Torsten Mattfeldt

FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters

Abstract. The aim of this study was to evaluate the possible correlation between preoperative FDG-PET results in human breast cancer and the prognostic markers Ki-67, c-erb B2, p53, oestrogen/progesterone receptor status, axillary lymph node status, tumour size and tumour grading. Seventy-five female patients with breast cancer were included in this prospective study. Patient selection was independent of tumour size and the suspected clinical stage of disease. A high-resolution full-ring scanner (Siemens ECAT HR+) was used for PET imaging. The FDG uptake of breast tumours was calculated as the tumour to background ratio (TBR). In resected cancer tissue specimens, the proliferative fraction was evaluated by Ki-67 immunostaining. Additionally, immunostaining of the prognostic markers c-erb B2, p53, and progesterone and oestrogen receptors was performed. Haematoxylin and eosin-stained sections were used for tumour grading. Correlations between FDG uptake and prognostic markers were assumed to be significant at P<0.05 using the Mann-Whitney U test. In ductal breast cancer, mean TBR was 17.3 (median 7.7, range 1.6–122.7), while in lobular cancer it was 6.5 (median 3.7, range 1.4–22.7). Mean proliferative fraction (% Ki-67 positive tumour cells) was 15%±13.8% (median 10%, range 0%–60%). Twenty-three carcinomas showed <5% Ki-67 positive tumour cells. Statistical analysis indicated a positive correlation between FDG uptake and proliferative index in ductal breast cancer (P<0.0001, r=0.63). By contrast, there was no correlation between FDG uptake and c-erb B2 (P=0.79), p53 (P=0.92), tumour grading (P=0.09), oestrogen receptor status (P=0.41), progesterone receptor status (P=0.34), axillary lymph node status (P=0.90) and tumour size (P=0.3). It is concluded that FDG uptake is significantly higher in ductal breast cancer than in lobular cancer (P<0.05). FDG uptake correlates with proliferative activity assessed by Ki-67 immunostaining (P<0.05). A significant correlation with the other prognostic markers, however, could not be demonstrated.

α-Methylacyl-CoA Racemase: Expression Levels of this Novel Cancer Biomarker Depend on Tumor Differentiation

alpha-Methylacyl-CoA racemase (AMACR) has previously been shown to be a highly sensitive marker for colorectal and clinically localized prostate cancer (PCa). However, AMACR expression was down-regulated at the transcript and protein level in hormone-refractory metastatic PCa, suggesting a hormone-dependent expression of AMACR. To further explore the hypothesis that AMACR is hormone regulated and plays a role in PCa progression AMACR protein expression was characterized in a broad range of PCa samples treated with variable amounts and lengths of exogenous anti-androgens. Analysis included standard slides and high-density tissue microarrays. AMACR protein expression was significantly increased in localized hormone-naive PCa as compared to benign (P < 0.001). Mean AMACR expression was lower in tissue samples from patients who had received neoadjuvant hormone treatment but still higher compared to hormone-refractory metastases. The hormone-sensitive tumor cell line, LNCaP, demonstrated stronger AMACR expression by Western blot analysis than the poorly differentiated cell lines DU-145 and PC-3. AMACR protein expression in cells after exposure to anti-androgen treatment was unchanged, whereas prostate-specific antigen, known to be androgen-regulated, demonstrated decreased protein expression. Surprisingly, this data suggests that AMACR expression is not regulated by androgens. Examination of colorectal cancer, which is not hormone regulated, demonstrated high levels of AMACR expression in well to moderately differentiated tumors and weak expression in anaplastic colorectal cancers. Taken together, these data suggest that AMACR expression is not hormone-dependent but may in fact be a marker of tumor differentiation.

CYSTIC TUMOURS OF THE PANCREAS : DIAGNOSTIC ACCURACY, PATHOLOGIC OBSERVATIONS AND SURGICAL CONSEQUENCES

Background: Cystic neoplasms of the pancreas account for only 1% of primary pancreatic lesions. However, patients with these tumors are diagnosed more frequently. Up to now, nonsurgical management is still the established form of treatment of benign cystic tumours of the pancreas. Methods: Between 1987 and 1996 we treated 51 patients with serous and mucinous cystadenoma and their malignant counterparts, serous and mucinous cystadenocarcinoma. Results: Eighty-five percent of the patients presented symptoms. Computed tomography and endoscopic cholangiopancreatography (ERCP) were the most sensitive diagnostic techniques; however, in three patients with serous cystadenoma and in one patient with serous cystadenocarcinoma, ERCP findings were completely normal. The tumour was resected in all but one patient. There was no perioperative mortality. After dismissal from the hospital, all patients in whom benign tumours had been resected are still alive; however, the late mortality of mucinous cystadenocarcinoma was 36% after a median follow-up of 6 years. Conclusion: Surgical resection is recommended in all cystic tumours, even in serous cystic tumours, because symptoms may develop and malignant transformation to serous cystadenocarcinoma is possible.

Molecular mediators of tumor angiogenesis: Enhanced expression and activation of vascular endothelial growth factor receptor KDR in primary breast cancer

The progression of breast cancer growth and its ability to metastasize are associated with the process of angiogenesis. In this study, we examined the protein expression of vascular endothelial growth factor (VEGF) and its specific and functional receptor KDR in human breast tissue. We investigated a total of 13 mammary carcinomas, 3 fibroadenomas, 5 specimens with fibrocystic breast disease as well as normal (adjacent to malignant) breast tissue using immunohistochemistry and Western blot analysis. In all carcinomas examined, functional KDR protein was present independent of tumor type, tumor stage and histological grade as demonstrated by tyrosine phosphorylation analysis of KDR. When malignant tissues were compared with their neighboring non‐neoplastic regions, activated KDR was found to be expressed to a much higher extent within the malignant tissue samples. In fibroadenomas, KDR was barely detectable, whereas in fibrocystic breast disease KDR expression was variable. Immunostaining of KDR was localized to endothelium and epithelium of mammary ducts in malignant and benign breast tissue, while VEGF immunoreactivity was primarily found in the endothelium and also in tumor cells and macrophages. Our data demonstrate that KDR activation is enhanced in breast cancer in vivo and emphasize the functional role of VEGF and KDR in the development of malignant breast disease. Int. J. Cancer (Pred. Oncol.) 84:293–298, 1999.

Biological characterisation of breast cancer by means of PET

Breast cancer is associated with increased glucose consumption and can therefore be visualised with the glucose analogue [18F]2-deoxy-2-fluoro-d-glucose (FDG) and positron emission tomography (PET). FDG uptake in the primary tumour can vary substantially, and specific tumour characteristics have been demonstrated to determine the degree of glucose metabolism. Factors with a major influence on FDG uptake in breast cancer comprise expression of glucose transporter Glut-1 and hexokinase I, number of viable tumour cells per volume, histological subtype, tumour grading, microvessel density and proliferative activity. Recently, an association between high FDG uptake and a worse prognosis was suggested. Several studies have been performed correlating FDG uptake with a variety of prognostic and molecular biomarkers as well as parameters predicting tumour response to therapy. However, a correlation with important clinical prognostic markers such as axillary lymph node status and size of the primary tumour, expression of oestrogen and progesterone receptors, proto-oncogene c-erbB-2 or VEGF could not be demonstrated. The lack of correlation with important markers of prognosis does not suggest that FDG uptake might be used as a prognostic criterion in breast cancer. Innovative radiotracers for specific imaging of tumoural perfusion ([15O]H2O), hormone receptor expression ([18F]FES), protein synthesis ([11C]methionine), proliferation rate ([18F]FLT) or bone mineralisation ([18F]fluoride) may provide additional information compared with that provided by FDG PET.

Serous cystadenocarcinoma of the pancreas

SummaryThe mucinous type of cystadenoma of the pancreas is known to have malignant potential, whereas the serous type is believed to be benign. Therefore, the therapeutic strategies for serous cystadenomas are less aggressive than in mucinous cystadenoma, where complete operative resection is the procedure of choice.A patient with a biopsy-proven serous cystadenocarcinoma with a lymph node metastasis is reported. Considering the reported case and a review of the literature, the origin of serous cystadenocarcinoma appears to be from cystadenoma lesions.Even if this development of cystadenocarcinoma in pre-existing serous cystadenoma lesions is a rare entity, a less aggressive treatment of this lesion should be avoided in favor of resection procedures because of the good chance of cure.

Intraductal papillary mucinous tumor of the pancreas

BACKGROUND Since 1996 the classification of pancreatic tumors was replaced by the new World Health Organization nomenclature. Formerly mucinous cystadenomas are now distinguished between intraductal papillary mucinous tumors of the pancreas (IPMT) and mucinous cystadenomas. METHODS We reevaluated the pathological specimen and surgical therapy of 23 consecutive patients and followed up these patients up for 4 years in median. Between 1987 and 1997 we treated 8 patients with IPMT and 15 patients with mucinous cystadenomas. RESULTS Eighty-five per cent of all patients were symptomatic. Ultrasonography and computed tomography were the most sensitive diagnostic techniques. In 25%, the entire pancreas was involved with IPMT; that was not the case in any of the patients with mucinous cystadenoma. All patients were resected with no perioperative mortality. After dismissal from the hospital, all resected patients are still alive after a median follow-up of 4 years. In no patient with IPMT, but in 1 patient with mucinous cystadenoma, the tumor recurred. CONCLUSION Surgical resection is the treatment of choice in all cystic tumors, and the late outcome of IPMT is as good as for mucinous cystadenoma.

Solid-pseudopapilläre Tumoren des Pankreas

Summary. We report on three female patients with solid pseudopapillary tumors of the pancreas. The histogenetic origin of this entity is still unclear. The tumor, usually occurring in young women, forms large masses (up to 10 cm in diameter) before becoming symptomatic. Metastases have very rarely been reported. In contrast to other pancreatic tumors, the main pancreatic duct was displaced, but of normal caliber without stenosis, in all our patients. Despite the large size of the tumors, they were curatively resected in all three cases. Two of the tumors infiltrated the parenchyma or adipose tissue of the pancreas but did not spread into the lymph nodes or other organs. All of the patients are alive and without signs of tumor recurrence up to 8 years after surgical resection.Zusammenfassung. Wir berichten über unsere Erfahrungen an 3 Patientinnen mit einem solid-pseudopapillären Tumor des Pankreas. Charakteristisch für diesen semimalignen Tumor sind das Vorkommen bei jungen Frauen, die auffallende Größe (bis 10 cm) und das seltene Auftreten von Metastasen. Trotz erheblicher Größe der Tumoren war in allen Fällen eine kurative Resektion möglich. Präoperatives Hauptunterscheidungsmerkmal zum duktalen Adenocarcinom war in allen Fällen die normale Weite des Pankreasgangs ohne Gangabbruch. Im Gegensatz zu den meisten anderen Tumoren des Pankreas hat dieser Tumor eine gute Prognose. Alle unsere Patientinnen sind z. Z. (bis zu 8 Jahren nach der Operation) rezidivfrei.Schlüsselwörter: Solid-pseudopapillärer Tumor – Pankreas – papillär-cystischer Tumor

Second-order stereology of benign and malignant alterations of the human mammary gland

The purpose of the present study was a quantitative characterization of the three‐dimensional arrangement of the epithelial component of benign and malignant alterations of the female breast by combining stereology with stochastic geometry. Twenty cases of fibrous mastopathy and 20 cases of invasive ductal mammary cancer were studied at the light microscopic level. Segmentation of the epithelial tissue component was performed with an image analyser. From the resulting binary images, unbiased estimates of the covariance C(r) and the intensity Vv of the epithelial volume component were obtained automatically by computer. From these data, estimates of the correlation function k(r), of the pair correlation function g(r), of the radial distribution function RDF(r) and of the reduced second moment function K(r) of epithelial volume were determined. The estimates of C(r) and RDF(r) differed between groups, but these functions depend on spatial pattern and Vv. As carcinomas showed a significantly higher epithelial volume density Vv than mastopathies, estimation of C(r) and RDF(r) alone did not permit a safe distinction between possibly different types of spatial arrangement of epithelium in the benign and malignant lesions. Analysis of the estimates of k(r), g(r) and K(r), which are not influenced by Vv, showed definite interaction between epithelial volume elements, with clustering at short distances and repulsion at long distances. In both groups, the null hypothesis of purely random arrangement of epithelium had to be rejected. The clearest distinction between groups was obtained by estimation of g(r), which showed that short‐range, tubular pattern as well as long‐range, lobular architecture are better preserved in benign than in malignant lesions. The low interindividual scatter of k(r), g(r) and K(r) indicates a high biological significance of spatial pattern, which is presumably under strict genetic control. Potential uses of the method are: (i) the identification of biomathematical models which could contribute to a better understanding of the growth processes involved, (ii) conditional simulation of the underlying three‐dimensional structures by computer, and (iii) supporting the diagnosis of mammary lesions with borderline histopathological appearance.

Chromosomal changes during progression of transitional cell carcinoma of the bladder and delineation of the amplified interval on chromosome arm 8q

The cascade of genetic alterations leading to malignant transformation has been described for adenocarcinoma of the colon but is not established for other common tumor entities. In the present study, different stages of transitional cell carcinoma (TCC) of the bladder are analyzed by comparative genomic hybridization. A dynamic pattern of the chromosomal changes during tumor progression is described. Deletion of chromosome arm 9q is the earliest genetic alteration in pTa tumors. In stage pT1 carcinomas, losses of 9q, 9p, and 11p and gain of 1q and 8q are the most common. In addition to the changes specific for earlier stages, gain of 5p and 20q becomes prominent in carcinomas stage ≥pT2. Association analysis reveals a remarkable cooccurrence of 9p deletion with gain of 5p and 20q in ≥pT2 tumors. In order to determine more precisely the size of the amplified segment and the degree of amplification on chromosome arm 8q in stage pT1 tumors, this region was analyzed by semiquantitative PCR using polymorphic microsatellite markers. These studies revealed an up to 13‐fold amplification. The common region of amplification could be narrowed down to 8q22.3 and between GAAT1A4 and D8S1834 (about 7 cM). Genes Chromosomes Cancer 23:167–174, 1998.