Development of adoptive immunotherapy with KK-LC-1-specific TCR-transduced γδT cells against lung cancer cells.

The present study analyzed the antitumor effect of γδT cells transduced with the TCR of cancer-specific CTLs to establish forceful cancer-specific adoptive immunotherapy. We cloned the TCRαß genes from CTLs showing HLA-B15 restricted recognition of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a cancer/germline gene antigen, identified in a lung adenocarcinoma case (F1121). The TCRαß and CD8 genes were transduced into γδT cells induced from PBLs of healthy volunteers stimulated with zoledronate and IL-2. The KK-LC-1-specific TCRαß-CD8 γδT cells showed cytotoxic activity against the KK-LC-1 positive lung cancer cell line F1121L and produced IFN-γ against F1121L and KK-LC-1 peptide-pulsed F1121 EBV-B cells. These responses were blocked by HLA class I and HLA-B/C antibodies. An in vivo assay using NOD/SCID mice with xenotransplantation of human lung cancer cells was performed, and the TCRαß-CD8 transduced γδT cells (TCRαß-CD8 γδT cells) were intravenously injected. Growth inhibition of KK-LC-1+ , HLA-B15+ lung cancer cells was confirmed in mice with injection of the TCRαß-CD8 γδT cells from 1 wk after xenotransplantation of cancer cells but not in those treated 2 wk after xenotransplantation. The resected specimens of the tumor, 2 wk after xenotransplantation, highly expressed FasL but not programmed death ligand-1 (PD-L1) by immunohistochemical staining. FasL highly expressed cancer cells xenotransplanted 2 wk ago were resistant to TCRαß-CD8 γδT cells injection. These results suggested that apoptosis of Fas-positive TCRαß-CD8 γδT cells may be induced by a Fas-mediated signal after interacting with FasL-positive cancer cells.

Evaluation of the R2* value in invasive ductal carcinoma with respect to hypoxic-related prognostic factors using iterative decomposition of water and fat with echo asymmetry and least-squares emission (IDEAL).

OBJECTIVE: To correlate the R2* value obtained by iterative decomposition of water and fat with echo asymmetry and least-squares emission (IDEAL) with fibrotic focus (FF), microvessel density and hypoxic biomarker (HIF-1α) in breast carcinoma. METHODS: Forty-two patients who were diagnosed with invasive ductal carcinoma (IDC) of the breast underwent breast MRI including IDEAL before surgery. The entire region of interest (ROI) was delineated on the R2* map, and average tumour R2* value was calculated for each ROI. Histological specimens were evaluated for the presence of FF, the microvessel density (the average microvessel density and the ratio of peripheral to central microvessel density), and the grading of HIF-1α. RESULTS: FF was identified in 47.6% (20/42) of IDCs. Average R2* value for IDC with FF (42.4±13.2 Hz) was significantly higher than that without FF (28.5±13.9 Hz) (P = 0.01). Spearman rank correlation suggested that the average R2* value correlated with the grade of HIF-1α and the ratio of peripheral to central microvessel density for IDCs (P < 0.001). CONCLUSION: Quantification of tumour R2* using IDEAL is associated with the presence of FF and the overexpression of HIF-1α, and may therefore be useful in predicting hypoxia of breast carcinoma. KEY POINTS: • R2* value obtained by IDEAL correlates with the overexpression of HIF-1α. • R2* value obtained by IDEAL is associated with fibrotic focus. • R2* quantification may be useful in predicting hypoxia of breast carcinoma.

[Intrapericardial Vessel Management for Lung Cancer Surgery].

Intrapericardial vessel management is one of the necessary techniques for respiratory surgeons. We collected cases that had undergone intrapericardial vessel management for lung cancer, and herein discuss the practical performance and safety of this treatment method. We identified 23 (5.6%) of 413 patients who had undergone lung cancer surgery during the 30-month period from January 2011 to June 2013 at our institution. Twenty cases had large sized tumors near the hilum. Three cases demonstrated severe adhesion in the intrathoracic region due to a previous operation. The lung cancer staging was stage ⅠA in 1 case, stage ⅠB in 4 cases, stage ⅡB in 5 cases, stage ⅢA in 11 cases, stage ⅢB in 1 case, and stage Ⅳ in 1 case. We performed lobectomy in 11 cases, bilobectomy in 6 cases, and pneumonectomy in 6 cases. The average operation time was 366 minutes (137-965). Post operative complications were observed in five cases, including two cases of air-leakage and three cases of arrhythmia. All cases were able to walk on foot at discharge. It is important to clearly understand intrapericardial anatomy in order to carry out successful intrapericadial vessel management.

[Student education with using training simulator for endoscopic surgery].

Video-assisted thoracic surgery (VATS) has become popular in the field of chest surgery. Recently, there has been a gradual reduction in the number of surgeons in Japan, which thus increases concerns regarding a potential shortage in the number of surgeons in the future. In this study, we evaluated the efficacy of using a surgical simulator with an endoscopic simulator to provide practical training for 245 medical students. Three different tests were performed with a one-week interval between each test, and the task completion time between the 1st and 2nd training sessions was then analyzed. A reduction in the time required to perform the tasks was observed. In addition, 95% of the subjects had a positive opinion regarding the application of the device for practical training, while 85% reported an increased interest in surgery. No significant relationships were observed between the task completion time and the degree of proficiency in performing the task or between the results of students choosing to become surgeons and those not choosing to become surgeons in the future according to a follow-up study. The students who later decided to become surgeons tended to express a positive opinion on the questionnaire compared with the non-departmental staff. As a result, providing student education using a training simulator for endoscopic surgery is therefore considered to have a beneficial effect in increasing the number of medical school students who later decide to become surgeons.

Prognostic implications of human leukocyte antigen class I expression in patients who underwent surgical resection for non-small-cell lung cancer.

BACKGROUND: The purpose of the present study was to clarify the prognostic significance of human leukocyte antigen (HLA) class I expression in patients with non-small-cell lung cancer who underwent complete surgical resection. PATIENTS AND METHODS: The expression of HLA class I molecules was evaluated in 403 resected NSCLC specimens using immunohistochemistry. The results were scored as the percentage of stained tumor cells and were categorized into three groups: 0%-24% (decreased), 25%-79% (heterogeneous), and 80% or more (normal). RESULTS: The expression of HLA class I was evaluated in 124 tumors in the normal expression group, 181 tumors in the heterogeneous expression group, and 98 tumors in the decreased expression group. The 5-year survival rate of all patients after surgery according to the HLA class I expression in the normal, heterogeneous, and decreased groups was 76.6%, 65.9%, and 76.1%, respectively. The prognosis was significantly better in the normal expression group than in the heterogeneous group. Normal HLA class I expression also correlated with favorable survival in patients with stage I disease. CONCLUSIONS: The normal expression of HLA class I was associated with a favorable prognosis compared with the heterogeneous expression group, but no significant difference was observed between the normal expression and decreased expression groups.

Intrapleural chemotherapy improves the survival of non-small cell lung cancer patients with positive pleural lavage cytology.

PURPOSE: Information regarding the treatment of pleural lavage cytology (PLC)-positive patients is still limited. This study evaluated the efficacy of intrapleural chemotherapy (IPC) in PLC-positive patients. METHODS: Three hundred eighty-six of the 567 lung cancer patients who underwent surgery had undergone PLC after thoracotomy, following by a complete resection were evaluated. IPC was performed after surgery, and cisplatin or adriamycin was injected intrapleurally through the thoracic tube. RESULTS: The pathological diagnosis showed that 17 patients (4.4 %) were positive for (or suspected to have) malignancy in their PLC. The univariate and multivariate analysis showed that only pleural invasion was a significant predictor of a PLC-positive status. The 5-year overall survival in PLC-positive patients was 38 % and that in PLC-negative patients was 84 %. Both the univariate (p < 0.01) and multivariate (p = 0.045) analyses showed that the status of PLC was significantly associated with the overall survival. Eight of the 17 PLC-positive patients underwent IPC. The 2-year OS rate in the patients treated with IPC was 88 % and that of those without IPC was 44 (p = 0.04). CONCLUSION: IPC improved the postoperative survival in PLC-positive NSCLC patients, and a further prospective evaluation regarding this therapy is warranted.

Two resected cases of benign adenomyoepithelioma.

BACKGROUND: Adenomyoepithelioma (AME) of the breast is an uncommon tumor characterized by the proliferation of ductal epithelial and myoepithelial cells with the heterogeneity. Although benign AME is relatively easy to differentiate from breast cancer by core needle biopsy (CNB) alone, a definitive diagnosis is often difficult. The imaging findings of AME are also variable, and there are particularly few reports about radiological features, including contrast-enhanced magnetic resonance imaging (MRI) and apparent diffusion coefficient (ADC) values in AME. CASE PRESENTATION: We present two cases of benign AME. Case 1 is a 30-year-old woman with a history of asthma. The cystic tumor shows smooth borders, and the intracystic solid component is irregular in shape and high vascularity. The pathological findings of the tumor were benign on CNB. The MRI scan showed a decreased ADC value. Case 2 is a 60-year-old woman with only a history of arrhythmia. The tumor shows a lobulated mass with cystic space and coarse calcifications. The pathological findings of the tumor were found to be benign by CNB. Dynamic MRI scan showed a fast washout pattern with a decreased ADC value. Both patients underwent excisional biopsy to confirm the diagnosis, and the pathological diagnosis was benign AME in both cases. CONCLUSIONS: The AME of the breast has little specific imaging information, so it can be difficult to diagnose based on pathological findings of biopsy specimen. In our case, the ADC values were exceptionally low, contrary to previous reports. It is essential to carefully diagnose AME, considering the discrepancies in imaging findings observed in this case.

Antitumor activity of human γδ T cells transducted with CD8 and with T-cell receptors of tumor-specific cytotoxic T lymphocytes.

The difficulty in the induction and preparation of a large number of autologous tumor-specific cytotoxic T lymphocytes (CTL) from individual patients is one of major problems in their application to adoptive immunotherapy. The present study tried to establish the useful antitumor effectors by using γδ T cells through tumor-specific TCRαß genes transduction, and evaluated the efficacy of their adoptive transfer in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice model. The TCRαß gene was cloned from the HLA-B15-restricted CTL clone specific of the Kita-Kyushu Lung Cancer antigen-1 (KK-LC-1). The cloned TCRαß as well as the CD8 gene were transduced into γδ T cells induced from peripheral blood lymphocytes (PBL). Cytotoxic T lymphocyte activity was examined using a standard 4 h (51) Cr release assay. Mice with a xenotransplanted tumor were treated with an injection of effector cells. Successful transduction of TCRαß was confirmed by the staining of KK-LC-1-specific tetramers. The γδ T cells transduced with TCRαß and CD8 showed CTL activity against the KK-LC-1-positive lung cancer cell line in a HLA B15-restricted manner. Adoptive transfer of the effector cells in a mice model resulted in marked growth suppression of KK-LC-1- and HLA-B15-positive xenotransplanted tumors. Co-transducing TCRαß and CD8 into γδ T cells yielded the same antigen-specific activity as an original CTL in vitro and in vivo. The TCRαß gene transduction into γδ T cells is a promising strategy for developing new adoptive immunotherapy.

Effects of hyaluronic acid and CD44 interaction on the proliferation and invasiveness of malignant pleural mesothelioma.

Hyaluronic acid (HA) has been proposed as a biochemical marker of malignant pleural mesothelioma (MPM). The present study focused on the implications of HA and CD44 interaction in the proliferation and invasiveness of MPM. The proliferation and invasive activity was evaluated in two human mesothelioma cell lines, ACC-MESO-1 and K921MSO, by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the transwell chamber model. The knockdown of CD44 gene expression was accomplished by transfection of the cells with small interfering RNA. Flow cytometry revealed that both the ACC-MESO-1 and K921MSO cell lines highly expressed CD44. Treatment with HA enhanced the proliferation in both mesothelioma cell lines in comparison to cells without HA treatment. The treatment with HA (25 µg/ml) also significantly upregulated the invasion of both types of cells. The silencing of CD44 significantly abrogated the effect of HA treatment on the proliferation of ACC-MESO-1 cells and significantly suppressed the proliferation of K921MSO cells. HA-CD44 binding is important for the migration and proliferation of mesothelioma cells. Therefore, the HA-CD44 interaction is a potentially useful therapeutic target in MPM.

Temporal trends in the surgical outcomes of patients with breast cancer.

BACKGROUND: The incidence of breast cancer has been increasing in Japan over the past three decades, and it is the currently the most common malignancy in Japan. This study investigated the temporal trends of the surgical outcomes in patients with breast cancer. METHODS: We evaluated 543 consecutive patients who underwent breast-cancer resection between 1980 and 2009. The temporal trends in the surgical outcome and clinicopathological features were evaluated separately for the periods covering 1980 to 1989, 1990 to 1999, and 2000 to 2009. RESULTS: The number of patients who underwent resection during these three respective periods were 133, 176, and 234, respectively. All patients were women. The percentage of patients at stages 0 or 1 was 63.2%, 58.5%, and 43.6%, respectively, during the three periods. The mean diameter of tumors in each period was 38, 29, and 30 mm, respectively. The percentage of tumors with positive ER expression was 62.5%, 64.3%, and 69.7%, respectively. In terms of surgical procedures, the use of Halsted's radical mastectomy decreased during each period: from 40.6% of cases to 8.5% and then to 0.4%, while the proportion of breast-conserving therapies increased, from 0% to 12.5%, and finally to 35.9%. The postoperative 10-year survival rates during the three periods were 75.9%, 83.5%, and 84.9%, respectively. The 10-year survival rates of patients with stage II disease during the three periods were 66.2%, 75.7%, and 90.7%, respectively. The prognosis of stage III disease in the three periods also showed a tendency toward improvement, increasing from 37.8% to 64.2%, and finally to 84.5%. CONCLUSION: The survival of patients with stage II and III disease has improved during the past 30 years. Along with the recent advances in drug therapy, the surgical treatment has become less invasive, often because of drug therapy-related modifications.

Differences in sensitivity to tumor-specific CTLs between primary and metastatic esophageal cancer cell lines derived from the same patient.

PURPOSE: MHC antigens and adhesion molecules, such as the intracellular adhesion molecule (ICAM-I), play an important role in cellular immune response. We examined the expression patterns of these molecules in both primary and metastatic esophageal carcinoma cells from the same patient and evaluated the cellular immune responses against these cells. MATERIALS AND METHODS: In the esophageal cancer patient (H122), tumor cell lines were established from primary and subcutaneous metastatic lesions. We compared the expression of cell surface molecules on the metastatic tumor cell line (H122SC) with that on the primary tumor cell line (H122ESO) using flow cytometry. Moreover, we analyzed the differences in cellular immune responses against these cell lines, which expressed similar levels of the Tara antigen, using the Tara antigen-specific CTL clone. RESULTS: H122SC ICAM-1 expression was significantly lower in H122ESO, and the Tara antigen-specific CTL clone produced lower levels of TNF in response to H122SC than H122ESO. ICAM-1 transfection into the H122SC rendered these cells as sensitive to the CTL clone as the H122ESO. CONCLUSION: The metastatic tumor cells displayed lower regulated ICAM-1 expression levels and were less sensitive to specific CTLs. ICAM-1 downregulation may be one mechanism by which tumor cells escape immunologic surveillance.

[Clinical characteristics of pulmonary hamartoma resected surgically as undiagnosed pulmonary nodule].

Pulmonary hamartoma is the most common tumor in benign lung neoplasm. We reviewed the clinical characteristics of 9 patients who had undergone surgical resection for pulmonary hamartoma between 2000 and 2009. There were 1 male and 8 female patients. The age of the patients ranged from 42 to 77 years old (mean 59). Calcification was not observed by computed tomography scan except in 1 patient. Although transbronchial lung biopsy (TBLB) was performed in 5 patients, no definitive diagnosis was obtained. Six patients underwent 18F-fluorodeoxyglucose (FDG)-positron emission tomography, and none of them showed any accumulation of FDG except for 1 patient. Concerning the operative procedures, a sleeve lobectomy was performed in 1 patient, a segmentectomy in 1, a lobectomy in 2, a partial resection of the lung in 3, and a nucleation in 2 patients. The postoperative courses were uneventful, and no findings of recurrence were observed in any of the patients after surgery. As a preoperative diagnosis of pulmonary hamartoma is often difficult in TBLB, it is necessary to perform surgical resection in the differential diagnosis of lung cancer or metastatic lung tumor, unless there are typical findings of pulmonary hamartoma in clinical imaging.

Pleural lavage cytology immediately after thoracotomy in patients with completely resected non-small cell lung cancer.

This study evaluated 325 patients who had undergone pleural lavage cytology (PLC) immediately after thoracotomy following a complete resection for non-small cell lung cancer (NSCLC) between 2004 and 2008. The number of patients with negative and positive findings in PLC was 309 and 13, respectively. The proportion of T1 in the PLC-positive group was significantly smaller than that of the PLC-negative group. The pathologic examinations revealed that the parietal pleural invasion was significantly more severe in the PLC-positive group than in the PLC-negative group. Pathologic lymphovascular invasion was also significantly more prominent in the PLC-positive group than in the PLC-negative group. The 5-year survival rate after surgery in the PLC-positive group and PLC-negative group was 54.7% and 79.0%, respectively. The positive finding in PLC showed a tendency of an unfavorable prognosis for NSCLC patents following complete resection. Further clinical studies will be necessary to evaluate the efficacy of adjuvant therapy for PLC-positive patients.

Esophageal bypass using a gastric tube for a malignant tracheoesophageal/bronchoesophageal fistula: a report of 4 cases.

Tracheoesophageal/bronchoesophageal fistulas are often caused by locally advanced esophageal cancer and lung cancer, and result in life-threatening conditions such as severe cough and dyspnea due to pneumonia. We herein report the clinical characteristics of 4 patients with tracheoesophageal/bronchoesophageal fistulas. All patients were men, and ranged in age from 40-69 years. Three patients had esophageal cancer and 1 had lung cancer. All 4 underwent esophageal bypass using a gastric tube with tube drainage of the distal side of the esophagus. Three patients died at 3, 4, and 5 months after surgery. However, these patients were allowed to enjoy food orally up until the last few days of life. One patient who underwent esophageal bypass and chemoradiotherapy has remained well for 5 years without any evidence of recurrence. This bypass procedure is therefore considered to be a feasible treatment choice for patients with tracheoesophageal/bronchoesophageal fistulas.

[Surgical treatment for patients with pulmonary sclerosing hemangioma].

Sclerosing hemangioma of the lung, a rare disease, is a low grade malignancy possibly originating from type II pneumocytes or Clara cells. We report the clinical characteristics of 8 patients who underwent surgical resection for sclerosing hemangioma between 2005 and 2010 in our hospital. All cases were female, and the average age was 50 (range: 28-83) years old. The median tumor doubling time was 965 days, suggesting they were slowly growing tumors. In the present cases, five patients had another lung disease: lung cancer in two, metastatic lung tumor in one and atypical adenomatous hyperplasia in two patients. Intraoperative frozen section examinations were performed in seven cases. Five patients were diagnosed correctly, but two patients were diagnosed with adenocarcinoma and organizing pneumonia. As a clinical characteristics, sclerosing hemangioma in the present study showed well-demarcated and slow-growing tumor. The postoperative clinical courses of all cases were uneventful, and no findings of recurrence distant metastasis, lymph node metastasis and local recurrence after surgery were observed in any of the patients.

Apocrine carcinoma of the breast.

Apocrine carcinoma is a rare variant of breast carcinoma, and accounts for 0.3 to 1.0% of all breast cancers. A 55-year-old Japanese female patient presented with a right breast tumor, which had been detected by mass-screening, and she was admitted to our hospital. The physical examination revealed an elastic hard lump in the upper lateral quadrant of the right breast. The tumor size was approximately 1.0 cm in diameter, and the border was clear. There were no palpable axillary lymph nodes nor supraclavicular nodes. Fine-needle aspiration cytology revealed invasive ductal carcinoma. The patient underwent a partial resection of the right breast (breast conserving therapy) and a right axillary lymphadenectomy. Macroscopically, the resected specimen revealed a white tumor measuring 1.2 x 1.2 x 1.0 cm. The TNM classification was diagnosed as T1cN0M0 stage I. Histopathologically, the tumor revealed a proliferation of atypical epithelial cells with apocrine differentiation, arranged in a papillotubular or cribriform growth pattern with stromal invasion. The tumor cells showed irregular round-shaped nuclei often containing prominent nucleoli, and had particularly abundant eosinophilic granular cytoplasm. In the immunohistochemical analysis, these carcinoma cells were positive for Gross Cystic Disease Fluid Protein 15 and the androgen receptor, whereas they were negative for the estrogen and progesterone receptors. Immunohistochemical staining for Her2 using the HercepTest was found to be negative (score 0). Thus, the pathological diagnosis was apocrine carcinoma. There were no metastases in the axillary lymph nodes. The patient has had no recurrence in 8 years after surgery.

[Management of patients with bronchial foreign bodies].

The aspiration of foreign bodies into the bronchus frequently occurs in children as well as in elderly people. Foreign bodies in the airway not only cause chronic cough and pneumonia, but also result in life-threatening conditions, such as dyspnea and cyanosis. This report presents the clinical characteristics of 6 patients with bronchial foreign bodies who were treated between 2006 and 2010, including 4 male and 2 female patients. The age of the patients ranged from 8 to 83 years old. Foreign bodies were located in the right bronchial tree in all the patients. Chest X-rays showed pneumonia or atelectasis in 5 out of 6 patients. The foreign bodies were an artificial teeth or a tooth in 5 patients, and a fish bone in 1 patient. Five patients had fiberoptic bronchoscopy under local anesthesia, although an 8-year-old girl required general anesthesia with a laryngeal mask. Surgery was needed in only one case. Bronchial foreign bodies present a large range of symptoms, from trivial symptoms to irreversible damage to the bronchus and the lung, which can be life threatening. Nonspecific respiratory symptoms may be mistakenly attributed to other medical diagnoses unless there is a clear history of aspiration. However, an early diagnosis is very important, because inflammatory granulation due to long-term impaction of foreign bodies makes its removal difficult.

Evaluation of topoisomerase I/topoisomerase IIalpha status in esophageal cancer.

Human DNA topoisomerases I and IIalpha (Topo-I and -II alpha) are essential for vital cellular processes such as DNA replication, transcription, translation, recombination, and repair. The purpose of this study was to investigate the clinical significance of the expression of Topo-I and Topo-II alpha. Twenty-nine specimens of esophageal squamous cell carcinoma from patients who had been treated by complete resection of the esophageal tumor were studied by an immunohistochemical analysis. High expression of Topo I and II alpha was identified in 48.7% and 55.2% of tumors, respectively. Neither the Topo-I nor -II alpha expression level had any association with clinical characteristics, including differentiation and the depth of tumor invasion, lymph node metastasis, or the patient prognosis. However, a significant positive correlation was observed between the expression levels of Topo-I and Topo-II alpha. Our study results underscore the potential role of topoisomerase expression in esophageal cancer and further exploratory investigation is necessary to evaluate topoisomerase expression as a surrogate marker in chemotherapy with topoisomerase inhibitor for esophageal cancer.

Clinicopathologic characteristics of mucinous carcinoma of the breast.

The mucinous carcinoma of breast cancer is a relatively rare malignant tumor. This study investigated the clinical and pathologic features of mucinous carcinoma. The medical records of 237 patients with invasive breast cancer who underwent surgery between 1995 and 2006 were reviewed. These cases included 10 patients (4.2%) with mucinous carcinoma. The age of the patients ranged from 43 to 71 years (mean, 55.5 years). The tumor size was T1 in 5 patients and T2 in 5 patients. Lymph node metastasis was diagnosed as being negative in 9 patients and positive in 1 patient. Six patients (60%) were positive both for estrogen and progesterone receptor. The 10-year survival rates of mucinous carcinoma and other types of invasive breast cancer were 87.5% and 80.7%, respectively. Mucinous carcinoma showed a lower incidence of lymph node metastasis than other types of invasive breast cancer. Mucinous carcinoma tended to have a better prognosis in comparison with other types of invasive breast carcinoma.

[Three cases of spindle cell carcinoma of the breast].

Spindle cell carcinoma of the breast is a rare variant of breast cancer composed of spindle-shaped sarcomatoid cancer cells. We report three females with spindle cell carcinoma of the breast who underwent resection, with a review of the literature. The females were 26, 52, and 58 years old, and the tumor diameters were 3.5, 3.5, and 9.0 cm, respectively. All three patients underwent Auchincloss method mastectomy. A cystic lesion accompanied by necrosis was observed in the tumor of two of the three patients. Axillary lymph node metastasis was pathologically diagnosed in one of the three patients. All three tumors were estrogen receptor- and progesterone receptor- negative, showed a proliferation of severely atypical spindle or polygonal epithelial cells, and were diagnosed as spindle cell carcinoma. One patient died of pulmonary, bone, and brain metastases 2 years after the operation, but the other two have followed a favorable course without recurrence for 5 years since the surgical resection.