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.

FcγR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer.

BACKGROUND: Antibody-dependent-mediated cytotoxicity (ADCC) is one of the modes of action for trastuzumab. Recent data have suggested that fragment C γ receptor (FcγR) polymorphisms have an effect on ADCC. This prospective phase II trial aimed to evaluate whether these polymorphisms are associated with clinical efficacies in patients who received trastuzumab. PATIENTS AND METHODS: Patients in a neoadjuvant (N) setting received Adriamycin and cyclophosphamide followed by weekly paclitaxel/trastuzumab. Patients in a metastatic (M) setting received single trastuzumab until progression. In total, 384 distinct single nucleotide polymorphisms of different FcγR, HER2, and fucosyltransferase loci were assessed. RESULTS: Fifteen operable and 35 metastatic HER2-positive breast cancer patients were enrolled in each of the N and M settings, respectively. The FcγR2A-131 H/H genotype was significantly correlated with the pathologically documented response (pathological response) (P = 0.015) and the objective response (P = 0.043). The FcγR3A-158 V/V genotype was not correlated with the pathological response, but exhibited a tendency to be correlated with the objective response. Patients with the FcγR2A-131 H/H genotype had significantly longer progression-free survival in the M setting (P = 0.034). CONCLUSION: The FcγR2A-131 H/H polymorphism predicted the pathological response to trastuzumab-based neoadjuvant chemotherapy in early-stage breast cancer, and the objective response to trastuzumab in metastatic breast cancer.

Frequent overexpression of epidermal growth factor receptor (EGFR) in mammary high grade ductal carcinomas with myoepithelial differentiation.

AIMS: To evaluate the expression of common biological markers and the epidermal growth factor receptor (EGFR) in mammary high grade ductal carcinomas with myoepithelial differentiation (DCMDs). MATERIALS/METHODS: Thirty DCMDs were clinicopathologically and immunohistochemically analysed and compared with 36 control cases of high grade conventional invasive ductal carcinoma (IDC). RESULTS: EGFR, HER2/neu, oestrogen receptor, progesterone receptor, and p53 expression was seen in 21, one, three, four, and 20 of the 30 DCMDs, compared with eight, nine, 18, 17, and five of the 36 conventional IDCs (p<0.05), respectively. In 16 of the 30 DCMDs, metastases were found in the brain, lung, bone, and liver, within a maximum of 47 months (mean, 13.9) after initial surgery, whereas only four of the 36 conventional IDCs metastasised to the lung and bone within a maximum of 27 months (mean, 18.0) after initial surgery (p=0.0001). There was a significant difference in disease free survival between DCMD and conventional IDC (p=0.001). EGFR was frequently overexpressed in DCMD compared with conventional IDC, whereas the expression of HER2/neu and hormone receptors was lower in DCMD. Fluorescent in situ hybridisation revealed that the mean EGFR to chromosome 7 centromere (CEP7) ratio of the 24 DCMD cases available for evaluation was 1.03, and EGFR gene amplification was not detected in the 21 DCMD cases with EGFR overexpression. CONCLUSION: Immunohistochemistry for myoepithelial markers and EGFR is useful for the accurate diagnosis and molecular target treatment of high grade DCMD.

Treatment of noninvasive carcinoma: fifteen-year results at the National Cancer Center Hospital in Tokyo.

The introduction of screening mammography (MMG) will lead to increased detection of preclinical early breast cancer in Japan. It has become more important to understand the nature of these lesions. We tried to elucidate the long term prognosis and clinical and pathological characteristics of noninvasive cancers. A total of 336 (5.4%) ductal carcinoma in situ (DCIS) and 32 (0.5%) lobular carcinoma in situ (LCIS) were diagnosed in 6 277 breast carcinomas at the National Cancer Center Hospital from 1962 to 1995. Most (80%) LCIS occurred in premenopausal women. LCIS has significantly higher bilaterality than that of DCIS. Local recurrence occurred in approximately 10% of patients after breast conserving surgery for DCIS and LCIS. Four patients died of breast carcinoma, which were initially diagnosed as noninfiltrating carcinoma. The 15-year cause specific survival rates of patients with DCIS and LCIS were 98.5 % and 100 %, respectively.

A case of malignant phyllodes tumor of the breast with osteosarcomatous features.

A 64-year postmenopausal woman had noticed a left breast lump 5 months before presentation and was admitted due to increasing tumor size. Physical examination showed a well demarcated, movable mass 5 cm in diameter in the upper outer quadrant of the left breast. The lesion was not painful. She had no past history of malignancy or chest wall irradiation. She had no family history of malignancy. Mammography revealed an irregular tumorous lesion with coarse calcifications in the left breast. Intracystic papillary cancer was suspected by ultrasonography. Aspiration breast cytology yielded insufficient material for diagnosis. Laboratory findings were all within the normal limits including alkaline phosphatase and three tumor markers (CEA, CA 15-3, ST-439). An excisional biopsy of the left breast tumor was performed. Histopathological examination revealed malignant phyllodes tumor with osteosarcomatous features and negative tumor margins. Positive vimentin and negative cytokeratin staining was confirmed by immunohistochemistry, suggesting that the tumor did not originate from epithelial cells of the breast. The estrogen receptor (ER) status of the tumor was negative but progesterone receptor (PgR) was weakly positive. Positive p53 nuclear immunoreaction but negative c-erbB-2 overexpression by immunohistochemical staining was observed in this tumor. There was no evidence of generalized disease. She has been well 6 months after surgery without adjuvant therapy.

Evaluation of histopathological criteria for identifying node-negative breast cancer with high risk of early recurrence in the NSAS-BC protocol study.

BACKGROUND: The histopathological criteria for high-risk node-negative primary breast cancer stated in the National Surgical Adjuvant Study of Breast Cancer (NSAS-BC) protocol were used to grade a consecutive series of 488 cases at our hospital. METHODS: To validate the criteria retrospectively, we examined the histological features of node-negative primary breast cancers which showed early relapse within 2 years after surgical therapy. RESULTS: Early relapse occurred in 12 patients, distant metastases in 11, and local recurrence in one. Among 278 cases followed for up to 1.5 years or longer, early systemic relapse was detected in 10 (5.8%) of 172 higher-grade tumors (9 invasive ductal carcinomas of nuclear grade 3 and one invasive ductal carcinoma of nuclear grade 2) and one stromal cell sarcoma. Among the 115 low-risk tumors, only one case (0.9%) of invasive ductal carcinomas with nuclear grade 1 showed early local recurrence. Early relapse occurred in only one (1.5%) of 67 tumors with an invasive component of 1.0 cm but in 11 (5.2%) of 211 tumors with an invasive component of 1.1 cm. The recurrence rate increased to 9.3% (8/86) when tumor invasion was 2.1 cm. In 12 cancers showing recurrence, strand structure, large central acellular zones, and squamoid features were histologically observed in four, two, and three cases, respectively. The present results confirmed the reported tendency of correlation between strand pattern and bone metastasis, large central acellular zones and lung and brain metastasis, and squamoid features and lung metastasis. Synchronous bilateral and unilateral multiple cancers were characterized by lower nuclear grades. CONCLUSIONS: At our hospital, the criteria used in the NSAS-BC protocol were demonstrated to identify node-negative cancers with high risk of early recurrence at a hospital level. To further identify groups prone to recurrence, longer follow-up would be necessary. In addition, the histological criteria could be improved to correlate with patient outcome more accurately.

Japanese late-onset breast cancer families: Their clinicopathological characteristics and absence of BRCA1 and BRCA2 germline mutations.

BACKGROUND: The causes and pathologic and prognostic phenotypes of late-onset familial breast cancers are still unknown. The purpose of this study was to document the clinicopathological features of late-onset familial breast cancers using genetic testing of BRCA1 and BRCA2. METHODS: We analyzed 11 breast cancers from 10 patients from 8 Japanese late-onset Breast cancer families. RESULTS: The average age of the patients was 55 years (range 43 to 89). Bilateral occurrence was noted in 2 patients (8%). All the tumors were invasive ductal carcinomas, except for 1 case of invasive lobular carcinoma. Tumor size ranged from 0.8 cm to 7.8 cm (median 2.3 cm) and lymph node metastasis occurred in 6 of the 11 patients (55%). Six (55%) of the 11 tumors were histologically grade 2 and 5 (45%) were histologically grade 3. Estrogen receptor (ER) positivity was 80% (8/10). Overexpression of c-erbB-2 and p53 protein was detected in 18% (2/11) and 9% (1/11) of the tumors, respectively. Five patients from 4 families received genetic testing but all were negative for BRCA1 and BRCA2 germline mutations. All the patients were alive after a median follow-up period of 32 months, except for 1 patient. CONCLUSIONS: In this study, no germline mutations of BRCA1 or BRCA2 were detected. However, there was a tendency towards ER-positive tumors, but the positivity of p53 protein was considered to be lower then that of sporadic tumors.

Diabetic mastopathy: a case report with reference to the findings of enhanced computed tomography.

We report a case of insulin-dependent diabetic fibrous mastopathy with special reference to the findings of computed tomography (CT). The patient was a 27-year-old woman with a history of insulin-dependent diabetes mellitus from childhood who presented with a right breast tumor. Physical examination showed a stony-hard, ill-defined but freely movable mass under the nipple of the right breast without nipple discharge. Mammography revealed a high-density mass shadow without microcalcifications or spicular formation. Ultrasonographic examination revealed an irregularly-shaped hypoechoic lesion with marked posterior acoustical shadowing. Contrast-enhanced CT revealed poor early phase contrast enhancement and slight delayed phase heterogeneous enhancement. Since core needle biopsy revealed fibrocystic disease, the lesion was suspicious for diabetic mastopathy. Incisional biopsy of the right breast lump was performed. On histopathological examination, the lesion showed fibrosis with dense lymphocytic infiltration around the lobules. Diabetic fibrous mastopathy was diagnosed. Physicians should be aware of the association of long-standing diabetes mellitus with the development of fibrous mastopathy. CT is considered a useful tool to differentiate diabetic mastopathy from breast cancer.

Seven cases of breast cancer recurrence limited to the central nervous system without other visceral metastases.

We report 7 rare cases of recurrent breast cancers who presented with central nervous system (CNS) metastases as the initial relapse site without any other organ metastases. The average age of the patients at surgery was 42.6 years old of age (median 45:range 32-60), and 6 of the 7 cases (86%) were premenopausal. The mean disease-free period was 25.7 months (median 22, range 2-60 months). The primary tumors were all invasive ductal carcinomas. The estrogen receptor and progesterone receptor status of the 3 tumors available for study were all negative. The metastatic CNS lesions included the cerebrum (4 cases), cerebellum, cervical spinal cord, and meninges. In 6 out of these 7 cases (86%), the CNS metastasis was the initial recurrent lesion. Multidisciplinary treatments including surgery, radiotherapy and systemic or intrathecal chemotherapy were given. Although the mean survival time from clinical manifestations of the metastases of the 4 deceased patients was 20 months (median 20.5; range 6-33), one patient treated with surgery and radiotherapy is been still alive18 years later. These cases were also notable for the fact that the only metastatic site was in the CNS only during the entire clinical course, except for 2 cases, one with ocular adnexa metastasis, and the other with cervical lymph node metastasis. Premenopausal patients with negative hormone receptor status are more likely to develop this type of recurrence, regardless of the histological type. It is necessary to pay attention to neurological symptoms and signs during follow-up of breast cancer patients.

Two special types of breast cancer presenting as progressive disease after neoadjuvant chemotherapy with docetaxel plus doxorubicin.

Seventy-eight patients with primary breast cancer over 3 cm in diameter in stages II A, II B, III A and III B according to the UICC classification received neoadjuvant chemotherapy from August 1, 1998 to June 30, 2000 at the Breast Division of the National Cancer Center Hospital. Neoadjuvant chemotherapy consisted of doxorubicin (Adriamycin: ADM) 50 mg/m(2) and docetaxel (Taxotere: DOC) 60 mg/m(2) every three weeks. The overall clinical response to this regimen was 88% (69/78). Although neoadjuvant chemotherapy with this regimen achieved good responses in patients with breast cancer, 2 patients presented with progressive disease (PD) after treatment. One patient had inflammatory breast cancer (IBC) and the other had primary squamous cell carcinoma (SCC) of the breast. There were 4 cases of IBC and one case of SCC of the breast who received neoadjuvant chemotherapy in this series. Our observations suggest that this regimen might not be effective for these types of breast cancer.

A proposal for the histopathological diagnosis of ductal carcinoma in situ of the breast.

BACKGROUND: As the incidence of ductal carcinoma in situ (DCIS) is increasing, it is necessary to make a guideline for the pathological examination and diagnosis of DCIS, by creating criteria based on clinical and biological aspects of the disease. METHOD: We collected biopsy specimens originally diagnosed as benign lesions, from patients who subsequently developed invasive carcinoma in the ipsilateral breast. The histology of the biopsy specimens was re-evaluated principally according to the 1995 Philadelphia Consensus on DCIS. Histopathological agreement on each biopsy specimen was made by the JBCS Study Group members under a multiviewer microscope. In the course of making conclusive agreements among the pathologists, we developed a consensus for the histopathological diagnosis of DCIS, especially non-comedo types. RESULTS: DCIS is defined as a carcinoma of ductal epithelial origin, without any evidence of stromal invasion. It is necessary to note the methods of pathologic examination required to diagnose DCIS. Stromal invasion is an important prognostic factor, and should be diagnosed with caution. Classification of proliferative ductal lesions as benign or malignant (DCIS), the subtype of DCIS (nuclear grade, architecture, and necrosis), and the histological grading of DCIS are proposed and recommended. CONCLUSION: Although we have made a new proposal according to current concepts, there are still several unresolved problems. Thus further examination and modification will be necessary in the future.

Differences in the progesterone receptor contents between familial breast cancers and sporadic breast cancers stratified by patient age.

In the present study, we investigated the estrogen (ER) and progesterone receptor (PR) contents of familial breast cancers (FBCs) and compared the findings with those of sporadic breast cancers., stratified by the patients' age. To evaluate the hormone receptor contents of Japanese FBCs, we collected a consecutive series of 250 FBCs and 2,533 sporadic breast cancers (SBCs). These patients were divided into the three groups stratified by the patients' age at initial surgery (group I, under 40 years old; group II, 40-60 years old; group III, over 60 years old). The clinicopathological features of FBCs and SBCs, including ERs and PRs, were analyzed for each group. In all age groups, the PR contents of FBCs were significantly lower than those of SBCs, particularly for group III. In FBCs, the PR content was significantly lower in group III than in groups I or II. In addition, there was a nonsignificant trend towards a high frequency of ER-positive, PR-negative tumors in FBC patients aged 60 years and over. These data indicate that the loss of ER function and/or loss of binding capacity of PR to progesterone was associated with some late-onset FBCS.

Male breast cancer in patients with a familial history of breast cancer.

We describe herein the clinical characteristics of five male breast carcinoma (MBC) patients with a familial history of breast carcinoma (FHBC). Four of these patients suffered from multiple primary cancers, being gastric and prostate cancer in 1, gastric cancer in 1, and asynchronous bilateral breast cancers in 2. The average age of these patients at diagnosis was not lower than that of MBC patients with no such familial history. The aggregation of cancer in these families had three prominent characteristics: (1) The families included women with early-onset breast cancers which had occurred at the ages of 38, 38, and 35 years, respectively, and/or early-onset uterine cancer which had occurred at the age of 35 years. (2) The incidence of multiple primary cancers was significantly higher in the siblings of MBC patients with a FHBC than without. (3) There were many cancers in hormone-related organs in two families.

Changes in the treatment outcome of node-positive breast cancer stratified by menopausal status: comparison of patients treated in 1965-75 versus those treated in 1976-86.

OBJECTIVE: The objective of this study was to examine whether and to what extent the outcome of treatment for lymph-node positive breast cancer patients improved between the periods 1965-75 and 1976-86. METHODS: The subjects were 1595 patients with breast cancer positive for lymph node metastasis who were treated at the National Cancer Center Hospital between 1965 and 1986. In order to analyze background factors and treatment outcome, we classified the patients into four groups stratified by the time of initial surgery (1965-75/1976-86) and menopausal status (premenopause/postmenopause). RESULTS: With respect to the clinicopathological background factors, significant changes between the periods 1965-75 and 1976-86 were more frequent use of modified radical mastectomy and postoperative adjuvant chemoendocrine therapy and less frequent use of postoperative radiotherapy in both pre- and postmenopausal patients. The 10-year disease-free and overall survival rates improved by approximately 15-20% between 1965-75 and 1976-86 in this group of patients, regardless of menopausal status. CONCLUSION: The patients with node-positive disease treated at our hospital showed an increase in both disease-free and overall survival from 1965 to 1986.

Validation and problems of St-Gallen recommendations of adjuvant therapy for node-negative invasive breast cancer in Japanese patients.

BACKGROUND: The objectives of this study were to confirm the favorable outcome of invasive breast cancer in Japanese patients without lymph node metastasis who did not receive adjuvant therapies and to validate the St-Gallen recommendations in this population. METHODS: The subjects were a consecutive series of 920 node-negative invasive breast cancer patients who underwent surgery between 1987 and 1994 at our hospital. These patients did not receive adjuvant chemotherapy. Ten-year disease-free (DFS) and overall survival (OS) rates were analyzed by the St-Gallen risk categories (Minimal/Low, Intermediate, High). RESULTS: The median age of the patients at surgery was 52 years and the median follow-up period of patients was 10.2 years. At 10 years, the respective DFS and OS rates of all patients were 84.6 and 86.7%. The DFS and OS of patients in the Minimal/Low risk category (25 patients) both showed 100%. The DFS and OS of patients in the Intermediate risk category (356 patients) showed 92.0 and 93.1%, respectively. The DFS and OS of patients in the High risk category (539 patients) showed 79.4 and 82.2%, respectively, indicating a significant difference between those in the Minimal/Intermediate risk category (381 patients) (p < 0.001, p < 0.001, respectively). The DFS and OS of patients who had one pathological lymph node metastasis (775 patients) showed 72.7 and 75.2%, respectively, which indicated a non-significant difference between those in the High risk category (381 patients) (p = 0.10). These data support the validation of adjuvant therapy for high-risk node-negative breast cancers in Japanese patients. However, quality control is needed to define the histological grade included in the risk categories. CONCLUSION: Japanese patients with invasive breast cancer without lymph node metastasis showed a survival advantage compared with their Caucasian counterparts. However, patients in the High risk group as defined by St-Gallen recommendations should be indicated for adjuvant therapy.

Association of breast cancer with meningioma: report of a case and review of the literature.

We report a case of meningioma subsequently developed in a patient with primary breast carcinoma. A 53-year-old woman received a left modified radical mastectomy because of stage IIA breast carcinoma. Histologically, the tumor was a predominantly intraductal carcinoma with negative lymph node metastasis. Estrogen receptor (ER) was negative but progesterone receptor (PR) of the left tumor was positive by immunohistochemistry. Four years later, cranial bone and/or brain metastasis was suspected from a routine follow-up bone scintigram. The patient showed no symptoms or signs at that time. Magnetic resonance imaging (MRI) and angiography revealed that the right parasagittal mass was suspicious of meningioma. A complete tumor removal was performed. On histological examination, this brain tumor was a transitional-type meningioma (meningotheliomatous and fibrous type) without malignant findings. ER was negative but PR was positive also in this tumor. She is currently well 6 years after the initial surgery. A review of the literature is presented with emphasis on the association between breast cancer and meningioma, which indicates a possible hormonal relationship. The knowledge of this association is important in the differential diagnosis of patients with breast cancer who develop central nervous manifestations.

Higher Level of P-glycoprotein Expression in Human Breast Cancer Cells after Radiation Therapy.

We investigated the effects of radiation on the expression of p53 protein and P-gp in breast cancer cells. Thirty-two preoperatively irradiated surgical specimens of stage I primary breast cancer were examined, and 39 surgical specimens of non-irradiated stage I breast cancer were selected as a control group. p53 and P-gp expression was detected by an immunohistochemical technique using rabbit polyclonal antibodies (RSP-53 and NCL-pGLYPp). The expression of p53 protein, defined as a nuclear immunoreaction in 20% or more of tumor cells, was detected in 4(13%) of the 32 cases in the irradiated group and 7 (18%) of the 39 cases in the non-irradiated group without any statistically significant difference. The expression of P-gp, defined as the presence of strong staining in more than 75% of the tumor cells, was detected in 19 (59%) of the cases in the irradiated group and 12(31%) of the cases in the non-irradiated group. P-gp expression was significantly higher in the former group than in the latter (P <0.05). There was no significant difference in P-gp expression between the stromal invasive component and the intraductal component in either the irradiated or the non-irradiated group. Radiotherapy possibly induces membranous P-gp expression in human breast cancer cells.

Clinicopathological Characteristics of Non-palpable Breast Cancer Presenting as Axillary Mass.

We present the clinical and pathological findings of non-palpable breast cancer presenting an axillary mass in 8 patients at the National Cencer Center Hospital and in 89 cases previously reported in Japan. Mammography and ultrasonography were positive in 26.4% and 26.8% of cases, respectively. 82(94.3%) of 87 patients underwent mastectomy as a local control. In 19(30.6%) of 62 patients, the pathological size of the lesion was less than 5 mm. In 15 patients primary tumors could not be identified pathologically. The number of nodes involved ranged from 1-55 with a median of 5. There was no significant correlation between the number of involved nodes and the size of the axillary mass, nor between the number of involved nodes and the pathological size of the primary breast lesion. The 5-year survival rate was 59.4%. There was no statistically significant difference in 5-year survival rates between occult breast cancer and palpable breast cancer in each nodal category. Only the number of involved nodes was a reliable prognostic factor. Unlike palpable breast cancer, the pathological size of the primary tumor was not a predictor of prognosis. In this respect, the biological behavior of occult breast cancer is quite different from that of palpable breast cancer.

Diagnostic Value of Enhanced Computed Tomography in the Detection of the Widely Spreading Intraductal Component of Breast Cancer: Case Reports.

We report cases of breast cancer with extensive intraductal component (EIC), the extent of which could be detected only by contrast-enhanced computed tomography (CT) scan. One case was a 32-year-old woman who presented left nipple bloody discharge without breast mass palpation. Mammography (MMG), galactography and ultrasonography (US) showed no abnormalities. Contrast helical CT scan revealed numerous patchy enhancement in the upper-outer quadrant of the left breast. Histological examnation revealed invasive ductal carcinoma with a predominant intraductal component. The second case was a 36- year-old woman who had noticed a left breast mass 2.4 cm in diameter. MMG and US suggested a localized breast cancer. Contrast helical CT scan revealed numerous patchy enhancement throughout the mammary gland in addition to the index tumor near the nipple. Histopathological results indicated invasive ductal carcinoma with widely spread ELC. In these two cases, the extent of intraductal cancer also correlated well with the CT findings. Breast CT scan can be an effective tool for determining the extent of the intraductal component of breast cancer, which is an important factor when considering breast-conserving therapy.