[Laparoscopic Total Gastrectomy(LTG)in Patient with Multiple Gastric Neuroendocrine Tumor Related to Multiple Endocrine Neoplasia Type 1 - Two Case Reports].

We herein report 2 cases of laparoscopic total gastrectomy(LTG)in patient with multiple gastric neuroendocrine tumor (NET)related to multiple endocrine neoplasia type 1(MEN1). Case 1: A 66-year-old female was diagnosed with multiple gastric NET. There was no finding of any other tumor, and parathyroid function was normal. She underwent LTG. Case 2: A 58-year-old female was diagnosed with multiple gastric NET. The patient had a previous history of surgery for pituitary gland tumor. There was no finding of any other tumor, and parathyroid function was normal. She underwent LTG. In our cases, we could perform complete resection of gastric NET by laparoscopic surgery. Multiple gastric NET is a good indication of laparoscopic gastrectomy.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with a central and peripheral carcinoid and multiple tumorlets: a case report emphasizing the role of neuropeptide hormones and human gonadotropin-alpha.

We report a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). We performed immunohistochemical analysis of 17 neuropeptides and human gonadotropin-alpha (hCGα), a trophoblastic peptide that promotes the proliferation of neuroendocrine cells. A 51-year-old woman with no history of smoking was found to have a nodule in the right middle lobe. Upon examination, the nodule was found to comprise diffuse linear and nodular neuroendocrine cell hyperplasia (NECH), numerous pulmonary tumorlets merging with one peripheral carcinoid, and an additional central carcinoid. Immunohistochemical analysis revealed diffuse but intense expression of the general neuroendocrine markers CD56, synaptophysin, and chromogranin A, together with gastrin-releasing peptide (GRP), calcitonin, and hCGα throughout the carcinoids, tumorlets, and NECH. Positive staining was also noted for adrenocorticotropic hormone, corticotropin-releasing hormone, met-enkephalin, vasoactive intestinal polypeptide, neurotensin, and growth hormone-releasing hormone in a few isolated cells of the carcinoids and the tumorlets, but staining for these proteins was entirely negative in the NECH lesions. The presence of these neuropeptides in neuroendocrine tumors might explain the presence of neuropeptide-producing tumors of the lungs, cases of which have been reported over the last 30 years. The preoperative serum proGRP level was high but returned to normal after surgical intervention, indicating that GRP was produced and secreted by carcinoids, tumorlets, and/or NECH lesions. It is also probable that neuroendocrine cells secreted GRP into the interstitium in a paracrine manner, leading to the development of dense fibrosis around the tumorlets. During the preoperative and postoperative periods, no evidence of bronchiolitis obliterans was noted, in contrast to some previously reported cases of DIPNECH.

Sentinel lymph node biopsy after neoadjuvant chemotherapy predicts pathological axillary lymph node status in breast cancer patients with clinically positive axillary lymph nodes at presentation.

BACKGROUND: It is still controversial whether axillary lymph node (ALN) dissection (ALND) can be omitted after negative sentinel lymph node (SLN) biopsy (SLNB) in breast cancer (BC) patients with clinically positive ALNs at presentation treated with neoadjuvant chemotherapy (NAC). The study aim was to analyze whether SLNB could be useful in these patients. METHODS: In a retrospective study, eligible patients were women with invasive BC with clinically positive ALNs at presentation, treated with NAC then a total or partial mastectomy, with an intraoperative histological examination of SLNs and non-SLNs suspicious for metastasis followed by ALND. Non-SLNs suspicious for metastasis were defined as hard or large nodes located in the same level of the axilla where clinically positive ALNs had been initially identified. The results of SLNB and clinicopathological characteristics were analyzed for correlation with pathological ALN status. RESULTS: In a consecutive series of 105 women with 107 BC cases, 81 (75.7 %) had at least 1 SLN, and the remaining 26 (24.3 %) had at least 1 non-SLN suspicious for metastasis. The intraoperative (or final) histological examination of these nodes revealed that the false-negative (FN) rate and accuracy were 8.2 (or 6.3) % and 95.1 (or 96.3) %, respectively. Estrogen receptor status at presentation, pathological tumor response, lymphovascular invasion after NAC, and NAC regimen were correlated with pathological ALN status. CONCLUSION: The histological examination of SLNs and that of non-SLNs suspicious for metastasis are useful for predicting pathological ALN status in BC patients with clinically positive ALNs at presentation who are treated with NAC.

Analysis of complete response by MRI following neoadjuvant chemotherapy predicts pathological tumor responses differently for molecular subtypes of breast cancer.

In the present study, clinical tumor response following neoadjuvant chemotherapy (NAC) was diagnosed by magnetic resonance imaging (MRI) and clinicopathological factors, including molecular subtypes at baseline, were analyzed for correlations with pathological tumor responses. In addition, clinicopathological factors were analyzed for a correlation with the MRI capacity to predict pathological complete response (pCR). Clinical tumor response evaluated by MRI following NAC was determined as a clinical CR (cCR) or a residual tumor. cCR was confirmed if no gadolinium enhancement or an enhancement equal to or less than that of glandular tissue was observed in any phase of the MRI. Pathological tumor responses following NAC were classified into grades 0 (no change) to 3 (no residual invasive cancer) according to criteria of the Japanese Breast Cancer Society. pCR was defined as grade 3 in the present study. Of 264 cases of invasive breast cancer in 260 patients (4 synchronous bilateral breast cancer cases), 59 (22%) were diagnosed by MRI following NAC as cCR and 98 (37%) were pathologically diagnosed as pCR. In terms of predicting pCR by MRI, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were 44, 90, 73, 73 and 73%, respectively. Tumor size, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtype and histological type were significantly correlated with pathological tumor responses. pCR rates increased in the following order: luminal/HER2-negative (14%), luminal/HER2-positive (32%), triple-negative (46%) and non-luminal/HER2-positive (73%) tumors. Sensitivity and specificity were the highest (60 and 100%, respectively) in triple-negative tumors. PPV decreased in the following order: triple-negative (100%), non-luminal/HER2-positive (92%), luminal/HER2-positive (46%) and luminal/HER2-negative (33%) tumors. In conclusion, MRI evaluation is useful for predicting pCR following NAC, particularly for triple-negative tumors.

ER-activating ability of breast cancer stromal fibroblasts is regulated independently of alteration of TP53 and PTEN tumor suppressor genes.

Carcinoma-associated fibroblasts (CAFs) are associated with tumor progression and metastasis, and are able to activate estrogen receptor (ER) in breast cancer. We established a stable transformant of a human breast cancer cell line to detect CAF-specific ER-activating ability, and found that this CAF ability varied among tumors. Some studies have reported a high frequency of alterations among tumor suppressor genes in stromal cells, but do not generally agree as to the frequency. Moreover, the activation mechanism of CAF-induced estrogen signals, including the effects of these gene aberrations, is not fully understood. We investigated the relevance of tumor suppressor gene aberrations and ER-activating ability in CAFs derived from 20 breast cancer patients. Although CAF-specific ER-activating abilities varied among individual cases, all CAFs maintained wild-type alleles for TP53 and PTEN. Also, copy number aberrations in these genes were not observed in any CAFs. Our results suggest that the ER-activating ability of the CAFs is regulated independently of aberrations in these genes; and that other mechanisms of tumor-stromal interaction may affect activation of estrogen signals in breast cancer.

Individual transcriptional activity of estrogen receptors in primary breast cancer and its clinical significance.

To predict the efficacy of hormonal therapy at the individual-level, immunohistochemical methods are used to analyze expression of classical molecular biomarkers such as estrogen receptor (ER), progesterone receptor (PgR), and HER2. However, the current diagnostic standard is not perfect for the individualization of diverse cases. Therefore, establishment of more accurate diagnostics is required. Previously, we established a novel method that enables analysis of ER transcriptional activation potential in clinical specimens using an adenovirus estrogen response element-green fluorescence protein (ERE-GFP) assay system. Using this assay, we assessed the ERE transcriptional activity of 62 primary breast cancer samples. In 40% of samples, we observed that ER protein expression was not consistent with ERE activity. Comparison of ERE activity with clinicopathological information revealed that ERE activity was significantly correlated with the ER target gene, PgR, rather than ER in terms of both protein and mRNA expression. Moreover, subgrouping of Luminal A-type breast cancer samples according to ERE activity revealed that ERα mRNA expression correlated with ER target gene mRNA expression in the high-, but not the low-, ERE-activity group. On the other hand, the low-ERE-activity group showed significantly higher mRNA expression of the malignancy biomarker Ki67 in association with disease recurrence in 5% of patients. Thus, these data suggest that ER expression does not always correlate with ER transcriptional activity. Therefore, in addition to ER protein expression, determination of ERE activity as an ER functional marker will be helpful for analysis of a variety of diverse breast cancer cases and the subsequent course of treatment.

[A case of intraductal mucinous neoplasms with the whole main pancreatic duct dilation treated via segment pancreatectomy].

The patient was a 77-year-old woman. She was diagnosed as intraducal papillary mucinous neoplasms (IPMN). She refused an operation for 3 years. After all, a nodule in the main pancreatic duct was pointed out, she agreed and was referred to us. Her past history showed pacemaker implantation for third-degree atrioventricular block, and no impaired glucose tolerance. Abdominal CT showed a dilated whole pancreatic duct and a multilocular cystic tumor. Endoscopic retrograde pancreatography showed a marked dilation of the main pancreatic duct. We diagnosed as main duct IPMN. Intraoperative US showed no nodule in pancreatic duct, and there was no suspicious lesion of invasive cancer. We performed segmental pancreatectomy between the left side of common bile duct and the pancreas tail. The tumor was resected with clear margins. Both cut-ends of the main pancreatic duct were anastomosed to a jejunal loop. The postoperative course was excellent. She was discharged on day 16. The glycemic control was good, she needed no treatment for diabetes. Total pancreatectomy has many problems such as insulin and pancreatic polypeptide deficiency, hypoglycemia, malabsorption, diarrhea and liver dysfunction. We avoided total pancreatectomy so that her quality of life was maintained. Still a careful follow -up is required.

Neoadjuvant endocrine therapy of breast cancer: which patients would benefit and what are the advantages?

Aromatase inhibitors (AIs) were more effective than tamoxifen as a neoadjuvant endocrine therapy (NAE) for postmenopausal women with estrogen receptor (ER)-positive breast cancer. Neoadjuvant AIs were shown to reduce tumor volume and to allow the performance of breast-conserving surgery (BCS) in cases that would normally require mastectomy. Predictive markers of neoadjuvant AIs may be ER-rich, progesterone receptor (PgR)-rich and human epidermal growth factor receptor 2 (HER2)-negative tumors. However, the ability of HER2 expression to predict a response to neoadjuvant AIs is controversial. Pathological tumor size, nodal status, Ki67 level, and ER score are predictive for the survival of postmenopausal women with breast cancer who have been treated with NAE. These factors could be useful in order to select patients who do not require chemotherapy. Indeed, neoadjuvant AIs are a potential treatment option for postmenopausal women with ER-rich breast cancer who prefer BCS despite having large tumors suitable for mastectomy.

Pathological tumor response to neoadjuvant chemotherapy using anthracycline and taxanes in patients with triple-negative breast cancer.

Although triple-negative breast cancer (TNBC) is associated with a poor prognosis, recent reports have indicated that a higher proportion of TNBC patients shows a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) than is the case for non-TNBC patients. The aim of this study was to identify markers that predict pCR to NAC in TNBC patients, and to clarify prognostic factors that affect the outcome of TNBC patients with residual disease (RD) after NAC. Among 44 TNBC patients who received anthracycline- and taxane-based combination NAC, we analyzed the relationship between pathological response and clinicopathological characteristics, including immunohistochemical parameters (cytokeratin 5/6, epidermal growth factor receptor, Ki-67, p53, breast cancer susceptibility protein 1 and topoisomerase IIα). We also assessed the prognostic impact on patients with RD by analyzing the correlation between disease-free survival (DFS) and clinicopathological parameters. Sixteen patients (36%) achieved a pCR and log-rank test showed that these patients had a significantly more favorable outcome than patients with RD (DFS, P=0.00184; overall survival, P=0.0080). Among the clinicopathological parameters examined, none was correlated with pathological response, with the exception of p53. Patients with immunohistochemical overexpression of p53 more frequently achieved a pCR than those without p53 overexpression (P=0.0484). In the patients with RD, the Cox proportional hazards model showed that the presence of lymphovascular invasion was significantly associated with shorter DFS (hazard ratio, 13.333; 95% CI 1.587-111.111; P=0.0171). p53 overexpression may be a key predictor of a favorable response to NAC. Since patients with RD, particularly those positive for lymphovascular invasion, had an extremely poor outcome, novel therapeutic approaches for these patients are warranted.

Immunohistochemical assessment of primary breast tumors and metachronous brain metastases, with particular regard to differences in the expression of biological markers and prognosis.

In this study, we conducted an immunohistochemical analysis of primary breast tumors and metachronous brain metastases to compare the differences in the expression of biological markers between the two. Carcinoma tissues from primary breast tumors and metachronous brain metastases collected from 21 patients were examined immunohistochemically for the expression status of the estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor (HER)-2, Ki-67, bcl-2 and p53, and the results were compared. In addition, the relationships between the expression of these factors and prognosis were evaluated. There were no significant differences in the frequencies of ER-, PgR-, HER-2-, bcl-2- or p53-positivity between the primary breast tumors and metachronous brain metastases. While the Ki-67 labeling index (LI) was high in both the primary breast tumors and brain metastases, it was significantly higher in the brain metastases than in the corresponding primary breast tumors (P=0.003). With regard to the prognosis, breast cancer patients who showed ER-positivity in the primary tumors showed significantly longer survival after primary diagnosis (P=0.0076). Furthermore, breast cancer patients who exhibited ER-positivity, bcl-2-positivity or p53-negativity in the primary tumors showed significantly longer intervals from primary diagnosis to the detection of the brain metastases. Of all the markers, only the Ki-67 LI was significantly higher in the brain metastases than in the primary breast tumors. We confirmed that the tumor characteristics were worse in the metachronous brain metastases.

Axillary lymph node dissection can be avoided in women with breast cancer with intraoperative, false-negative sentinel lymph node biopsies.

BACKGROUND: It is currently unclear which patients with breast cancer with sentinel lymph node (SLN) metastases do not need axillary lymph node dissection (ALND). PATIENTS AND METHODS: A cohort of 1,132 women who had unilateral invasive breast cancer with clinically negative nodes or nodes suspicious for metastasis, were intraoperatively diagnosed as having negative SLNs, and did not undergo an immediate ALND. Our intraoperative histological investigation uses H&E staining of a frozen section from a maximum cut surface of each SLN. Of these 1,132 women, 132 (11.7%) were postoperatively diagnosed as having positive SLNs, which classifies them as having an intraoperative, false-negative SLN biopsy (SLNB). Patient and tumor characteristics, treatment methods, and the prognoses of these patients were investigated and compared with the remaining 1,000 patients who were negative for SLNB. RESULTS: Of the 132 patients with intraoperative, false-negative SLNB, none underwent a further ALND. With a median follow-up period of 58.1 months, none of these patients exhibited recurrence in the axillary nodes. Their recurrence-free survival rates were not statistically different from those of patients with negative SLNB. CONCLUSIONS: ALND can be avoided in most patients with breast cancer with intraoperative, false-negative SLNB.

True recurrences and new primary tumors have different clinical features in invasive breast cancer patients with ipsilateral breast tumor relapse after breast-conserving treatment.

Ipsilateral breast tumor relapse (IBTR) after breast-conserving treatment (BCT) may represent two distinct types of lesion, including a true recurrence (TR) or a new primary tumor (NPT). The aim of this study was to ascertain the difference between TRs and NPTs and to show the clinical significance of classifying IBTR into these two types of recurrence. Patients (n = 2,075) with unilateral invasive breast cancer who underwent BCT between 1987 and 2005 at Saitama Cancer Center were analyzed. IBTR was classified into TR and NPT, which was based on all clinical and pathological features of both a primary tumor and IBTR that can be evaluated. IBTR-free survival and the risk factors were analyzed in order to compare the findings for TR and NPT. In addition, the salvage surgical methods for IBTR and overall survival after IBTR were analyzed. Sixty patients with IBTR were classified into 52 with TR and eight with NPT. IBTR-free survival was significantly shorter in the patients with TR than those with NPT. Young age, tumor size, a positive surgical margin, and omission of radiation therapy (RT) were significant risk factors for TR. Omission of RT was the only significant risk factor for NPT. In 27 patients who underwent a repeat lumpectomy for TR, four had a second IBTR. The overall survival after IBTR was worse in patients with TR than NPT. TR and NPT show quite different clinical features. Classifying IBTR into TR or NPT can therefore help to select the most appropriate treatment for IBTR.

Ipsilateral breast tumor relapse after breast conserving surgery in women with breast cancer.

Ipsilateral breast tumor relapse (IBTR) is a potentially a significant problem after breast conserving surgery (BCS). With a median follow-up period of 64.7 months, IBTR occurred as a first relapse in 67 (3.0%) of a total of 2243 patients and distant recurrence occurred in 167 (7.4%). A positive surgical margin and the omission of radiotherapy (RT) were independently associated with IBTR. The five-year cumulative IBTR rates were 5.1% in patients with positive margins and 2.0% in the patients with negative margins. The five-year cumulative IBTR rates were 1.8% in patients with RT and 8.1% in patients without RT. IBTR was independently associated with distant-recurrence-free survival rates as well as age, nodal metastasis, lymphovascular invasion and progesterone receptor status. The five-year distant-recurrence-free survival rates were 81.9% in patients with IBTR and 93.2% in patients without IBTR. In order to prevent IBTR, a negative margin and the administration of RT are therefore considered to be important in patients who undergo BCS.

Positive sentinel lymph node biopsy predicts the number of metastatic axillary nodes of breast cancer.

It remains to be clarified whether a positive sentinel lymph node biopsy (SLNB) can predict the number of metastatic axillary nodes. This study examined a consecutive series of women with unilateral invasive breast cancer who underwent axillary lymph node dissection after an intra-operative positive SLNB. The numbers of positive and negative sentinel lymph nodes (SLNs) were analyzed for a likelihood of pN1a, pN2a, and pN3a diseases as per the UICC TNM classification. Of the 368 study patients, 165 (45%) had one positive SLN and one or more negative SLNs. This result represented the most common combination of positive and negative SLNs. It was also the most predictive indicator (93%) of pN1a disease and the least predictive indicator (7% or 0%) of pN2a or pN3a disease, respectively. The numbers of positive and negative SLNs can predict the number of metastatic axillary nodes in breast cancer patients.