Domenico Marrano

Neoplastic involvement of nipple-areolar complex in invasive breast cancer

The neoplastic involvement of the nipple-areolar complex was histologically studied in 1,291 available consecutive mastectomy specimens with primary invasive breast carcinoma. Tumor involvement of the nipple-areolar complex was found in 150 specimens (12 percent) and was not suspected on gross examination in 99 patients (8 percent). A significant finding of our study was the relatively high rate of tumor foci in the nipple-areolar complex (7 percent) in those patients with early invasive stage I or II breast carcinoma eligible for conservative therapy. Analysis of nipple-areolar complex involvement with consideration of different clinico-morphologic variables indicates that it was directly associated with tumor size. No significant correlation was found with axillary metastases, tumor histologic type, or with the presence of noninvasive cancer in the vicinity of the dominant tumor. Our estimate of the significant change of finding tumor in the nipple-areolar complex, especially in the patient group eligible for conservative therapy, underlines the need for postoperative radiation.

Pancreatic Metastases: Observations of Three Cases and Review of the Literature

Background: The aim of the study is to analyze pancreatic metastases and their clinical, radiological, therapeutic and prognostic features. Methods: Three cases of pancreatic metastases observed and a world literature review of 333 cases were recorded. Results: Pancreatic metastases are due more frequently to renal cell carcinoma; they are usually metachronous and characterized by a long period of time between the resection of the primary tumor and their detection. The differential diagnosis with other pancreatic masses is difficult, but an accurate anamnesis, some peculiar findings of imaging techniques and percutaneous fine needle aspiration could allow preoperative diagnosis. Pancreatic resections are the treatment of choice allowing the better palliation and improving survival. 150/234 pancreatic metastases underwent pancreatic resections (resectability index = 64.1%); 88/132 patients are alive with a mean follow-up of 27.1 months; of the 44 dead patients the mean survival time was 21.3 months. Among pancreatic metastases the primary tumor with better prognosis is renal cell carcinoma. Conclusion: Pancreatic metastases are rare; their preoperative diagnosis is difficult but useful and possible. Surgical resection is suggested because the patient still may have a prolonged survival.

DIFFERENTIATION PATHWAYS IN PRIMARY INVASIVE BREAST CARCINOMA AS SUGGESTED BY INTERMEDIATE FILAMENT AND BIOPATHOLOGICAL MARKER EXPRESSION

The expression of intermediate filament proteins (IFPs) in 65 primary breast carcinomas was analysed by a panel of specific antibodies. Results were integrated with the oestrogen and progesterone receptor (ER and PGR) status, Ki‐67 marking, and epidermal growth factor receptor (EGFr) expression. Invasive breast carcinomas could be divided into three main groups: group 1 revealed positivity only for ‘simple epithelial’ cytokeratins (CKs 7, 8, 18, and 19); group 2 also stained with the antibodies K8.12 and 34βE12; while group 3 showed co‐expression of CKs 14 and 17, vimentin, and α‐smooth muscle actin. Group 3 consistently comprised tumours with the highest Ki‐67 levels, EGFr positivity, and ER‐PGR negative status. On the other hand, groups 1 and 2 usually exhibited a positive hormonal status, lower proliferative activity, and EGFr negativity. The results of this study indicate that the determination of IFPs can significantly contribute to the identification of groups of patients with different biopathological settings and possibly different clinical behaviour.

c-erbB-2 over-expression in amplified and non-amplified breast carcinoma samples

We investigated c‐erbB‐2 oncogene amplification and over‐expression in 79 invasive breast carcinoma samples using fluorescence in situ hybridization (FISH) and immuno‐histochemistry, with the aim of studying relationships between neoplasms over‐expressing c‐erbB‐2 with or without amplification and bio‐pathological parameters used in clinical breast cancer. Nineteen samples showed amplification, and all of these were positive by immuno‐histochemistry. Moderate or intense immunostaining was present in a further 22 samples without c‐erbB‐2 amplification and was not related to any increased number of c‐erbB‐2 signals: 15 samples exhibited chromosome 17 polysomy, 3 monosomy and 4 no FISH abnormalities. Thirty‐eight samples were immunonegative: 18 exhibited chromosome 17 polysomy, 9 monosomy and 11 no alterations. Samples having c‐erbB‐2 over‐expression associated with amplification showed DNA aneuploidy and hormonal receptor loss to a greater extent than those expressing c‐erbB‐2 without amplification or immunonegative samples (χ2 test, p = 0.007, 0.008 and 0.008, respectively). The proliferation rate, detected by Ag‐NOR staining, was highest in amplified samples (Kruskal Wallis test, p = 0.009). Our results indicate that tumours showing both c‐erbB‐2 over‐expression and amplification exhibit more aggressive biological characteristics than those with only over‐expression or immunonegative tumours. Since both c‐erbB‐2 amplification and over‐expression have been related to negative responses to chemotherapy and poor prognosis, these differences might have clinical implications. The combination of FISH and immuno‐histochemistry may be helpful to achieve this aim. Int. J. Cancer (Pred. Oncol.) 84:273–277, 1999.

Do early symptoms of pancreatic cancer exist that can allow an earlier diagnosis

Diagnosis of pancreatic cancer is made late, and prognosis remains extremely poor. This study was carried out to investigate whether symptoms exist before pain or jaundice that could suggest pancreatic cancer and favor earlier diagnosis. The study involved 305 patients with confirmed pancreatic cancer and 305 controls. All subjects were interviewed personally at least twice about their clinical history; pancreatic cancer patients were asked about any disturbances before abdominal pain or jaundice. Of the 305 pancreatic cancer patients, 151 (49.5%) had some prior disturbances, 108 (35.4%) 6 months or less before pain or jaundice and 43 (14.1%) more than 6 months before. Among the latter, 14 (4.6% of all patients) had had anorexia and/or early satiety and/or asthenia (7–20 months before pain or jaundice), 11 (3.6%) had disgust for coffee and/or smoking and/or wine (7–20 months before), 14 (4.6%) had diabetes (7–24 months before), and four (1.3%) had acute pancreatitis (8–26 months before). Among the controls, the only reports of these symptoms were two (0.7%) cases of asthenia (4 and 6 years earlier), 22 (7.2%) cases of diabetes (of which only two [0.7%] were diagnosed 7–24 months before the interview), and one (0.33%) case of acute pancreatitis (10 years earlier). Apart from acute pancreatitis, all the other differences between patients and controls were statistically significant. In approximately 15% of patients, disturbances existed more than 6 months before pain or jaundice, which, although not specific, could raise suspicion of the possibility of pancreatic cancer. These disturbances could represent the one current opportunity for an earlier diagnosis in a significant minority of pancreatic cancer patients.

β-Galactoside α2,6 sialyltransferase in human colon cancer : Contribution of multiple transcripts to regulation of enzyme activity and reactivity with Sambucus nigra agglutinin

Colon cancer tissues display an increased activity of β‐galactoside α2,6 sialyltransferase (ST6Gal.I) and an increased reactivity with the lectin from Sambucus nigra (SNA), specific for α2,6‐sialyl‐linkages. Experimental and clinical studies indicate a contribution of these alterations to tumor progression, but their molecular bases are largely unknown. In many tissues, ST6Gal.I is transcriptionally regulated through the usage of different promoters that originate mRNAs diverging in the 5`‐untranslated regions. RT‐PCR analysis of 14 carcinoma samples, all expressing an increased ST6Gal.I enzyme activity, and of the corresponding normal mucosa revealed the presence of at least 2 transcripts. One, containing the 5`‐untranslated exons, Y+Z, is thought to represent the “housekeeping” expression, and another previously described in hepatic tissues. Both the Y+Z and the hepatic transcripts were detectable in normal and cancer tissues but that latter form had a marked tendency to accumulate in cancer. The extent of α2,6‐sialylation of glycoconjugates, as determined by SNA‐dot blot analysis, was markedly enhanced in all cancer specimens, but the level of reactivity only partially correlated with the level of enzyme expression. Western blot analysis revealed a strikingly heterogeneous pattern of SNA reactivity among cancer tissues. These data indicate that: i) during neoplastic transformation of colonic cells, ST6Gal.I expression may be modulated through a differential promoter usage; ii) the extent of α2,6‐sialylation of cancer cell membranes is not a direct function of the ST6Gal.I activity, strongly suggesting the existence of other, more complex mechanisms of regulation. Int. J. Cancer 88:58–65, 2000.

Clone heterogeneity in diploid and aneuploid breast carcinomas as detected by FISH

We investigated the relationship between DNA ploidy and alterations in chromosomes 1, 8, 12, 16, 17, and 18 in 63 breast carcinoma samples by static cytofluorometry and fluorescence in situ hybridization. Thirty specimens were diploid and 33 were aneuploid. In aneuploid samples, the DNA index value ranged from 1.3 to 3.1, with a main peak near tetraploid values. Diploid clones were present in 21 of 33 aneuploid specimens. Fluorescence in situ hybridization analysis showed a heterogeneous degree of alterations in diploid specimens: one sample was normal, 16 samples had one to three chromosome alterations involving mostly chromosomes 1, 16, and 17, and 13 samples an even higher degree of alterations. The 33 aneuploid specimens showed a very high number of signals (four, five, or more). All the investigated chromosomes were affected in 23 of 33 specimens. Alterations in chromosomes 1 and 17 were detected to a similar percentage in diploid and aneuploid samples, whereas chromosome 16 monosomy was more frequent in diploid samples. Overrepresentation of chromosomes 8, 12, 16, and 18 was significantly higher in aneuploid than in diploid samples. Based on these results, we suggest that diploid and aneuploid breast carcinomas are genetically related. Chromosome 1 and 17 alterations and chromosome 16 monosomy are early changes. Allelic and chromosomal accumulations occur during progression of breast carcinoma by different mechanisms. The high clone heterogeneity found in 17 of 33 aneuploid samples could not be completely explained by endoreduplication and led to the suggestion that chromosomal instability concurs with aneuploidy development. This different evolutionary pathway might be clinically relevant because clone heterogeneity might cause metastasis development and resistance to therapy.

Villin, intestinal brush border hydrolases and keratin polypeptides in intestinal metaplasia and gastric cancer; an immunohistologic study emphasizing the different degrees of intestinal and gastric differentiation in signet ring cell carcinomas

Gastric carcinomas have been assayed for the presence of villin and for the small intestinal hydrolases aminopeptidase N and sucrase isomaltase. These proteins seem not to be present in normal stomach epithelium. However intestinal metaplasia in stomach, and tumour cells in the glandular patterns of gastric carcinoma were positive for all three markers, showing characteristic apical positivity. In contrast, in diffuse gastric carcinomas the percentage of signet ring cells positive for these markers varied from 10–100% with each marker showing a similar percentage of positive cells. Testing of gastric carcinomas with antibodies specific for different keratin polypeptides showed that while all 7 tumours were positive for keratins 8 and 18,2 were also positive for keratin 7. In the keratin 7 positive tumours all tumour cells were keratin 7 positive. The keratin 8 antibody also reacted on routinely fixed specimens. Thus gastric carcinomas reveal different degrees of gastric and intestinal differentiation

Quantitative p21WAF-1/p53 immunohistochemical analysis defines groups of primary invasive breast carcinomas with different prognostic indicators

We used image cytometry to quantify the immunohistochemical expression of p21waf‐1 and p53 in primary breast carcinoma. Ratio analysis of the quantified p53/p21waf‐1 protein expression allowed us to define 3 groups of carcinomas, each characterized by specific pathological and biological profiles. The negative (NEG) group, characterized by negligible expression of both proteins, comprised small‐sized, low‐grade tumors associated with high contents of hormonal receptors and low growth fraction. In the NEG group, Ki‐67 labelling index area (%LIa) was the only significant prognostic indicator. The P53H group, characterized by prevalence of p53 %LIa, was constituted by large‐sized, high‐grade tumors showing low hormonal receptor contents and high growth fraction. In the P53H group, both p53 and Ki‐67 were inversely associated with both estrogen receptor (ER) and progesterone receptor (PGR), suggesting that extensive p53 immunostaining is related to poor differentiation and high proliferation. Only N status was prognostically significant in the P53H group. The P21H group, characterized by prevalence of p21waf‐1 %LIa, displayed intermediate pathological and biological features. A significant association between p53 and p21waf‐1 expression suggested functional stabilization of wtp53 and therefore possible DNA damage‐dependent G1/S arrest (genetic instability) in the P21H group; P21waf‐1expression was significantly associated with the presence of node metastasis. Patients in the P21H group had a higher recurrence rate and a shorter disease‐free time interval from surgery with respect to the NEG group. Proportional hazard regression analysis disclosed Ki‐67 %LIa and, to a lesser degree, PGR %LIa as significant relapse‐free survival prognostic indicators.

The role of ultrasound in the differential diagnosis of serous and mucinous cystic tumours of the pancreas

Objective: To evaluate the usefulness of a series of ultrasound parameters in the differential diagnosis between serous and mucinous forms of cystic tumours of the pancreas. Setting: Retrospective comparative study between the histological analysis of surgical specimens from cystic tumours of the pancreas (4 serous cystadenomas, 6 mucinous cystadenomas and 11 mucinous cystadenocarcinomas) and ultrasound evaluation. Methods: The ultrasound images of the 21 tumours were analysed by an operator who did not know the result of the histological diagnosis and were divided according to Johnsons criteria (number of cysts >6 and diameter <2 cm for serous tumours; number of cysts <6 and diameter >2cm for mucinous tumours) and according to other anatomicopathological parameters such as the presence of septae, endocystic projections, central scar, central calcification and/or in the tumour wall. Results: The ultrasound study gave a correct diagnosis in two out of the four (50%) serous cystic tumours. A central scar and internal calcification was present in one of them. Fifteen (88.2%) of the 17 mucinous tumours were correctly diagnosed; one presented peripheral calcifications and three endocystic projections. Conclusion: Ultrasound has a high degree of sensitivity in the differential diagnosis of serous and mucinous cystic tumours of the pancreas if the ultrasound aspects corresponding to the anatomicopathological structure of the neoplasms are correctly evaluated.