Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease.

BACKGROUND: Several recent studies have reported on the overexpression of human epidermal growth factor receptor (HER)2 in extramammary Paget disease (EMPD). However, there are only a few cases in which both overexpression and gene amplification of HER2 have been examined. OBJECTIVES: To evaluate the overexpression and gene amplification of HER2 using a standardized method with a large number of cases of EMPD. METHODS: Immunohistochemically, the overexpression of the HER2 protein was examined in 104 cases of EMPD, including 31 intraepithelial cases and 73 invasive cases (35 superficially invasive and 38 deeply invasive). When the HER2 protein was overexpressed or potentially overexpressed, further analysis of amplification of the gene encoding HER2, ERBB2, was undertaken using fluorescence in situ hybridization. RESULTS: The HER2 protein was overexpressed in 16 cases (15%) in total, and in 13 of 73 cases (18%) of invasive EMPD. The ERBB2 gene was amplified in all cases with a HER2 score of 3+. A HER2 score of 3+ or 2+, and ERBB2 amplification were significantly more frequent in the cases of deeply invasive EMPD than in intraepithelial/superficially invasive EMPD (24% vs. 6%/3%, P=0·012) and were correlated with a larger number of lymph-node metastases (P=0·047). Log-rank tests for survival curves showed that lymph-node metastasis and ERBB2 amplification were significant prognostic factors (P=0·0001 and P=0·043, respectively). However, by a multivariate analysis, only lymph-node status was a significant indicator of Paget-disease-specific survival (P=0·0001). CONCLUSIONS: A subset of EMPD, both intraepithelial and invasive, showed HER2 overexpression and gene amplification. These HER2 alterations were correlated with biologically aggressive EMPDs, i.e. those with deep invasion and lymph-node metastasis. Clinical trials of HER2-targeted therapy are awaited for improvement of the prognosis of patients with aggressive EMPD.

Factors related to postoperative delirium in patients with lower limb ischaemia: a prospective cohort study.

OBJECTIVES: To preoperatively determine candidates at definitive risk of postoperative delirium (POD), we identified relevant factors in patients with arteriosclerosis obliterans who underwent bypass surgery. DESIGN: A prospective cohort study. PATIENTS AND METHODS: 299 patients (age ≥ 60 years) who underwent bypasses in 1995-2006 were enrolled. Cognitive impairment was assessed by the Revised Hasegawa Dementia Scale, the Confusion Assessment Method was also used, and severity was graded as Grade I-III (mild to severe) based on the Delirium Rating Scale. All patients were followed for 3 years. RESULTS: POD occurred in 88 patients (29%), with a median age of 75 (10) years (IQR). Onset was 2 (1) days postoperatively, and a duration of 2 (2) days was observed. POD was hyperactive in 89% and was Grade I, II, and III in 11%, 68%, and 21% respectively. Multiple logistic regression analysis identified the following risk factors for POD: age ≥ 72 years (<0.0001), end-stage renal failure (0.001), multiple occlusive lesions (<0.0001), cognitive impairment (0.003), and critical limb ischaemia (0.034). The 3-year survival rate was similar when comparing POD and non-POD patients (84% vs. 88%, NS). CONCLUSIONS: This study identified 5 risk factors for POD in patients undergoing bypasses for limb ischaemia. Long-term outcomes were similar when comparing the patients who experienced POD with those who did not.

Modified primary tumour/vessel tumour/nodal tumour classification for patients with invasive ductal carcinoma of the breast.

BACKGROUND: We previously reported that the primary tumour/vessel tumour/nodal tumour (PVN) classification is significantly superior to the UICC pTNM classification and the Nottingham Prognostic Index for accurately predicting the outcome of patients with invasive ductal carcinoma of the breast in a manner that is independent of the nodal status and the hormone receptor status. METHODS: The purpose of the present study was to compare the outcome predictive power of a modified PVN classification to that of the newly devised pathological UICC pTNM classification and the reclassified Nottingham Prognostic Index in a different group of patients with invasive ductal carcinoma (n=1042) using multivariate analyses by the Cox proportional hazard regression model. RESULTS: The modified PVN classification clearly exhibited a superior significant power, compared with the other classifications, for the accurate prediction of tumour recurrence and tumour-related death among patients with invasive ductal carcinoma in a manner that was independent of the nodal status, the hormone receptor status, and adjuvant therapy status. CONCLUSION: The modified PVN classification is a useful classification system for predicting the outcome of invasive ductal carcinoma of the breast.

Clinical characteristics and outcomes of women with stage IV endometrial cancer.

Treatment strategies for patients with stage IV endometrial cancer (EC) remain controversial. Some studies have suggested that optimal cytoreduction improves survival. We retrospectively analyzed the clinical characteristics and outcomes of 41 women with stage IV EC. The results of preoperative cytologic evaluation and biopsy of the endometrium were reviewed by a single pathologist for patients in whom stage IV EC was diagnosed preoperatively. Of the 41 patients with stage IV EC (median age, 62 years), 31 had surgical stage IV disease and 10 had clinical stage IV disease. Twenty-eight patients were diagnosed of stage IV EC before surgery or without surgery. Progression-free survival and overall survival were 10.4 and 21.3 months, respectively. On univariate analysis, grade 1 or 2 endometrioid subtype, 0 or 1 sites of extraperitoneal metastasis, and hormonal therapy were associated with good outcomes. Multivariate analysis revealed that grade 1 or 2 endometrioid subtype (P=0.005, hazard ratio [HR] 0.23 [0.08-0.65]) and 0 or 1 sites of extraperitoneal metastasis (P=0.001, HR 0.24 [0.10-0.57]) were independent predictors of survival. Neither surgery as primary therapy nor optimal cytoreduction was significantly related to overall survival in either the 28 patients in whom stage IV was diagnosed preoperatively or in all 41 patients. In women with stage IV EC, histologic features and extent of disease are more important determinants of outcomes than any kind of treatment. The indication for surgery should be carefully considered in this subset of patients.

Radical hysterectomy for FIGO stage I-IIB adenocarcinoma of the uterine cervix.

A retrospective analysis was carried out to identify risk factors for survival and relapse in patients with FIGO stage I-IIB cervical adenocarcinoma (AC), who underwent radical hysterectomy, and to compare outcome and spread pattern with those of squamous cell carcinoma (SCC). One hundred and twenty-three FIGO stage I-IIB patients with AC and 455 patients with SCC, who all underwent primary radical hysterectomy, were reviewed. Among the patients with AC, Cox model identified tumour size (95% CI: 1.35-30.71) and node metastasis (95% CI: 5.09-53.44) as independent prognostic factors for survival, and infiltration to vagina (95% CI: 1.15-5.76) and node metastasis (95% CI: 6.39-58.87) as independent prognostic factors for relapse. No significant difference was found in survival or relapse between the AC and SCC groups, after adjusting for other clinicopathological characteristics using Cox model. No significant difference was found in the positive rates of lymph nodes or location of initial failure sites between the two groups, but ovarian metastatic rate was significantly higher in patients with pathologic stage IIB AC (P=0.02). Positive node is a common independent prognostic factor for survival and relapse of patients with AC. FIGO stage I-IIB patients with AC or SCC, who underwent radical hysterectomy, have similar prognosis and spread pattern, but different ovarian metastasis rates.

Surgical treatment for neuroendocrine carcinoma of the uterine cervix.

OBJECTIVE: To identify the best operative approach for neuroendocrine cervical carcinoma (NECC). METHODS: The records of surgically treated patients with stages IB to IIB NECC were reviewed. RESULTS: Of 10 patients who met the study criteria for NECC and underwent radical hysterectomy, 4 had pT1bN0, 4 had pT1bN1, 1 had pT2aN0, and 1 had pT2bN1 disease. Those with pT1bN1 or pT2bN1 disease received postoperative adjuvant radiotherapy and/or chemotherapy, and recurrence occurred in 7 patients (70%). Among these 7 patients, 5 (71%) had a primary NECC tumor with deep stromal invasion and 5 (71%) had extrauterine disease (parametrium and/or lymph node). The recurrences in 6 patients (86%) were located outside the pelvis (lung, liver, or brain). Stromal invasion was 6 mm or less in the 3 patients who did not experience disease recurrence. CONCLUSIONS: Pelvic control by radical hysterectomy may not be beneficial for patients with NECC except for those with an early invasive lesion.

Muir-torre syndrome with intriguing squamous lesions: a case report and review of the literature.

Muir-Torre syndrome (MTS) is an autosomal, dominantly inherited disorder characterized by sebaceous neoplasms and visceral malignancies. We report a 56-year-old woman who underwent resections of extraocular sebaceous carcinoma, sebaceous epithelioma, actinic keratosis, and keratoacanthoma (KA)-like squamous cell carcinoma (SCC) with venous invasion metachronously over a 9-year period. Because of the mixed, unusual features of the skin lesions, and her history of endometrial and colorectal cancers that had been resected 12 years and 1 year, respectively, before the present event, a possible diagnosis of Muir-Torre syndrome was suggested. Immunohistochemical studies revealed loss of hMSH2 expression in all the cutaneous lesions including the actinic keratosis, and also in the endometrial and colorectal cancers. This patient presented with intriguing squamous lesions including keratoacanthoma-like squamous cell carcinoma that showed venous invasion and actinic keratosis, and associated loss of hMSH2 expression, in addition to the sebaceous neoplasms typical of Muir-Torre syndrome.

Prognostic significance of positive peritoneal cytology in endometrial carcinoma confined to the uterus.

A retrospective analysis was performed to evaluate the prognostic significance of peritoneal cytology in patients with endometrial carcinoma limited to the uterus. A total of 280 patients with surgically staged endometrial carcinoma that was histologically confined to the uterus were examined clinicopathologically. The median length of follow-up was 62 (range, 12-135) months. All patients underwent hysterectomy and salpingo-oophorectomy with selective lymphadenectomy, and only three patients received adjuvant postoperative therapy. No preoperative adjuvant therapy was employed. In all, 48 patients (17%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative peritoneal cytology was 91 or 95%, respectively, showing no significant difference (log-rank, P=0.42). The disease-free survival rate at 36 months was 90% among patients with positive cytology, compared with that of 94% among patients with negative cytology, and the difference was not significant (log-rank, P=0.52). Multivariate proportional hazards model revealed only histologic grade to be an independent prognostic factor of survival (P=0.0003, 95% CI 3.02 - 40.27) among the factors analysed (age, peritoneal cytology, and depth of myometrial invasion). Multivariate analysis revealed that histologic grade (P=0.02, 95% CI 1.21-9.92) was also the only independent prognostic factor of disease-free survival. We concluded that the presence of positive peritoneal cytology is not an independent prognostic factor in patients with endometrial carcinoma confined to the uterus, and adjuvant therapy does not appear to be beneficial in these patients.

High accumulation of plasminogen and tissue plasminogen activator at the flow surface of mural fibrin in the human arterial system.

PURPOSE: We assessed the fibrinolytic activity of the organized mural thrombus lining of aneurysms and prosthetic grafts. METHODS: Between May 1995 and April 1998, the full-thickness mural thrombi of aneurysms and the pseudointima lining of vascular grafts were obtained from 12 patients, ranging from 55 to 78 years in age, who underwent elective surgery. These included five aortic arch aneurysms, four abdominal aortic aneurysms, and three patent synthetic vascular grafts. The specimens were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)/immunoblot and immunohistochemistry for human plasmin/plasminogen, tissue plasminogen activator (tPA), and fibrin degradation product (D-dimer). RESULTS: In the SDS-PAGE/immunoblot, 25- and 27-kd bands appeared specifically in experimental fibrin plates after limited digestion by plasmin and were also recognized in the mural thrombi. The presence of bands at 25 and 27 kd, which were most prominent in sections near the flow surface layer, was consistent with the hypothesis that the mural fibrin was digested by the endogenous plasmin. Apparent immunoreactivity was found at the flow surface of the masses at a thickness of 10 to 400 micrometer suggesting the presence of a plasminogen and tPA-rich layer, with D-dimer as a consequential product of fibrinolysis. CONCLUSION: The hypothesis that fibrin surfaces in the arterial system acquire fibrinolytic activity because of digestion by circulating endogenous plasmin was confirmed; this may contribute to the antithrombogenicity of these flow surfaces.

Postoperative delirium in patients with chronic lower limb ischaemia: what are the specific markers?

OBJECTIVES: we determined the incidence and specific markers of postoperative delirium in elderly patients with chronic lower limb ischaemia. PATIENTS AND METHODS: since April, 1995, 110 patients aged 60 years or older (mean: 71.6+/-6.6 years) who underwent bypass surgery were assessed regarding aetiological factors of delirium: age, sex, dementia, body-mass index, hypertension, diabetes, cerebral disease, laboratory test results, severity of limb ischaemia, type of arterial occlusion, operative time, and blood transfusion. RESULTS: discriminant analysis showed statistical significance in the following five variables: age >/=70 years; critical limb ischaemia (and/or ankle pressure <40 mmHg); dementia; duration of operation >/=7 hours; low serum albumin. The overall percentage of cases correctly classified was 78.2% (Wilks>> Lambda=0.695, p<0.001); the standardized regression coefficients of the five variables were 0.648, 0.500, 0.329, 0.218, and 0.200, respectively. In logistic regression, the regression coefficients for old age and critical limb ischaemia were 2.646 (14.1 of odds ratio; 95% confidence interval, 2.7-72.0) and 1.337 (3.8; 1.3-10.9), respectively. CONCLUSIONS: the incidence of postoperative delirium in elderly patients with chronic lower-limb ischaemia was as high as 42.3%, and an age of over 70 years and critical limb ischaemia were identified as specific markers, with 14.1 times and 3.8 times the odds of suffering from delirium after bypass surgery.

Inconsistent association of Epstein-Barr virus with CD56 (NCAM)-positive angiocentric lymphoma occuring in sites other than the upper and lower respiratory tract.

We previously described nine cases of angiocentric lymphoma of a possible natural killer (NK)-cell lineage with a surface CD3-CD56+ phenotype occurring in sites other than the upper and lower respiratory tract. This study was performed to investigate the association of Epstein-Barr virus (EBV) with these lymphomas, using the polymerase chain reaction (PCR) for the presence of EBV-DNA, in situ hybridization (ISH) for EBV-encoded small RNAs (EBERs) and immunohistology for EBV-determined nuclear antigen-2 (EBNA-2) and latent membrane protein-1 (LMP-1) in paraffin sections. PCR and ISH produced almost identical results, and EBERs were identified in the nuclei of the lymphoma cells of three cases, two of which exhibited LMP-1 in the cytoplasm of tumour cells without EBNA-2 expression. Molecular genetic analysis revealed EBV to be incorporated into these three EBER-positive cases either clonally or biclonally. It was revealed by re-evaluation of their morphology with the established EBV status on each case that, in contrast to the rather variable and irregular cellular composition of the EBV-positive tumours, the EBV-negative tumours stood out because of their remarkably uniform 'blastoid' appearance, and could be grouped as blastic NK-cell lymphoma. The relationship of the EBV-positive cases with nasal NK-cell tumours has yet to be clarified.

Ki-1 (CD30) positive anaplastic large cell lymphoma of T-cell phenotype developing in association with long-standing tuberculous pyothorax: report of a case with detection of Epstein-Barr virus genome in the tumor cells.

We report a case of CD30 positive anaplastic large cell lymphoma of T-cell phenotype developing in association with long-standing tuberculous pyothorax. Phenotypic analysis showed CD1a-, CD2+, CD3+, CD4+, CD5-, CD8-, CD10-, CD19-, CD20 +/-, CD21-, CD25-, CD56-, T-cell receptor (TCR) alpha/beta antigens-, and HLA-DR+ phenotype. Neither rearrangement of TCR beta and gamma chain genes or of immunoglobulin heavy chain gene was detected in DNA extract from fresh material. The lymphoma cells were also shown to express the latent membrane protein-1 and the Epstein-Barr virus (EBV)-encoded nuclear antigen-2 by immunohistochemistry and EBV-encoded small RNAs by in situ hybridization.

Angioimmunoblastic T-cell lymphoma (angioimmunoblastic lymphadenopathy with dysproteinemia [AILD]-type T-cell lymphoma) followed by Hodgkin's disease associated with Epstein-Barr virus.

A patient is described with angioimmunoblastic T-cell lymphoma (AIL) (angioimmunoblastic lymphadenopathy with dysproteinemia [AILD]-type T-cell lymphoma), which was later followed by Hodgkin's disease. At the time of the initial diagnosis, histological examination of a cervical lymph node showed a typical picture of AIL with abundant clear cells which were CD45RO+, CD43+, and CD20-, and there was no evidence of a monoclonal B-cell proliferation by immunohistochemical analysis. In situ hybridization for Epstein-Barr virus (EBV) was negative. Interposed by a bout of recurrence, the patient developed, 16 years later, a left subparotid mass which showed histologic features of Hodgkin's disease, mixed cellularity type. Diagnostic Reed-Sternberg cells and their variants were CD30+, CD15- and CD20+. Neither rearrangement of TCR beta and gamma chain genes nor of immunoglobulin heavy chain and kappa light chain genes was detected in DNA extract from fresh material. In situ hybridization showed the presence of EBV within the Reed-Sternberg cells. The data show that EBV was not etiologically related to AIL in this case. Further, the deficit in cellular immunity that accompanied AIL conceivably permit primary EBV infection or reactivation of latent infection, which eventuated in development of Hodgkin's disease, but the exact pathogenesis remains uncertain.

[Null-cell non-Hodgkin's lymphoma presenting with a mass in the chest wall after tuberculous pyothorax].

A 59-year-old male, who was treated with artificial pneumothorax for pulmonary tuberculosis 42 years previously, presented with a painful mass in the left lateral chest wall and lymph node swelling in the left neck. A chest CT-scan revealed a tumor shadow extending from the outer chest wall to the pleural cavity containing pus surrounded by calcified pleura. 67Ga scintigraphy showed accumulation of the radionuclide in the left lateral chest and left neck. Biopsy specimen obtained from both the chest tumor and cervical lymph node revealed diffuse large cell lymphoma. Immunostaining failed to demonstrate CD1, CD3, CD4, CD8, CD13, CD20, immunoglobulin, alpha, gamma, mu, delta, kappa and lambda chains, indicating null cell characteristics. Chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, prednisolone and bleomycin and irradiation resulted in a temporary decrease of the tumor and lymph nodes, but the patient died of pneumonia 14 months after the onset of disease. Since the levels of serum lactate dehydrogenase and immunosuppressive acidic protein varied in parallel to the disease activity, they appeared to be useful for the assessment of therapeutic effects during the clinical course. Approximately 100 cases of non-Hodgkin's lymphoma developing after tuberculous pyothorax have been reported in this country, among which the incidence of null cell type is exceedingly rare.

High expression of the Epstein-Barr virus latent protein EB nuclear antigen-2 on pyothorax-associated lymphomas.

Pyothorax-associated lymphoma (PAL) is a rare tumor associated with long-standing tuberculous pyothorax. Most of these lymphomas are B-cell lymphomas of high-grade malignancy. Over 50 cases have been reported in Japan, but no cases have been described in Western countries. Its pathogenesis remains unknown. We studied immunohistologically the expression of Epstein-Barr virus- (EBV) encoded latent gene products, EB nuclear antigen-2 and LMP-1, in four cases of PAL. Fifty B-cell lymphomas unrelated to pyothorax, and five EBV-bearing lymphoblastic tumors produced in severe combined immune deficient mice (severe combined immune deficient-EBV+ tumors) were also studied as controls. Marked expression of EB nuclear antigen-2 was demonstrated on all four PALs. LMP-1 was also present in all cases, but both the staining intensity and the number of stained cells remained less than on severe combined immune deficient-EBV+ tumors. Neither EB nuclear antigen-2 nor LMP-1 was observed in the 50 control B-cell lymphomas. Additional molecular genetic analysis revealed that EBVs are incorporated into each PAL clonally. These results confirm the definite association of EBV with PALs, although the significance of weak expression of LMP-1 awaits further study.

Immunophenotypic and molecular analysis of a case of lymphocytic interstitial pneumonia.

A case of lymphocytic interstitial pneumonia was studied immunophenotypically and with molecular methods in order to clarify its lymphocytic clonality. The patient, a 43 year old Japanese female, underwent lobectomy for a suspected malignant lymphoma as no clear diagnosis could be made from the biopsy specimen. An ill-demarcated, yellowish and elastic firm lesion measuring 60 x 35 x 20 mm in size was located in the peripheral part of the middle lobe of the right lung. Histologically, the alveolar, peribronchial-vascular and subpleural interstitia within the lesion were thickened markedly with severe cellular infiltration largely composed of small lymphocytes with germinal centers. Immunostaining revealed immunoglobulin (Ig) kappa and Ig lambda-bearing cells to be evenly distributed, suggestive of polyspecificity. Immunoglobulin gene analysis further demonstrated the unrearranged germ-line DNA but no rearranged band. These results strongly indicated a reactive process rather than a neoplastic nature for the lesion.