Shinji Itoyama

High expression of cyclooxygenase-2 in macrophages of human colonic adenoma.

Cyclooxygenase (COX)‐2 is a possible molecular target for suppression of colon carcinogenesis by non‐steroidal anti‐inflammatory drugs (NSAIDs). However, the expression of COX‐2 in human colonic tumors during the adenoma‐carcinoma sequence has not been elucidated. In the present study, we examined immuno‐histochemically the expression and localization of the COX‐2 protein in human colonic adenomas and cancers. Twelve human colonic adenomas and 9 advanced cancers were studied. Immunoreactive COX‐2 was predominantly and strongly expressed in sub‐epithelial interstitial cells broadly present in the surface area of adenomas. The staining pattern of macrophages was similar to that observed for COX‐2 in adenomas. Adjacent normal colonic mucosa was negative for COX‐2 expression. In contrast, COX‐2 was relatively weakly expressed in both tumor cells and interstitial cells in advanced colon cancers. In conclusion, the target of NSAIDs in preventing colon carcinogenesis may be the COX‐2 expressed in interstitial cells, possibly macrophages, of colonic adenomas. Int. J. Cancer 83:470–475, 1999.

Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP

MDR1 (P-glycoprotein), multidrug resistance-associated protein (MRP) and lung resistance protein (LRP) are associated with multidrug resistance in various cancer cells. It is known that P-glycoprotein and MRP are also expressed in several normal tissues. However, the exact location of LRP in normal tissues is still unclear. In order to obtain more insight into the physiological role of LRP, its expression in human normal tissues was examined by an immunohistochemical technique, using one monoclonal antibody, LRP-56. Reverse transcriptase-polymerase chain reaction (RT-PCR) was also utilized for several cell lines and fresh-frozen tissues. P-glycoprotein was found to be expressed in the kidney, adrenal, brain vessels, muscle, lung, pancreas, liver, intestine, placenta and testis. MRP was expressed in the kidney, adrenal, lung, pancreas, muscle, intestine, thyroid and prostate, and its distribution mostly overlapped with that of P-glycoprotein. Interestingly, MRP was not expressed in the liver. LRP at 110 kDa was expressed in the kidney, adrenal, heart, lung, muscle, thyroid, prostate, bone marrow and testis. These findings suggest that LRP as well as P-glycoprotein and MRP plays distinct roles in the physiology of various organs.

Immunophenotype of lymphocytic infiltration in medullary carcinoma of the breast

Medullary carcinoma (MC) of the breast is characterized by large anaplastic cells and infiltration by benign lymphocytes. Patients with this pattern of breast carcinoma are considered to have a better prognosis than those with other histological subtypes. We reviewed cases of primary breast carcinoma that were surgically resected between 1990 and 2004. Of these, 13 cases of medullary carcinoma of the breast with lymphocyte infiltration were reported. Tests for CD3, CD4, CD8, CD20, CD56, TIA-1, and granzyme B were performed on paraffin sections. We found that the MC contained very few NK cells, as assessed by their reactivity with the CD56 antibodies. However, MC had a significantly greater percentage of CD3, CD8, TIA-1, and granzyme B lymphocytes infiltrating the stroma of the tumor. Furthermore, more CD8-positive than CD4-positive T-cell lymphocytes were present within the tumor cell nests in MC, as opposed to the proportion in usual ductal carcinoma. The infiltrating cytotoxic/suppressor T cells in MC represent host resistance against cancer, and the high grading of the T-cell infiltration could explain, in part, a key mechanism controlling the good prognosis for this type of tumor and solve the pathological paradox of MC.

Clinical and pathologic features of invasive micropapillary carcinoma

BackgroundInvasive micropapillary carcinoma (IMC) of the breast is a rare subtype of breast carcinoma that has an extremely high incidence of lymph node metastases and poor clinical outcome. This histological subtype of breast carcinoma has remained unclear due to the rarity of cases. Many questions exist on the clinicopathological significance of this subtype, especially regarding prognosis.MethodsWe reviewed all 671 cases of primary breast carcinoma that were surgically resected at our institute between 1990 and 2003. Of these, 27 cases of invasive ductal carcinoma of the breast with a pure or partial micropapillary component were reported. The cases were analyzed using various parameters, including age at presentation, tumor size, tumor grade, presence of lymphatic invasion, and axially lymph node status.ResultsThe patients’ age at presentation ranged from 31 to 74 years (mean 52.4 years). Tumor size ranged from 0.7 to 10 cm (mean 4 cm). 88.9% (24 of 27) of the cases had lymphatic invasion. Of cases who underwent with axillary dissection, 66.6% (18 of 27) had positive lymph nodes. Clinical follow up data were available for 17 cases with IMC for 1 to 72 months. Among these, 10 patients died from breast carcinoma within 5 years.ConclusionWhile our series is too small to make conclusions about the behavior of IMC, the difference in 6-year survival rate between the patients with IMC and those with breast carcinoma in general was statistically significant. Recognition of this distinctive and aggressive variant of infiltrating carcinoma is important because of its poor prognosis and high incidence of lymph node metastases.

Expression of multidrug resistance-associated protein (MRP) in anaplastic carcinoma of the thyroid.

Although the incidence is very low, the prognosis of anaplastic carcinoma of the thyroid is very poor regardless of the results of various therapeutic trials. We found that the mechanism of anti-cancer drug resistance in anaplastic carcinoma of the thyroid was not explicable only in terms of expression of the mdr1 and its gene product, P-glycoprotein. Therefore, expression of multidrug resistance-associated protein (MRP) mRNA was examined in 11 anaplastic thyroid carcinomas and eight anaplastic thyroid carcinoma cell lines. High MRP mRNA expression was recognized in 7/11 and 8/8, respectively. Our results may contribute to elucidation of the mechanism of anti-cancer drug resistance in this neoplasm.

Carcinosarcoma of the skin: Immunohistochemical and electron microscopic observations

A rapidly growing, hemorrhagic, exophytic tumor on the upper back of a 44‐year‐old male patient was investigated. Histological, immunohistochemical, and electron microscopic studies revealed both basal cell carcinoma‐like and spindle cell sarcoma‐like structures intermingled in the same tumor. Clinical consequences to this patient were mainly dependent on the sarcomatous element.

Hyperactivated STAT3 in ALK-positive diffuse large B-cell lymphoma with clathrin-ALK fusion.

Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma is a rare subtype of diffuse large B-cell lymphoma (DLBCL). Although a few cases of ALK-positive large B-cell lymphoma harbor nucleophosmin-ALK chromosomal translocation similar to ALK-positive anaplastic large cell lymphoma, most reported cases are characterized by t(2;17)(p23;q23) involving the clathrin gene. Here, we report 2 cases of ALK-positive DLBCL. The 2 cases presented similar morphologic features and immunohistochemical characteristics, that is, positivity for ALK, IgA, CD138, and MUM1; weak positivity for CD30 and CD79a; and negativity for CD20. The clathrin-ALK transcript was identified by reverse transcription-polymerase chain reaction, and the sequence was determined by direct sequencing. Recently, the essential role of STAT3 activation as well as STAT 5 activation in nucleophosmin-ALK fusion protein-mediated lymphomagenesis was reported. However, differential effects of ALK-fusion variant proteins on proliferation, transformation, and invasion properties were reported. Thus, we evaluated the phosphorylation status of STAT 3 and STAT 5, and found highly hyperphosphorylated STAT 3 on tyrosine 705 but not STAT 5 in our 2 cases of ALK-positive DLBCL with clathrin-ALK fusion. Furthermore, STAT 5A expression was not detected in either of the ALK-positive DLBCL cases, although 11 of the 36 ALK-negative DLBCL cases revealed STAT 5A expression. Expression of the antiapoptotic proteins survivin and BCL-X(L), which were believed to be the targets of STAT 3, was investigated. However, there were no significant associations between expression of survivin or BCL-X(L) and ALK positivity among the diffuse large B-cell lymphomas. In summary, similar signaling transduction mechanism involving STAT proteins seems to underlie DLBCL harboring the clathrin-ALK or nucleophosmin-ALK fusion gene.

No evidence of a correlation between BCL10 expression and API2‐MALT1 gene rearrangement in ocular adnexal MALT lymphoma

In the present study, 62 cases of ocular adnexal lymphoproliferative disorders were reviewed clinicopathologically. Of them, 51 were extranodal marginal zone B‐cell lymphoma (MALT lymphoma), five were diffuse large B‐cell lymphoma (DLBCL), one was peripheral T‐cell lymphoma, one was NK/T cell lymphoma, nasal type, and four were reactive lymphoid hyperplasia. These lymphoma cases showed a favorable clinical course and localized disease, except for the case of NK/T cell lymphoma, although 19 cases (32.8%) had a recurrence of disease. To clarify the correlation between BCL10 protein expression and API2–MALT1 gene rearrangement, the 51 cases of MALT lymphoma and 5 cases of DLBCL were analyzed by immunohistochemical and RT‐PCR methods. Nuclear BCL10 expression was identified in 58% of MALT lymphoma cases, but not in any DLBCL cases. There was no evidence of a correlation between aberrant nuclear BCL10 expression and the clinical parameters examined in the present study. API2–MALT1 transcription was not demonstrated in either the MALT lymphoma cases or the DLBCL cases studied using a multiplex one‐tube reverse transcriptase‐PCR method. These findings indicate that the nuclear expression of BCL10 is unlikely to correlate with the API2‐MALT1 fusion gene in ocular adnexal MALT lymphoma.

Expression of E-cadherin, α-catenin, and β-catenin in tubulolobular carcinoma of the breast

Tubulolobular carcinoma (TLC) of the breast is a rare subtype of breast carcinoma categorized by Fisher et al. (Hum Pathol 8:679–683, 1977) as a tubular variant of lobular carcinoma. E-cadherin is a transmembrane glycoprotein, and complete loss of E-cadherin expression has been observed in invasive lobular carcinoma. Ductal carcinoma retains at least some expression of E-cadherin. Moreover, the adhesive function of E-cadherin is dependent on the integrity of the catenin components, which link E-cadherin to the actin filaments. In order to achieve improved categorization of TLC, we decided to investigate both E-cadherin and the catenins in TLCs and invasive lobular carcinomas. We reviewed all 1,430 cases of primary breast carcinoma that were surgically resected at Saitama Medical Center, Saitama Medical School, and at Saitama Red Cross Hospital between 1990 and 2005. Among these, 16 cases of TLC were reported retrospectively. The results were compared with those of 20 cases of invasive lobular carcinomas that were included as controls. Tumor tissue was immunostained for E-cadherin, α-catenin, and β-catenin. The presence of immunoreactivity in the TLC was seen in 12 (75%) cases for E-cadherin, in 8 (50%) cases for α-catenin, and in 10 (62.5%) cases for β-catenin. However, plasma-membrane-associated staining for E-cadherin, α-catenin, and β-catenin was completely absent in invasive lobular carcinomas. These results suggest the possibility that TLCs are not a variant of lobular carcinoma, but rather ductal carcinomas with a lobular growth pattern.

Clinicopathological analyses in patients with other iatrogenic immunodeficiency-associated lymphoproliferative diseases and rheumatoid arthritis

Abstract Despite numerous attempts to uncover the mechanism of other iatrogenic immunodeficiency-associated lymphoproliferative diseases (OIIA-LPDs), this mechanism remains poorly understood, especially in rheumatoid arthritis (RA) patients. We analyzed the data on 23 patients with LPDs and RA. Patients were categorized into three groups according to whether they had methotrexate (MTX); MTX-regressive LPDs, MTX-persistent LPDs or other drugs-mediated LPDs. The LPDs seen in OIIA-LPDs-RA might have a unique behavior to think about several rare phenotypes. The overall survival of all patients was 74% at 5 years, and those of the three groups were 100%, 64% and 60%, respectively. Among the 6 patients who died, 4 had LPDs that were detected late, and thus adequate treatment was not given. In addition, several patients with diffuse large B cell lymphoma with a complex karyotype achieved complete remission (CR). Only one among the 17 patients who achieved CR relapsed. OIIA-LPDs-RA appeared to have a better prognosis than other more common types of lymphomas. Regarding RA treatment, various anti-RA drugs were given to the patients after developing LPDs, including MTX, but no recurrent patients were documented.