional histopathologic tumor characteristics, DNA content measurements, cell kinetic data, and investigations of tumor suppressor gene expressions might be of valuable information in breast cancer patients. Against this background we investigated immunohistochemically overexpression of the interphase associated protein proliferating cell nuclear antigen (PCNA) and the mutant p53 protein in routinely paraffin-embedded surgical specimens from 180 breast cancer patients with known nuclear DNA profiles. The mean clinical follow-up was 16 years (range 13-20 years). The percentage of PCNA immunoreactive tumor cell nuclei ranged between < 5% and 60% (mean 13.59 +/- 10.85%). There was a direct association between high levels of PCNA expression (> 20%) and p53 protein overexpression (p = 0.001), high histologic tumor grade (p = 0.009), and DNA aneuploidy (p = 0.019). Mutant p53 protein overexpression was found in 44 of 180 (24%) cases and was significantly related to high histologic tumor grade (p = 0.004), DNA aneuploidy (p = 0.001), and high levels of PCNA expression (p = 0.001). Patients with highly proliferative carcinomas (> 20% PCNA expression) had a shortened distant metastases-free survival when their neoplasms overexpressed p53. In contrast, the distant metastases-free survival of patients with highly proliferative, p53-negative tumors was significantly longer (p = 0.03). Immunohistochemical p53 protein overexpression thus appears to be indicative of an increased malignant potential in breast cancer patients. Highly proliferative tumors composed of p53 immunoreactive neoplastic cells clinically seem to behave more aggressively than the highly proliferative p53-negative tumors.

Immunohistochemical expression of the mutant p53 protein and nuclear DNA content during the transition from benign to malignant breast disease.

Immunohistochemical expression of the cellular phosphoprotein p53 was investigated in archival, formalin-fixed, and paraffin-embedded surgical breast tissue specimens from 543 patients using the polyclonal antibody CM-1. Cytometric DNA assessments were performed on histopathologically or cytopathologically identified cell nuclei using image analysis. The series included five samples of normal resting breast parenchyma, 35 benign lesions including benign tumors, 54 hyperplastic lesions with and without atypia, 109 carcinomas in situ, and 340 invasive adenocarcinomas. In 56 of the latter cases specimens from corresponding lymph node metastases also were investigated. Mutant p53 protein expression was absent in normal resting parenchyma and in benign lesions, including benign tumors and epithelial hyperplasias. However, 14 of the 54 hyperplasias (26%) were found to be of DNA aneuploid type. Thirteen of 109 (12%) carcinomas in situ and 79 of 340 (23%) invasive neoplasms expressed the mutant p53 protein. Eight of nine (89%) p53 immunoreactive carcinomas in situ and 62 of 78 (80%) invasive carcinomas with p53 expression were DNA aneuploid. In invasive carcinomas p53 expression was absent in well differentiate neoplasms. In contrast, 58 of 158 (37%) poorly differentiated invasive carcinomas immuoreacted. Intraductal carcinomas of comedo type and poorly differentiated invasive carcinomas of comedo type expressed the mutant p53 protein in seven of 18 cases (39%) and in 14 of 22 cases (64%), respectively. The staining behavior of lymph node metastases was the same as that of the corresponding primary tumors. The present findings suggest that chromosomal alterations as indicated by DNA aneuploidy occur in precancerous lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemical expression of the mucin-type glycoprotein A-80 and prognosis in human breast cancer.

Immunohistochemical expression of the tumour associated mucin-type glycoprotein A-80 was investigated in a series of 173 breast cancer patients with a clinical follow-up between 13 and 19 years. A routine immunoperoxidase technique was used in formalin-fixed, paraffin-embedded surgical tumour specimens. One hundred and fifty of 173 tumours (87%) immunostained with MAb A-80. The degree of A-80 immunoreactivity was related to the tumour grade but not to lymph node status, tumour size, or nuclear DNA distribution pattern. In univariate analysis the degree of A-80 expression was found to be of significant prognostic value both in node negative and in node positive breast cancer patients (P = 0.03). Patients with non-A-80 immunoreactive tumours had significant longer distant metastases-free survival times and fewer relapses than women with carcinomas composed of A-80 immunoreactive tumour cells. This prognostic value was reduced in a multivariate analysis, including lymph node status, tumour size, and nuclear DNA distribution pattern, but retained borderline significance (P = 0.08). In conclusion, the findings of this study indicate that expression of the mucin-type glycoprotein A-80 as determined by immunohistochemistry seems to be related to clinical outcome in breast cancer patients.

Prognostic value of the combined assessment of proliferating cell nuclear antigen immunostaining and nuclear DNA content in invasive human mammary carcinomas.

The expression of the S-phase associated, nuclear protein proliferating cell nuclear antigen (PCNA) was investigated in routinely paraffin-embedded surgical specimens from 209 breast cancer patients. Cytometric DNA assessments were performed on fine-needle aspirates, upon which the primary diagnosis of breast cancer had been based. The mean clinical follow-up was 16 years (range 13-20 years). The percentage of PCNA immunoreactive tumour cells ranged between less than 5 to 60% (mean value 13.34%). There was a direct association between PCNA expression, high histological tumour grade (p < 0.01), and DNA aneuploidy (p = 0.009). In a subgroup of 22 patients with near-diploid DNA distribution patterns the PCNA expression yielded additional prognostic information. Patients with tumours of near-diploid DNA histograms and more than 20% of PCNA immunoreactive neoplastic cells had a significantly worse clinical course, than patients with near-diploid tumours containing less than 20% PCNA immunoreactive cells (p = 0.0001). In contrast, the PCNA immunoreactivity did not yield additional prognostic information for patients with distinctly diploid or highly aneuploid tumour variants. In a multivariate analysis comprising all 209 patients, nodal status (p < 0.01), tumour size (p < 0.01), and DNA ploidy (p < 0.01) were found to have significant prognostic effect. The findings indicate that carcinomas characterised by high proliferative activity and near-diploid DNA distribution patterns can show rapid tumour progression. The combined assessment of the PCNA immunoreactivity and of the nuclear DNA content in routinely processed surgical specimens of breast cancer patients appears to be of prognostic value.