Is colorectal surveillance indicated in patients with PTEN mutations?

AIM: Patients with germline phosphatase and tensin homologue (PTEN) mutations develop hamartomatous lesions in several organs and are at increased risk of various malignancies. We assessed the lifetime risk of benign and malignant gastrointestinal lesions in patients with a proven PTEN mutation. METHOD: Data on gender, mutation, dates of birth, last contact, and diagnosis, location and type of gastrointestinal lesions were collected from nine countries. The lifetime risk of gastrointestinal lesions was calculated by Kaplan-Meier methods. RESULTS: A total of 156 patients (67 men, 43%) from 101 families with a PTEN mutation were included. Patients were born between 1928 and 2008. Benign gastrointestinal polyps were reported in 49 (31%) patients at a mean age of 38 years (range 18-62 years) and were most often hamartomas. Twenty-two (44%) patients had upper as well as lower gastrointestinal lesions, 14 (29%) had only colonic lesions and 13 (27%) had gastrointestinal lesions at unknown sites. The cumulative risk of developing benign gastrointestinal polyps was 70% at age 60. Four patients (two men) developed colorectal carcinoma at 53, 57, 59 and 62 years, respectively. The cumulative risk of developing colorectal carcinoma was 18% at age 60. Except for one carcinoid in the small intestine, no upper gastrointestinal cancers were observed. CONCLUSION: Benign gastrointestinal lesions are common in PTEN mutation carriers, and a three- to four-fold increased lifetime risk of colorectal cancer compared with the general population may exist. Colorectal screening of patients with germline PTEN mutations is recommended, starting at age 40 years.

Gonosomal mosaicism for an NF1 deletion in a sperm donor: evidence of the need for coordinated, long-term communication of health information among relevant parties.

BACKGROUND: Screening of gamete donors can reduce but cannot eliminate the risks for medical problems in donor-conceived offspring. We present a case of gonosomal mosaicism discovered in an anonymous sperm donor after receiving two reports of neurofibromatosis type 1 (NF1) in donor-conceived offspring, to illustrate that long-term, systematic investigation of health issues in donors and offspring can be invaluable to the welfare of these individuals. METHODS: A repeat physical evaluation and ophthalmology examination were performed on the donor. DNA samples were examined by RTPCR fragment analysis, multiplex ligation-dependent probe amplification (MLPA) and targeted array-comparative genomic hybridization (aCGH). RESULTS: Gonosomal mosaicism for a deletion mutation in the NF1 gene was identified in 20% of sperm and a smaller percentage of lymphocytes. CONCLUSIONS: Long-term communication of medical information among donors, recipients and donor-conceived offspring is beneficial for the health management of all parties. Development of a secure, coordinated data system is critical to achieving this goal. Recommendations are provided for management and communication of critical information based on this experience.

A case of lymphoblastoid natural killer (NK)-cell lymphoma: association with the NK-cell receptor complex CD94/NKG2 and TP53 intragenic deletion.

The clinical, histological, phenotypic and genotypic features of a lymphoblastoid natural killer (NK)-cell lymphoma presenting in the skin in a young caucasian woman are described. The disease behaved aggressively, but long-lasting remission was obtained by combination chemotherapy followed by autologous bone marrow transplantation. The blastoid cells were positive for terminal deoxynucleotidyl transferase, CD34, CD56 and CD4. Furthermore, the NK-cell receptor complex CD94/NKG2 was strongly expressed, as shown by examination with reverse transcription-polymerase chain reaction. The T-cell receptor (TCR)-gamma genes were in germline, and with the exception of CD4 all T-cell antigens were negative, including CD3, TCR-beta, TCR-delta, TIA-1, granzyme B and perforin. Epstein-Barr virus was negative, and no expression was seen of myeloid cell-associated markers. Molecular analysis showed no abnormalities of the CDKN2A (p16), CDKN2B (p15) or TNFRSF6 (Fas) genes. By contrast, a 34-bp deletion in exon 7 of the TP53 (p53) gene was detected. It is suggested that lymphoblastoid NK-cell lymphoma, which is a rare but distinctive disease, originates from NK cell precursors and may be associated with and possibly caused by alterations in the TP53 gene. Experience is too limited to warrant therapeutic suggestions. However, stem cell transplantation may be a useful option in younger patients.

Urokinase plasminogen activator is localized in stromal cells in ductal breast cancer.

Urokinase plasminogen activator (uPA) regulates a proteolytic cascade that facilitates cancer invasion through degradation of the extracellular matrix, and high levels of uPA in human breast cancer tissue correlate with poor prognosis. We previously found that, in ductal breast cancer, uPA mRNA is highly expressed by myofibroblasts surrounding invasively growing cancer cells. However, the localization of uPA protein has not been settled in the published literature. Because uPA is a secreted molecule, it could conceivably be localized differently from its mRNA. We have studied the localization of uPA immunoreactivity in detail. Twenty-five cases of invasive ductal carcinoma were analyzed with three different uPA antibody preparations, all of which gave an essentially identical stromal staining pattern. Using double immunofluorescence, we identified uPA immunoreactivity in myofibroblasts and macrophages in all cases examined. Additionally, in approximately half of the tumors, we saw uPA staining of endothelial cells. In 3 of the 25 cases, a small subpopulation of the cancer cells was uPA-positive. We conclude that uPA immunoreactivity is almost exclusively associated with stromal cells, which thus play a major role in generation of proteolytic activity in ductal breast cancer.

Cytogenetically unrelated clones in therapy-related myelodysplasia and acute myeloid leukemia: experience from the Copenhagen series updated to 180 consecutive cases.

During the period from 1995 to 1997, we studied 19 new cases of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML), extending our series to 180 consecutive cases: 123 patients with t-MDS and 57 patients with t-AML. Cytogenetically unrelated clones were observed in 13 patients: 11 patients with two unrelated clones, one patient with three unrelated clones, and one patient with four unrelated clones. Twelve cases of unrelated clones presented as t-MDS, whereas only one case presented as overt t-AML. Partial or complete deletions of the long arms or monosomy for chromosome 5 or chromosome 7, which are characteristic of t-MDS and t-AML, were observed in both unrelated clones in four patients and in one unrelated clone only in six patients, whereas three patients showed aberrations in both clones that were uncharacteristic of t-MDS or t-AML. Three different interpretations of the origin and significance of cytogenetically unrelated clones in t-MDS and t-AML are presented, although the disease is still considered to be monoclonal. First, patients with different defects of the long arm of chromosome 5 or chromosome 7 in two unrelated clones often seem to have acquired these aberrations as independent events. For this reason, it is possible that they may play an important role in leukemic transformation, for instance, by activating or potentiating the effect of a genetic change that is present in all cells but not disclosed as a visible chromosome abnormality. In cases with involvement of other chromosomes, unrelated clones sometimes develop by cytogenetic change in only a subclone of cells, indicating that they play a role only in tumor progression. Finally, unrelated clones in t-MDS and t-AML may represent two different monoclonal diseases: the primary tumor and t-MDS. This view is supported by the significant excess of unrelated clones observed in t-MDS following multiple myeloma (4 in 13 cases) compared with other diseases (9 in 167 cases; P = 0.02), and by results from a case with a balanced translocation that is highly characteristic of non-Hodgkin's lymphoma in one clone and a t-MDS-associated deletion of the long arm of chromosome 5 in another.

[Late recurrence of stomach cancer in a patient treated with a H2 receptor antagonist]. / Sent recidiv af cancer ventriculi hos en patient i H2-receptorantagonistbehandling.

We report a case where a patient developed recurrence of an adenocarcinoma of the stomach ten years after primary surgery. Besides the late recurrence, the case is interesting as the patient participated in a trial investigating the effect of cimetidine on survival after gastric cancer and received cimetidine for two years after surgery. Considering the well documented anti-tumour and immunomodulating effects of histamine type-2 receptor antagonists, it might be interesting to examine the effect on survival after surgery for gastric cancer in patients receiving prolonged treatment with such an antagonist.

Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases.

In inflammatory and neoplastic disorders of the colon a defect barrier function of the mucosa may result in absorption of bacterial products from the intestinal lumen. These products may further recruit inflammatory cells and thus augment the inflammatory response. A novel lipocalin in neutrophils, neutrophil gelatinase associated lipocalin (NGAL), with the ability to bind bacterial formylpeptides, has been described and therefore it is of interest to investigate the expression of this protein in diseases of the colon. Expression of NGAL was investigated by immunohistochemistry and by mRNA in situ hybridisation in normal colon and in neoplastic and inflammatory colorectal diseases. A very high expression of NGAL was seen in colonic epithelium in areas of inflammation, both in non-malignant epithelium (diverticulitis, inflammatory bowel disease, and appendicitis) as well as in premalignant and malignant neoplastic lesions of the colon. In adenocarcinoma, the NGAL expression was especially abundant in the transitional mucosa and in the superficial ulcerated area. On the other hand, no NGAL expression could be detected in lymph node metastases from these adenocarcinomas. A weak expression of NGAL in some epithelial cells was only occasionally seen in normal colon. In conclusion, NGAL synthesis is induced in epithelial cells in inflammatory and neoplastic, colorectal diseases. NGAL may serve an important anti-inflammatory function as a scavenger of bacterial products.

92 kDa type IV collagenase (MMP-9) is expressed in neutrophils and macrophages but not in malignant epithelial cells in human colon cancer.

Degradation of the extracellular matrix during cancer invasion is accomplished by the concerted action of several proteolytic enzymes, including matrix metalloproteinases (MMPs). We have studied the immunohistochemical localization of one of these enzymes, 92-kDa type IV collagenase (MMP-9), in short-term fixed specimens of 19 colon adenocarcinomas and 2 biopsies of adjacent normal colon. Staining was confined to neutrophils and macrophages, as identified by double staining. All neutrophils were positive in all cases. Some positively stained tumor-infiltrating macrophages were seen in 6 (32%) of the tumors, located adjacent to invasive tumor glands. No cancer cells were stained in any of the cases. In normal colon tissue, staining was only seen of scattered neutrophils in vessels and of macrophages in Peyer's patches. Routinely processed specimens from 7 of the 19 carcinomas were analyzed by in situ hybridization. In agreement with previous results, a MMP-9 mRNA signal was in all cases seen in a subpopulation of tissue macrophages surrounding invasive tumor glands, while no MMP-9 mRNA was detected in any other cell types, including neutrophils and cancer cells. Our results indicate that in this type of cancer all neutrophils contain MMP-9, which has been produced before they infiltrate the tumors; that a subpopulation of the tumor-infiltrating macrophages most likely in all cases produces MMP-9 but that the content of this protein is low due to a rapid turnover and that malignant epithelial cells do not produce or contain detectable amounts of MMP-9. These findings extend previous results indicating that stromal cells are actively involved in the generation and regulation of extracellular proteolysis during cancer invasion.

Messenger RNA for urokinase plasminogen activator is expressed in myofibroblasts adjacent to cancer cells in human breast cancer.

Urokinase plasminogen activator (uPA) is a serine proteinase involved in degradation of the extracellular matrix during cancer invasion. uPA is up-regulated in breast cancer, and high levels of uPA in tumor extracts are strongly associated with poor prognosis. Like several other matrix proteinases, uPA is in some types of cancer, including breast cancer, expressed by stromal cells. The present study was undertaken to determine the identity of the uPA-expressing stromal cells in breast cancer tissue. By in situ hybridization, a positive signal for uPA mRNA was in 26 of 28 ductal and four of five lobular carcinomas demonstrated in stromal cells adjacent to nests of cancer cells, whereas only one ductal carcinoma showed a positive reaction in the epithelial component itself. The positive stromal cells were found in both the peripheral and central parts of the tumors. Stromal cells surrounding carcinoma in situ lesions were uPA mRNA positive in a few cases, and no signal was observed in the neighboring nonmalignant tissue. Cell identification was done by immunostaining with Ab to markers for the following cell types: myoepithelial cells, myofibroblasts, smooth muscle cells, macrophages, endothelial cells, and epithelial cells. The only one of these cell types that had a distribution similar to the uPA mRNA-expressing cells was myofibroblasts, recognized as extravascular alpha-smooth muscle actin-positive and cytokeratin-negative cells. On adjacent sections, colocalization was found of cells positive for uPA mRNA and cells positive for alpha-smooth muscle actin and negative for cytokeratin. We concluded that the uPA mRNA-expressing cells are myofibroblasts. The myofibroblasts have previously been found to be abundant in breast cancer tissue. They primarily originate by differentiation of fibroblasts, probably induced by cytokines released from the cancer cells. The present findings suggest that the myofibroblasts, through production of uPA, play an active role in breast cancer invasion.