Sumika Matsukita

Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in mucinous carcinoma of the breast: comparison with invasive ductal carcinoma

Aims:  Mucinous carcinoma of the breast usually shows less frequent lymph node metastasis and more favourable outcome compared with invasive ductal carcinoma. The aim of this study is to compare the expression profiles of several mucins in mucinous carcinomas and invasive ductal carcinomas to gain insight into the relationship between the less aggressive biological nature of mucinous carcinoma and the role of mucins.

Expression of mucin core proteins in extramammary Paget's disease

Extramammary Pagets disease (EPD) is a relatively common skin cancer wherein tumor cells have mucin in their cytoplasm. However, little is known about mucin expression in EPD. We examined immunohistochemically the expression of mucin core proteins (MUC1, MUC2, MUC5AC and MUC6) in 36 cases of EPD and found different patterns of expression in intraepithelial (n = 36), microinvasive (n = 13) and invasive lesions (n = 6). In normal skin, MUC1 was expressed in the sebaceous, eccrine and apocrine glands. MUC2, MUC5AC and MUC6 were not expressed in any of these. In the 36 intraepithelial lesions, MUC1 and MUC5AC were expressed in 35 and 36 lesions, respectively. MUC1 expression was also observed in all 13 microinvasive lesions and in all six invasive lesions. In contrast to the intraepithelial lesions, a decrease or loss of MUC5AC expression was observed in five out of 13 microinvasive lesions and in all six invasive lesions. MUC2 and MUC6 were not expressed in any of the EPD lesions examined. The combination of immunohistochemical staining for MUC1 and MUC5AC was useful for identifying invasive Paget cells. The decrease or loss of MUC5AC expression may have an important role in the invasive growth of Paget cells.

Mucin expression in pleomorphic adenoma of salivary gland: a potential role for MUC1 as a marker to predict recurrence

Background: Pleomorphic adenoma of the salivary gland (PA) is essentially a benign neoplasm. However, patients with recurrent PA are difficult to manage. There are rare reports on useful immunohistochemical markers to detect a high risk of recurrence when the primary lesions are resected. Aims: To find a new marker to predict the recurrence of PA. Methods: Primary lesions of PA were collected from nine patients showing subsequent recurrence and from 40 patients without recurrence during at least 10 years of follow up of the disease. Paraffin wax embedded tumour samples of the two groups were examined for the expression profiles of MUC1 (differentially glycosylated forms), MUC2, MUC4, MUC5AC, and MUC6 using immunohistochemistry. Several clinicopathological factors were also examined. Results: In univariate analysis of the factors examined, MUC1/DF3 high expression (more than 30% of the neoplastic cells stained) in the primary lesions was seen more frequently in patients with recurrence (four of nine) than in those without recurrence (three of 40; p  =  0.011). Larger tumour size (more than 3.0 cm) of the primary PA was also a significant (p  =  0.035) risk factor for the recurrence of PA. In multivariate analysis, only high expression of MUC1/DF3 was found to be a significant independent risk factor for the recurrence of PA (p  =  0.021). Conclusions: Expression of MUC1/DF3 in PA is a useful marker to predict its recurrence. Those patients with PA showing positive MUC1/DF3 expression should be followed up carefully.

The Antimetastatic Role of Thrombomodulin Expression in Islet Cell-Derived Tumors and Its Diagnostic Value

Islet cell tumors, endocrine neoplasm arising from pancreatic islets of Langerhans, are histologically difficult to diagnose as benign or malignant. Molecular markers are associated with the clinical characteristics that most of insulinoma are usually benign tumors, whereas other islet cell tumors are malignant but have not been identified. In this context, we newly found that an endothelial anticoagulant thrombomodulin was expressed in the normal islet β cells and insulinoma, but not of other islet components or noninsulinoma islet cell tumors. Clinically, all of the subjects (n = 15) of the insulinoma group showed no metastasis together with thrombomodulin expression in the lesions, whereas the other islet cell tumor groups showed a high incidence of metastasis (82%) and a low expression rate of thrombomodulin (6%). To examine the functional role of thrombomodulin, especially regarding the clinical characteristics of islet cell tumors, we tested the effect of exogenous thrombomodulin overexpression on cell adhesiveness and proliferation using MIN6 insulinoma cell line. In cell-based experiments, thrombomodulin overexpression reduced cell proliferation and enhanced Ca2+-independent cell aggregation, possibly through direct interaction with neural cell adhesion molecule. Taken together, these results are suggesting that thrombomodulin may act as antimetastatic molecule of insulinomas. In addition, thrombomodulin is a clinically useful molecular marker not only for identifying β-cell–origin islet cell tumors (i.e., insulinomas) but also for predicting disease prognosis of islet cell tumors.

Primitive neuroectodermal tumor of the transverse colonic mesentery defined by the presence of EWS-FLI1 chimeric mRNA in a Japanese woman.

EWS-FLI1 chimeric mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Based on the above findings, we finally diagnosed the tumor as PNET of the colonic mesentery. There has been no recurrence for 20 months after operation. PNET arising in the mesentery is very rare, and we distinguished PNET from other tumors by immunohistochemical examination and by demonstration of the presence of EWS-FLI1 chimeric mRNA in the tumor.

Hemangioma of the Umbilical Cord: Stenotic Change of the Umbilical Vessels

We report a rare case of an umbilical cord hemangioma diagnosed by ultrasound at 16 weeks of gestation. The umbilical cord consisted of a hemangioma nodule and pseudocysts near the placental insertion, a large gelatin-like swelling adjacent to the nodule on its fetal side, and a short normal part extending to the navel. At 17 weeks of gestation, this condition resulted in the intrauterine death of the fetus. Microscopically, there were communications between the capillary of the hemangioma and the umbilical vessels, verifying the origin of the tumor. Moreover, the umbilical vein and one of the arteries changed stenotically due to the intravascular proliferation of the hemangioma. These findings indicate the possibility of a pathological association between the umbilical cord hemangioma and fetal demise due to impaired umbilical circulation.

Comparative study for histology, proliferative activity, glycoproteins, and p53 protein between old and recent colorectal adenomas in Japan

The incidence of colorectal carcinoma is increasing in Japan. Malignant transformation in colorectal neoplasia is usually considered to be owing to adenoma-carcinoma sequence. Elucidation of the recent alteration in the biological properties of colorectal adenoma is sure to be useful to understand the recent increase of the colorectal carcinoma in Japan. We compared the histopathological feature, mitotic index, proliferative activity (Ki-67 labeling index), expression of glycoproteins such as MUC2 mucin, sialyl Lewis A (SLe(a)) and sialyl dimeric Lewis X (SLe(x)), and p53 protein overexpression, between 108 adenomas in the old period (Group A, from 1969 to 1985) and 140 adenomas in the recent period (Group B, from 1995 to 1998). The histological dysplasia, mitotic index and Ki-67 labeling index of the adenomas were significantly higher in Group B than in Group A. In contrast, the expression of MUC2 mucin, which is considered to be a differentiation factor of intestinal mucosal epithelium, was significantly reduced in Group B than in Group A. The SLe(a) and SLe(x) expressions showed no significant difference between them. The p53 expression showed no significant difference between them, except for the moderate dysplasia. These findings indicate that recent colorectal adenomas show more advanced degrees of histological dysplasia, more rapid growth, and reduced differentiation than colorectal adenomas, which developed at earlier times, and may be related with the recent high incidence of colorectal carcinoma in Japan.

Production of a High-affinity Monoclonal Antibody Reactive with Folate Receptors Alpha and Beta

Folate receptors α (FRα) and β (FRβ) are two isoforms of the cell surface glycoprotein that binds folate. The expression of FRα is rare in normal cells and elevated in cancer cells. Thus, FRα-based tumor-targeted therapy has been a focus area of laboratory research and clinical trials. Recently, it was shown that a significant fraction of tumor-associated macrophages expresses FRβ and that these cells can enhance tumor growth. Although FRα and FRβ share 70% identity in their deduced amino acid sequence, a monoclonal antibody (MAb) reactive with both receptors has not been developed. A MAb that can target both FRα-expressing cancer cells and FRβ-expressing tumor-associated macrophages may provide a more potent therapeutic tool for cancer than individual anti-FRα or anti-FRβ MAbs. In this study, we developed a MAb that recognizes both FRα and FRβ (anti-FRαβ). The anti-FRαβ specifically stained trophoblasts and macrophages from human placenta, synovial macrophages from rheumatoid arthritis patient, liver macrophages from cynomolgus monkey and common marmoset, and cancer cells and tumor-associated macrophages from ovary and lung carcinomas. Surface plasmon resonance showed that the anti-FRαβ bound to soluble forms of the FRα and FRβ proteins with high affinity (KD=6.26×10(-9) M and 4.33×10(-9) M, respectively). In vitro functional analysis of the anti-FRαβ showed that this MAb mediates complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis of FRα-expressing and FRβ-expressing cell lines. The anti-FRαβ MAb is a promising therapeutic candidate for cancers in which macrophages promote tumor progression.

Successful surgical treatment of severe burn in an immunocompromised patient under long-term treatment for frequently relapsing nephrotic syndrome.

We recently successfully performed allogeneic skin grafting for severe burn in an immunocompromised patient treated over the long term with immunosuppressants and believe that the case can serve as a good reference for severe burn treatment facilities confronted with similar cases. A 16-year-old male with frequently relapsing nephrotic syndrome, developed at the age of 2 years and subsequently treated with oral prednisolone (35 mg/d) and cyclosporine (75 mg/d), was brought to us for the treatment of severe burns to the face, chest, abdomen, and bilateral upper and lower limbs (44% TBSA) after throwing an 18-L tank of thinner into a bonfire. After resolving the shock, three sessions of surgical treatment consisting of debridement and skin grafting with autografts and allografts were performed by day 12 postinjury. Delayed wound healing possibly from an adverse effect of postoperative steroid was observed. Moreover, the patient was highly predisposed to infection because of a severely compromised immune system and had six septic episodes throughout treatment. However, his immunocompromised state allowed the allografts to remain engrafted in the abdomen without rejection during a 298-day treatment period. Although all postburn scars were fragile because of reduced wound tensile strength, they were very soft. Despite some remaining ulcerous surfaces, the patient could be discharged on day 149 postinjury. Zhao et al demonstrated that low-dose cyclosporine coadministered with steroid can substantially prolong skin allograft survival through their interaction. Because long-term engraftment of allografts can be achieved in patients treated with cyclosporine and steroid, as demonstrated in this case, it may be worthwhile to actively formulate a treatment strategy involving allografts. However, careful follow-up is still needed for the present patient, as the allografts, which currently exhibit clinical persistence, are likely to undergo gradual deterioration after future reduction or discontinuation of medications for nephrotic syndrome.