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.

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.

The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways.

CHIP is a U-box-type ubiquitin ligase that induces ubiquitylation and degradation of its substrates, which include several oncogenic proteins. The relationship between CHIP and tumour progression, however, has not been elucidated. Here, we show that CHIP suppresses tumour progression in human breast cancer by inhibiting oncogenic pathways. CHIP levels were negatively correlated with the malignancy of human breast tumour tissues. In a nude mouse xenograft model, tumour growth and metastasis were significantly inhibited by CHIP expression. In contrast, knockdown of CHIP (shCHIP) in breast cancer cells resulted in rapid tumour growth and metastastic phenotypes in mice. In cell-based experiments, anchorage-independent growth and invasiveness of shCHIP cells was significantly elevated due to increased expression of Bcl2, Akt1, Smad and Twist. Proteomic analysis identified the transcriptional co-activator SRC-3 (refs 13, 14, 15, 16, 17, 18, 19) as a direct target for ubiquitylation and degradation by CHIP. Knocking down SRC-3 in shCHIP cells reduced the expression of Smad and Twist, and suppressed tumour metastasis in vivo. Conversely, SRC-3 co-expression prevented CHIP-induced suppression of metastasis formation. These observations demonstrate that CHIP inhibits anchorage-independent cell growth and metastatic potential by degrading oncogenic proteins including SRC-3.

Nipple adenoma found in a mastectomy specimen: report of a case with special regard to the proliferation pattern.

We report a case of nipple adenoma incidentally found in a mastectomy specimen, and describe its unique histological appearance and the immunohistochemical distribution of Ki-67 positive tumor cells. A 45-year-old woman with no symptoms or sign related to the nipple had a left mastectomy for invasive breast cancer. A small nipple adenoma, 7 mm in size, was incidentally recognized in the nipple of the resected breast. Histologically, the tumor in the nipple was composed of numerous proliferative ducts with a tubular and florid papillomatous appearance. Many demarcations between squamous cells of the epidermis and tumor cells were recognized in the summit as well as the lateral wall of the nipple. A high Ki-67 labeling index (20.3%) was recognized in the tumor cells in the superficial region, and a low labeling index (0.7%) was seen in the deeper region of the tumor. Based on these proliferative patterns, the symptoms and clinical signs related to the nipple that are often found in patients with nipple adenoma are thought to be associated with the destruction of the epidermis of the nipple by the invasion of benign tumor cells with high proliferative activity.

Immunohistochemical study of the relationship between Ki-67 labeling index of proliferating cells of gynecomastia, histological phase and duration of disease.

Gynecomastia is a benign proliferative lesion caused by various etiological factors and may result from a relative imbalance between serum estrogen and androgen levels. The histological alterations are similar, and gynecomastia can progress from a florid type to a fibrous type. The Ki-67 labeling index (LI) of gynecomastia specimen was investigated and higher Ki-67 LI was observed in florid and intermediate than in fibrous gynecomastia (P = 0.017). A correlation was found between the duration of disease and Ki-67 LI (P = 0.041): the shorter the duration the higher the Ki-67 LI. Thus, Ki-67 LI seems a useful tool to examine proliferation activity of gynecomastia and can assist in determination of appropriate treatment of gynecomastia with hormonal therapy.

High incidence of microscopic gastrointestinal stromal tumors in the stomach.

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms with an annual incidence of approximately 10 to 20 per 1 million cases. Although pathologists have often observed incidental small GISTs in the stomach resected from patients with gastric cancer, no report on the real incidence of gastric GISTs is available. In this study, 100 whole stomachs resected from patients with gastric cancer were sectioned at 5-mm intervals and hematoxylin and eosin-stained slides (a mean of 130 slides for each case) were examined for microscopic GISTs. KIT (CD117), CD34, and desmin expression of the incidental tumors was evaluated by immunohistochemistry, and genomic DNA extracted from formalin-fixed and paraffin-embedded tumor tissues was analyzed for c-kit gene mutations in exon 11. In 35 of the 100 whole stomachs, we found 50 microscopic GISTs, all of which were positive for KIT and/or CD34 and negative for desmin. Most microscopic GISTs (45/50, 90%) were located in the upper stomach. Two of the 25 (8%) microscopic GISTs had c-kit gene mutations. Fifty-one leiomyomas with positive expression for desmin were observed in 28 of the 100 stomachs. Both leiomyomas and GISTs were found in 12 stomachs. These results indicate that microscopic GISTs are common in the upper portion of the stomach. Considering the annual incidence of clinical GISTs, only few microscopic GISTs may grow into a clinical size with malignant potential. Further studies are required to clarify the genetic events responsible for the transformation of microscopic GISTs to clinical GISTs.

Extremely well-differentiated adenocarcinoma of the gastric cardia: a unique case with columnar cells and laminated stones.

Extremely well-differentiated adenocarcinoma (EWDA) is an unusual gastric cancer that is histologically too bland to be diagnosed as malignant neoplasm, particularly using biopsy. EWDA may be a gastric counterpart of 'adenoma malignum' or minimal deviation adenocarcinoma (MDA) in the uterine cervix; however, the clinicopathological features of EWDA remain less apparent than those of MDA. A 60-year-old male was complaining of dysphagia. He had been made aware of a small submucosal tumor in the cardia 2 years before the onset of this symptom. Endoscopic ultrasonographic examination revealed a large cardiac tumor consisting of thickened layers, as observed in Borrmann type IV. Three mucosal biopsies suggested only benign changes including adenoma and hyperplastic polyps. At the fourth biopsy, cytologically bland columnar cells were located in the submucosa along with stromal fibrosis and laminated stones. The possibility that non-neoplastic aberrant pancreas with lithiasis formed the tumor was denied at laparotomy by a frozen section that revealed benign-looking glands invading the diaphragm. Immunohistochemically the cancer glands were positive for CA19-9 and human gastric mucin, but not for p53 or MUC2. To our knowledge, this is a previously unknown combination of EWDA and psammomatous calcification in the stomach.