Wenche Reed

Elevated levels of p27, p21 and cyclin D1 correlate with positive oestrogen and progesterone receptor status in node-negative breast carcinoma patients

Abstract The search for better prognostic indicators and new treatment modalities in node-negative breast carcinoma patients is important. The aim of this study was to determine the immunohistochemical expression of central cell regulator proteins in relation to hormone receptor status, tumour-cell differentiation and prognosis. We investigated the immunoreactivity of p27, p21, cdk4, cyclin D1 and p53 in 77 node-negative breast carcinomas, with long-term follow-up (mean 163 months; range 20−227). Nuclear staining for p27 was seen in 87% of the carcinomas, for cdk4 in 92%, for p21 in 68%, for cyclin D1 in 58% and for p53 in 18%. Oestrogen receptor (ER) and progesterone receptor (PgR) nuclear staining was seen in 69% and 65% of the tumours, respectively. No correlation between the levels of p21 and p53 was observed. P21 overexpression was, however, associated with positive ER status. Elevated levels of p27 and cyclin D1 correlated with positive hormone status (both ER and PgR). We did find a significant correlation between p27 and cyclin D1 and histological grade of the tumours, with extensive positive immunostaining of p27 and cyclin D1 in well-differentiated carcinomas. The only significant prognostic factor in our series was histological grading. Ten-year relapse-free survival was significantly prolonged in patients with histological grade I tumours versus histological grade II and III tumours. Our results suggest that the expression of p27 and cyclin D1 is closely linked to hormone receptor status in breast carcinomas and to tumour differentiation, a finding that may be of importance in the treatment of hormone-dependent tumours.

Extraskeletal myxoid chondrosarcoma : multimodal diagnosis and identification of a new cytogenetic subgroup characterized by t(9;17)(q22;q11)

Extraskeletal myxoid chondrosarcoma is a rare malignant soft tissue tumour that can be difficult to diagnose correctly, especially preoperatively. We describe four cases of extraskeletal myxoid chondrosarcoma of the extremities diagnosed by a multimodal approach. The cytological examination of fine-needle aspirates showed small and round, mildly pleomorphic cells lying in sheets and cords, but also dispersed within a myxoid and metachromatic intercellular substance. Histological, electron microscopic and immunocytochemical examination also yielded findings compatible with the diagnosis of extraskeletal myxoid chondrosarcoma. Cytogenetic analysis demonstrated a t(9;22)(q22;q12) in two tumours and a t(9;17)(q22;q11) in the third and fourth. The translocation t(9;22)(q22;q12) has been described repeatedly in extraskeletal myxoid chondrosarcoma but never in other tumours; hence, the detection of this pathognomonic chromosome abnormality in short-term cultured cells from fine-needle aspirates verified the diagnosis in two of the cases. The t(9;17)(q22;q11) found in the last two cases probably represents a new cytogenetic subgroup of extraskeletal myxoid chondrosarcoma as it, too, is unknown in other contexts. The multimodal approach taken in these four cases enabled a definite diagnosis of a rare malignant tumour whose cytological and histological features alone are usually not sufficiently distinct to rule out other differential diagnostic possibilities.

The Prognostic Impact of Hormone Receptors and c-erbB-2 in Pregnancy-Associated Breast Cancer and Their Correlation with BRCAI and Cell Cycle Modulators

A population-based series of 122 patients with pregnancy-associated breast carcinomas was histologically revised and the relationship between hormone receptors, cerbB-2, BRCA1, p27, cyclin E, and cyclin D1 was studied. The 5-year overall survival was 41%; 70% had tumor size >20 mm; 72% had metastasized to regional lymph nodes; 95% were histologic grade II or III; 66% and 75% were negative for estrogen and progesterone receptor, respectively; and c-erbB-2 expression was high (44%). BRCA1 expression was reduced in 33% of the cases. The expression of p27, cyclin D 1, and cyclin E was low, 11%, 9%, and 16%, respectively. Cyclin D I was positively associated with the hormone receptors (p<0.01). In multivariate analysis, lymph node status, progesterone receptor, and c-erbB-2 were significant prognostic factors. In subdividing the group according to lymph node status, c-erbB-2 and progesterone receptor retained a prognostic significance in the node positive group only. In conclusion, pregnancy-associated breast carcinomas are aggressive tumors, with low expression of hormone receptors, BRCA1, p27, and cyclin E and DI, and high expression of c-erbB-2.

Chromosome banding analysis of gynecomastias and breast carcinomas in men.

Male breast cancer is 100 times less frequent than its female counterpart and accounts for less than 1% of all cancers in men. Although men with breast cancer also often have gynecomastia, it is still unknown whether gynecomastia per se predisposes the male breast to malignant disease. We describe the cytogenetic analysis of three gynecomastias and four breast cancers in men. No chromosome abnormalities were detected in two cases of gynecomastia, with no other concomitant breast disease. The third gynecomastia sample, taken from a site where a breast carcinoma had previously been removed, had a t(2;11)(p24;p13) as the sole chromosome change; this is the first time that an abnormal karyotype has been described in gynecomastia. All four cancers had clonal chromosome abnormalities. Several cytogenetically unrelated clones were found in the breast tumor and in a metastasis from case 1. In the carcinoma of case 2, a single abnormal clone was found, characterized by loss of the Y chromosome, monosomy 17, and a deletion of the long arm of chromosome 18. In the carcinoma of case 3, a clone with loss of the Y chromosome as the sole change dominated, accompanied by the gain of an X chromosome in a subclone. In the lymph node metastasis examined from case 4, a single clone carrying trisomies for chromosomes 5 and 16 was detected. Our findings, especially when collated with data on the six karyotypically abnormal breast carcinomas in men described previously, indicate that gain of the X chromosome, gain of chromosome 5, loss of the Y chromosome, loss of chromosome 17, and del(18)(q21) are nonrandom abnormalities in male breast carcinomas. Genes Chromosomes Cancer 23:16–20, 1998.

Evaluation of complete cytoreductive surgery and two intraperitoneal chemotherapy techniques in pseudomyxoma peritonei

BACKGROUND Pseudomyxoma peritonei (PMP) is a low-grade malignancy characterized by mucinous tumor on the peritoneal surface. Treatment involves cytoreductive surgery (CRS) to remove all macroscopic tumor and perioperative intraperitoneal chemotherapy (PIC) to eliminate remaining microscopic disease. PATIENTS AND METHODS Between 1994 and 2009, 93 patients were treated at the Norwegian Radium Hospital with complete CRS and PIC. PIC was administered as early postoperative intraperitoneal chemotherapy (EPIC) using mitomycin C (MMC) and 5-fluoruracil (n = 48) and as hyperthermic intraperitoneal chemotherapy (HIPEC) using MMC (n = 45). Patients were classified into three histopathological subgroups: Disseminated peritoneal adenomucinosis (n = 57), peritoneal mucinous carcinomatosis (n = 21) and an intermediate group (n = 15). Tumor distribution by peritoneal cancer index (PCI) was PCI ≤ 10 (n = 31), PCI 11-20 (n = 29), PCI ≥ 21 (n = 33). RESULTS Recurrence was diagnosed in 38 patients and 25 patients died during follow-up. Estimated 10-year overall survival (OS) was 69% and 10-year disease-free survival (DFS) was 47%. Mean OS was 154 months (95% CI 131-171) and median OS was not reached (follow-up median 85 months (3-207)). Low-grade malignant histology (p = 0.001) and female gender (p = 0.045) were associated with improved OS. Almost equal OS and DFS were observed between patients treated with EPIC and HIPEC. CONCLUSIONS Patients treated for PMP with complete CRS and PIC achieved satisfactory long-term outcome. The most important prognostic factor was histopathological differentiation, but acceptable survival was observed even in patients with aggressive histology and extensive intraperitoneal tumor growth. Administration of EPIC and HIPEC was equally efficacious with respect to long-term outcome.

Primary osteosarcoma of the breast.

Several rare tumors of the breast should be kept in mind as differential diagnosis to the common carcinomas. Of these, various types of sarcomas are seen, having an estimated frequency of less than 1% of all malignant breast tumors [1,2]. The most frequent histological subtype is malignant fibroushistiocytoma, followed by angiosarcoma and liposarcoma, but nearly all subtypes of sarcomas have been observed in breast [3]. Radiation induced sarcoma has been reported to occur in 0.1% of all epithelial breast cancer patients, the frequency calculated to be 1.9 times the expected [4]. Most radiation induced sarcomas of the breast are angiosarcomas, although radiation induced osteosarcoma of the chest wall after breast cancer irradiation has been reported [5]. Primary osteosarcomas (OS) of the breast are infrequently reported, and to our knowledge less than a hundred cases have been published. The low number of published cases [6] justifies this report of four patients with primary OS of the breast treated at our institution during the last 15 years.

Immunotoxin targeting EpCAM effectively inhibits peritoneal tumor growth in experimental models of mucinous peritoneal surface malignancies

Cytoreductive surgery and intraperitoneal (i.p.) chemotherapy constitute a curative treatment option in mucinous peritoneal surface malignancies of intestinal origin, but treatment outcome is highly variable and the search for novel therapies is warranted. Immunotoxins are attractive candidates for targeted therapy in the peritoneal cavity because of direct cytotoxicity, distinct mechanisms of action and tumor cell selectivity. The MOC31PE immunotoxin targets the tumor‐associated adhesion protein EpCAM (Epithelial Cell Adhesion Molecule), and has been administered safely in early clinical trials. In our work, the efficacy of i.p. administration of MOC31PE alone and together with mitomycin C (MMC) was investigated in unique animal models of human mucinous peritoneal surface malignancies. In initial model validation experiments, clear differences in efficacy were demonstrated between MMC and oxaliplatin, favoring MMC in five investigated tumor models. Subsequently, MOC31PE and MMC were given as single i.p. injections alone and in combination. In the PMCA‐2 model, moderate growth inhibition was obtained with both drugs, while the combination resulted in at least additive effects; whereas the PMP‐2 model was highly sensitive to both drugs separately and in combination and intermediate sensitivity was found for the PMCA‐3 model. Furthermore, results from ex vivo experiments on freshly obtained mucinous tumor tissue from animals and patients suggested that classic mechanisms of immunotoxin activity were involved, i.e., inhibition of protein synthesis and induction of apoptosis. The present results suggest that adding MOC31PE to MMC‐based i.p. chemotherapy should be further explored for EpCAM‐expressing peritoneal surface malignancies, and a phase I trial is in preparation.

Exploring the peritoneal surface malignancy phenotype—a pilot immunohistochemical study of human pseudomyxoma peritonei and derived animal models

Peritoneal surface malignancies are characterized by the propensity for tumor growth on peritoneal surfaces without development of extraperitoneal metastases, but the molecular basis for this phenomenon is incompletely understood. Five human tumors and corresponding orthotopic animal models of human pseudomyxoma peritonei and peritoneal mucinous carcinomatosis from colorectal carcinoma were extensively characterized by immunohistochemical analysis of molecular markers of tissue differentiation (carcinoembryonal antigen, CK20, CK7, and vimentin), proliferation and metastasis (Ki-67, vascular endothelial growth factor, and S100A4), mucins (MUC1, MUC2, MUC4, MUC5AC), and adhesion molecules (E-cadherin, N-cadherin, P-cadherin, claudin 1, claudin 3, and claudin 4). Macro- and microscopic growth patterns of implanted human tissues were preserved through passages in the animals, as were with few exception immunohistochemical staining profiles, supporting the relevance of the models as tools for studying the human disease. Tissue differentiation marker expression was in accordance with previously published results and high Ki-67 score confirmed high proliferative capacity, whereas absence of metastatic capacity was supported by low expression levels of the studied metastasis markers. These mucinous tumors expressed high levels of MUC2 and MUC4, whereas MUC1 was not expressed and MUC5AC expression was variable. Similarly, specific adhesion molecules from the cadherin and claudin families were shown to be of relevance in the investigated samples. The results indicate that mucinous peritoneal surface malignancies of intestinal origin are characterized by the presence of specific molecular markers and represent a step toward understanding the complexity of this intriguing phenotypic entity.

Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype

BackgroundPseudomyxoma peritonei (PMP) is a rare malignant disease, most commonly originating from appendiceal lesions and characterized by accumulation of mucinous tumor tissue in the peritoneal cavity. Since the disease is infrequent, the task of carrying out studies of treatment efficacy and disease biology in the clinical setting is challenging, warranting the development of relevant in vitro and in vivo PMP models.MethodsHuman tumor tissue was implanted in the peritoneal cavity of nude mice to establish two orthotopic models exhibiting noninvasive intraperitoneal growth without metastasis development.ResultsXenograft tissues have retained essential properties of the original human tumors, such as macro- and microscopic growth patterns, mucin production as well as expression of carcinoembryonal antigen, cytokeratins 20 and 7 and the proliferation marker pKi67. Upon microscopic examination, the human tumors were categorized as the PMCA-I (peritoneal mucinous carcinomatosis of intermediate features) subtype, which was conserved through 14 examined passages in mice, for the first time modeling this particular histopathologic category.ConclusionIn conclusion, two novel orthotopic models of human PMP have been established that consistently portray a distinct histopathologic subtype and reflect essential human tumor properties. Xenografts can easily and reproducibly be transferred to new generations of mice with acceptable passage periods, rendering the models as attractive tools for further studies of PMP biology and treatment.

Optimizing sharing of hospital biobank samples

Implementing technical guidelines and standards as well as ways to boost cooperation should facilitate sharing of hospital biobank samples. Implementing technical guidelines and standards as well as ways to boost cooperation should facilitate sharing of hospital biobank samples.