High-grade lung adenocarcinoma with fetal lung-like morphology: clinicopathologic, immunohistochemical, and molecular analyses of 17 cases.

Low-grade lung adenocarcinoma of fetal lung type, which is well characterized by its unique clinicopathologic and molecular features, is recognized as a distinct variant of lung cancer. In contrast, high-grade lung adenocarcinoma with fetal lung-like morphology (HG-LAFM) has not been studied widely. To characterize this subset better, we analyzed 17 high-grade adenocarcinomas with at least focal component resembling a developing epithelium in the pseudoglandular phase of the fetal lung. These rare (ca. 0.4%) carcinomas occurred predominantly in elderly men with a heavy smoking history, who showed elevated serum α-fetoprotein in 4 of 5 cases tested. Histologic examination revealed a fetal lung-like component as a focal finding accounting for 5% to 60% of the total tumor volume. It was invariably admixed with tissues having a morphology not resembling that of a fetal lung. A coexisting non-fetal lung-like element was quite heterogenous in appearance, showing various growth patterns. However, clear-cell (88%), hepatoid (29%), and large cell neuroendocrine carcinoma (24%) histology seemed overrepresented. HG-LAFM was characterized immunohistochemically by frequent expression of α-fetoprotein (41%), glypican-3 (88%), SALL-4 (59%), neuroendocrine markers (82%), CDX-2 (35%), and p53 (65%). HG-LAFM was molecularly heterogenous in that EGFR or KRAS mutation was observed in 22% of cases tested for both. Our data indicate that HG-LAFMs might form a coherent subgroup of lung adenocarcinomas. However, the uniformly focal nature of the fetal lung-like element, widely diverse coexisting non-fetal lung-like histology, and inhomogenous molecular profiles lead us to believe that HG-LAFM is best regarded as a morphologic pattern showing characteristic association with several clinicopathologic parameters rather than a specific tumor entity.

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

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.

Vascular invasion in triple-negative carcinoma of the breast identified by endothelial lymphatic and blood vessel markers.

The aim of this study was to determine lymph vessel invasion (LVI) and blood vessel invasion (BVI) using established biological markers and clinicopathological findings for triple-negative breast carcinoma. We reviewed all 202 cases of primary breast carcinoma that were surgically resected at Saitama Medical Center, Saitama Medical School, between 2006 and 2009. Tumor tissue was immunostained for estrogen receptor, progesterone receptor, Her2/neu, D2-40, and CD34. Among these, 26 cases of triple-negative carcinoma were reported retrospectively. The results were compared with those of 176 cases of non-triple-negative carcinomas that were included as controls. The frequency of LVI examined by hematoxylin and eosin and D2-40 (triple negative, 7 of 26; non-triple negative, 61 of 176) was not significantly different, and neither was BVI examined by HE, Elastica van Gieson, CD34 (triple negative, 2 of 26; non-triple negative, 16 of 176), and lymph node metastasis (triple negative 9 of 26, non-triple negative, 65 of 176). However, a specific pattern of distant metastasis with a high frequency of visceral metastases was detected in triple-negative carcinoma cases (triple negative, 6 of 26; non-triple negative, 8 of 176). Our findings show that triple-negative carcinoma of the breast may have a distinct biological behavior.

Y-box binding protein-1 expression in diffuse large B-cell lymphoma: an impact on prognosis in the rituximab era.

The expression of YB-1 has been reported to predict poor clinical outcome in many human malignancies, including hematopoietic malignancies. In this study, we investigated the correlations between YB-1 expression and the clinicopathological features of patients with diffuse large B-cell lymphoma (DLBCL) in a single institution. The expression of YB-1 was analyzed in 168 cases by immunohistochemistry. Fifteen out of 168 cases (8.9%) showed cytoplasmic expression of YB-1. The expression of YB-1 was significantly associated with 5-year overall survival (OS) (p = 0.023). Rituximab plus CHOP therapy (n = 94) improved the 5-year survival rate in both YB-1-positive and -negative patients. In conclusion, the data presented in this report provide evidence that the cytoplasmic expression of YB-1 is a poor prognosis factor in DLBCL treated with CHOP therapy, whereas rituximab improves the survival of both YB-1-positive and -negative patients with DLBCL.

[Acute-onset eosinophilic leukemia associated with tumor lysis syndrome after imatinib and steroid pulse therapy].

An 83-year-old woman had been suffering from palpitations and fatigue for a month. An annual screening test revealed an increased WBC count so she was referred to our hospital. CBC showed extremely elevated WBC count (186,300/microl), in which the population of blastic eosinophils was over 90%. The eosinophils expressed CD7/13/33/34/DR, and the karyotype demonstrated 47,XX,+8. The fusion gene of FIP1-LP/PDGFRalpha in peripheral blood was negative. As plural effusion due to the underlying disease progressively worsened, she was given prednisolone and hydroxyurea, but the effect was limited. Steroid pulse therapy and imatinib (100 mg/day) were administrated. As a result, a prompt response was observed. The WBC count rapidly decreased, but tumor lysis syndrome led to acute renal failure and disseminated intravasucular coagulation appeared. Supportive therapies such as artificial dialysis and transfusions were conducted, but unfortunately she died because of alveolar hemorrhage.

Mucosa-associated lymphoid tissue lymphoma of the appendix vermiformis.

A 60-year-old woman with right lower abdominal pain was admitted to our hospital. Computed tomography demonstrated right hydronephrosis and an irregular mass of 4 x 3 cm adjacent to the ileocecal region and iliopsoas muscle. Preoperative serum soluble anti-interleukin-2 receptor antibody was elevated (689 U/ml). Laparotomy showed an appendiceal tumor invading the cecum, mesocolon, right ureter, and duodenum. Right hemicolectomy with partial resection of the right ureter was performed. Histologic examination revealed diffuse infiltration of centrocyte-like cells, scattered plasma cells, and immunoblasts. The centrocyte-like cells were immunohistochemically positive for CD20 and CD79a, and were negative for BCL2, CD3, CD5, and CD10; this was compatible with primary mucosa-associated lymphoid tissue (MALT) lymphoma. The patient has shown a favorable course without recurrence for 2 years postoperatively. This is the sixth documented case of primary MALT lymphoma of the appendix. The spectrum of sites in which gastrointestinal MALT lymphomas occur should be expanded to include the appendix.

Diagnostic accuracy of multidetector-row computed tomography for hilar cholangiocarcinoma.

BACKGROUND AND AIM: The aim of this study was to investigate the diagnostic reliability of multidetector-row computed tomography (MDCT) for the evaluation of tumor spread in hilar cholangiocarcinoma. METHODS: Images obtained from a 16-detector row scanner of 22 patients were interpreted. The diagnostic accuracy of longitudinal ductal spread, vertical invasion (including hepatic parenchyma), and lymph node metastasis was assessed with reference to histopathological findings. RESULTS: The location of the tumor was correctly diagnosed in 95% of cases (21/22), but in five of these cases, the cut end of the intrahepatic bile duct was positive, resulting in 77% diagnostic accuracy for longitudinal spread. Among the patients with a negative bile duct surgical margin, there was a significant difference in the measurement of tumor spread between MDCT and microscopic investigation (P < 0.001). For vertical invasion, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MDCT were 69%, 100%, 100%, and 69% for the liver parenchyma, respectively. The sensitivity, specificity, PPV, and NPV of MDCT for lymph node metastasis were 50%, 75%, 43%, and 80%, respectively. CONCLUSIONS: The diagnostic accuracy of MDCT for tumor location and vertical invasion was satisfactory, but ductal spread was underestimated in comparison with microscopic measurements.

[The expression of thymidylate synthase (TS) and excision repair complementing-1 (ERCC-1) protein in patients with unresectable colorectal cancer treated with mFOLFOX6 therapy].

Thymidylate synthase (TS) and excision repair complementing-1 (ERCC-1) were known to be important biomarkers to predict a tumor response to 5-fluorouracil (5-FU) and oxaliplatin, but the relationship between these expressions and tumor response were still unclear. The aim of this study was to determine whether the expression of TS and ERCC-1 protein predict a tumor response in patients with unresectable colorectal cancer treated with mFOLFOX6 therapy as first-line treatment. Fifty patients with unresectable colorectal cancer treated with mFOLFOX6 therapy were enrolled in this study. The expression of TS and ERCC-1 protein in primary cancer cells were examined using immunohistochemistry. There were no significant differences between response rate and the expression of TS or ERCC-1 protein (TS: p>0.99, ERCC-1: p= 0.50). There were no significant differences between progression-free survival time and the expression of TS or ERCC-1 protein (TS: p=0.60, ERCC-1: p=0.60). In this study, the expression TS and ERCC-1 protein may not be useful for the prediction of tumor response in patients with unresectable colorectal cancer treated with mFOLFOX6 therapy.

Co-existence of acute myeloid leukemia with multilineage dysplasia and Epstein-Barr virus-associated T-cell lymphoproliferative disorder in a patient with rheumatoid arthritis: a case report.

Rheumatoid arthritis (RA) is an autoimmune disease mediated by inflammatory processes mainly at the joints. Recently, awareness of Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder (T-LPD) has been heightened for its association with methotraxate usage in RA patients. In the contrary, acute myeloid leukemia with multilineage dysplasia (AML-MLD) has never been documented to be present concomitantly with the above two conditions. In this report we present a case of an autopsy-proven co-existence of AML-MLD and EBV-associated T-LPD in a patient with RA.

Pagetoid spread to oral mucosa from submandibular gland salivary duct carcinoma: a case report.

Salivary duct carcinoma is a high-grade malignant tumor arising predominantly in the major salivary glands. We describe herein a rare presentation of salivary duct carcinoma arising in the submandibular gland and showing pagetoid spread to the oral mucosa. A 46-year-old man was admitted with a 2-year history of swelling in the floor of the mouth. Resection of the submandibular gland tumor was followed by mucosal biopsy around the aperture of the right Wharton's duct. The tumor recurred in the oral mucosa with pagetoid spread and extended widely in the oral cavity for the following 10 years, despite chemo- and radiotherapy. Mucosal spread, although a relatively remote possibility, can occur in the setting of salivary duct carcinoma.

Preoperative evaluation of the longitudinal spread of extrahepatic bile duct cancer using multidetector computed tomography.

BACKGROUND/PURPOSE: The aim of this study was to compare the diagnostic accuracy of multidetector computed tomography (MDCT) and direct cholangiography in evaluating the longitudinal spread of extrahepatic bile duct cancer. METHODS: Images obtained from a 16-detector row scanner (MDCT) and from direct cholangiography (via either endoscopic naso-biliary drainage or percutaneous transhepatic biliary drainage) of 47 patients with histopathologically proven extrahepatic bile duct cancer were retrospectively interpreted. Differences between measures of longitudinal tumor spread determined by each modality and measures of macroscopic spread in resected specimens were assessed and compared. RESULTS: Assessments carried out using MDCT differed significantly less from the macroscopic measurements than those made using direct cholangiography (P < 0.0001). Provided the diagnosis was defined as being accurate, based on a diagnostic difference of within +/-5 mm, the diagnostic accuracy of MDCT (96%) was significantly higher than that of direct cholangiography (70%) (P = 0.028). Preoperative evaluation with direct cholangiography resulted in a 30% underestimation of the incidence. CONCLUSION: MDCT is superior to direct cholangiography for evaluating the preoperative longitudinal extent of bile duct cancer. Consequently, the utility of MDCT for preoperative evaluation of extrahepatic bile duct cancer warrants further examination.

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.

Clinicopathological study of breast tissue in female-to-male transsexuals.

PURPOSE: Gender identity disorder is defined as persistent feelings of gender discomfort and the inappropriateness of one's anatomical sex. To study the effects of androgens on female breast tissue, we examined mammary glands from female-to-male transsexual (FTMT) women using androgen therapy and from those not using androgen therapy. METHODS: Female-to-male transsexual breast tissue is a rare specimen in surgical pathology and there are no well-defined guidelines for its examination. We evaluated the clinicopathologic findings of 186 FTMT mammary glands. RESULTS: The patients' ages at presentation ranged from 18 to 49 years (mean 27.4 years). We detected breast carcinoma in only 1 of 130 FTMT women who had not used androgen therapy and in none of 56 FTMT women who had used androgen therapy. CONCLUSION: We described the histopathological morphology of FTMT breast tissue. The frequency of carcinoma and hyperplasia did not differ significantly between FTMT women who had used androgen therapy and those who had not. These findings suggest that androgen does not alter the risk of carcinoma developing in the mammary glands of FTMT women.

Basal cytokeratin expression in relation to biological factors in breast cancer.

The objective of this study was to determine the predictive impact of several established tumor biological markers and clinicopathological findings for basal-like carcinoma. Expression was determined by immunohistochemistry using antibodies to cytokeratins 5/6, 14, and 17, and the cases were divided into basal-like carcinoma and non basal-like carcinoma. These subgroups were compared in terms of biological markers (HER2, estrogen receptor, progesterone receptor, Ki-67, P-53, and P-glycoprotein) and clinicopathological behavior. Of the 49 basal-like carcinoma cases, 25(51.0%) were P-53-positive, whereas 100 (35.9%) of the 278 non basal-like carcinoma cases were P-53-positive. A high ratio of nuclear Ki-67 expression was detected in 39 (79.6%) of 49 basal-like carcinoma cases and was significantly more common than in non basal-like carcinoma cases (81/278, 29.1%). P-glycoprotein expression was identified in 29 (59.2%) of 49 basal-like carcinomas but only 85 (30.6%) of 278 non basal-like carcinomas. We observed high levels of P-53, Ki-67, and P-glycoprotein, with the reduction or loss of estrogen receptor, progesterone receptor, and HER2 being more obvious, in basal-like carcinomas than in non basal-like carcinomas. Our findings provide further evidence that basal-like carcinoma has different mechanisms of histogenesis.

Severe degenerative change of multiple organs mediated by chronic active Epstein-Barr virus infection with infected T-cell expansion.

We here report the case of a young Japanese woman diagnosed with chronic active Epstein-Barr virus (EBV) infection. Intensive therapy with the CHOP regimen was partially able to control virus expansion, but various central nervous system symptoms appeared and gradually progressed. EBV-encoded RNA, detected using in situ hybridization, disclosed the presence of EBV in liver and bone marrow tissue, and real-time PCR revealed the presence of EBV in the cerebrospinal fluid (CSF) and serum. CD3+CD4+CD8-CD56- T-cell expansion in the peripheral blood (PB) and CSF was also observed. Atrophic brain changes were progressive, and the patient died of central nervous system disturbance and pulmonary hemorrhage a year after diagnosis. Autopsy revealed that EBV-infected T lymphocytes with a phenotype similar to those seen in PB and CSF had infiltrated multiple organs: the lymph nodes, bone marrow, endocardium, pericardium, myocardium, spleen, liver, and spinal cord. There have been few previous reports of severe degenerative changes in the myocardium, liver, and spinal cord in patients with EBV infection. Although EBV occasionally infiltrates the central nervous system and brain, atrophic changes mediated by EBV are rare. The autopsy results of this case suggest the possibility of EBV-mediated, severe degenerative changes in multiple organs.

Primary diffuse large B-cell lymphoma of the breast.

Diffuse large B cell lymphoma (DLBL) of the breast is a rare subtype of breast tumor, the diagnosis of which is based on the cytological and histopathological features of this unique neoplasm. A 28-year-old woman noticed a mass in her right breast. It could not be definitely diagnosed clinically by diagnostic imaging (mammography, ultrasonography), so malignant tumor not otherwise specified was diagnosed. Fine-needle aspiration cytology (FNAC) suggested that it was malignant lymphoma; however it was difficult to distinguish from reactive lymphocytes. Excisional biopsy of the breast mass suggested malignant lymphoma. Based on the diagnosis of malignant lymphoma by FNAC and excisional biopsy, lumpectomy was performed and DLBL was diagnosed histologically according to the World Health Organization classification. DLBL is difficult to distinguish from other types of malignant lymphoma by routine immunohistochemical evaluation. Some previous studies have showed that the octamer-binding transcription factor 2 (Oct2) and coactivator B-cell Oct-binding protein 1 (BOB.1) and the pan-B-cell markers CD20 and CD79a may aid in the diagnosis of malignant lymphoma. In our case, the staining of large atypical lymphocytes for CD20, CD79a, BOB.1 and Oct2 was strongly positive and supports the notion that BOB.1 and Oct2 are also useful immunohistochemical markers for DLBL of the breast.

Hodgkin-like anaplastic large cell lymphoma (previously designated in the REAL classification) has same immunophenotypic features to classical Hodgkin lymphoma.

In the WHO classification, the majority of Hodgkin-like ALCL cases as defined by the REAL classification are considered to be CHL. However, establishing a histological diagnosis for the gray zone between CHL and ALCL is often confusing. In this study, we re-evaluated such cases by performing immunohistochemistry with antibodies against PAX-5/BSAP, Oct.2, and BOB.1/OBF.1. Expression of PAX-5/BSAP was observed in 88% (76/87) of CHL specimens and none (0/11) of ALK-positive ALCL specimens. Among specimens of Hodgkin-like ALCL and ALK-negative ALCL, expression of PAX-5/BSAP was observed in 77% (20/26) and 18% (3/17), respectively. Most of the PAX-5/BSAP-positive specimens were negative for Oct.2 and/or BOB.1/OBF.1 except for four CHL specimens. Our results may support the WHO classification in which most cases of Hodgkin-like ALCL are classified as CHL. However, the patients with Hodgkin-like ALCL with CHL-immunophenotype (PAX-5/BSAP-positive and negative for Oct.2 and/or BOB.1) did not have a favorable outcome, with a 5-year OS rate of 58%.

N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo.

The Eker rat is an animal model of renal carcinogenesis and carries a transposon insertion in the Tsc2 (tuberous sclerosis-2) gene. We previously generated transgenic Eker rats and identified coding sequences in the Tsc2 gene that are responsible for suppression of renal carcinogenesis in Eker rats. Tsc2-RGH, a transgene that expresses the carboxy terminal region (amino acids 1425-1755) of the Tsc2 product (tuberin), partially suppressed renal carcinogenesis. However, Tsc2-DRG, which expresses a mutant tuberin lacking the carboxy-terminal region (Delta aa 1425-1755), did not suppress renal carcinogenesis. Here, we found that introduction of both Tsc2-RGH and Tsc2-DRG in Eker rats completely suppressed renal carcinogenesis and rescued homozygous (Tsc2(Ek/Ek)) mutants from embryonic lethality in a complementary manner. Co-introduction of Tsc2-RGH and Tsc2-DRG, but not introduction of either alone, efficiently suppressed phosphorylation of p70 S6K. Thus, the functional domains of N-terminal hamartin binding and C-terminal tumor suppression in tuberin can separate in vivo.

Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis.

We report on a patient of rheumatoid arthritis (RA) who sequentially developed an axillary mass and a fatal interstitial pneumonia during a 2-year course of methotrexate (MTX) therapy. Autopsy revealed a systemic lymph node involvement and the diagnosis of Epstein-Barr virus (EBV)-related lymphoproliferative disease (LPD) with the features of lymphomatoid granulomatosis was made. The lung tissue specimens revealed a typical diffuse alveolar damage (DAD), and small nodules consisting of atypical B lymphocytes showing positive staining for EBV were sparsely recognized only in basal lungs. This is the first report of a RA patient receiving MTX therapy sequentially developing MTX-associated lymphomatoid granulomatosis and DAD.