Atsushi Fukuuchi

Clinicopathological study of SDHB mutation-related pheochromocytoma and sympathetic paraganglioma

Pheochromocytoma (PCC) and paraganglioma (PGL) are genetically and phenotypically heterogeneous catecholamine-producing neoplasms. They can occur sporadically or as a part of hereditary disease. Approximately 30% of PCC/PGL are believed to be caused by germline mutations (Welander et al. 2011). Of these, succinate dehydrogenase subunit B (SDHB) gene mutation is considered a high-risk factor for malignancy. Loss of heterozygosity at the SDHB locus (1p36)wasobserved inall tumorswithSDHBmutation, and Gimenez-Roqueplo et al. (2003) strongly suggested that SDHB is a tumor suppressorgene. Subsequently, loss of SDHB protein immunoreactivity in SDHB-mutated PCC/PGL (SDHB–PCC/PGL) was reported with 100% sensitivity and 84% specificity (van Nederveen et al. 2009). Thus, SDHB immunohistochemistry can be used to screen SDHB– PCC/PGL using paraffin-embedded pathological materials. SDHB mutation is the only established factor that indicates future metastasis. Therefore, it is important to analyze the histological characteristics of SDHB–PCC/PGL. It is generally accepted that it is difficult to distinguish histological differences between benign and malignant PCC/PGL. The current consensus is that a long-term follow-up is required after the surgery to screen for recurrence or metastasis in all PCC/PGL patients, regardless whether hereditary or sporadic in origin. Kimura et al. (2014) proposed a histological grading system called the Grading of Adrenal PCC and PGL (GAPP) classification for predicting metastasis. GAPP is composed of six factors: histological pattern, cellularity, presence or absence of comedo-type necrosis, vascular or capsular invasion, Ki67labeling index (%), and elevated catecholamine type. Each factor was assigned a point and the number of points was summated. Tumor scores of 0–2, 3–6, and 7–10 were classified into well differentiated (WD), moderately

Mid-mediastinal parathyroid lesions: preoperative localization and surgical approach in two cases.

Although hyperfunctioning mediastinal parathyroid lesions that require median sternotomy or thoracotomy for removal are occasionally present, the majority are located in the anterior mediastinum closely associated with the thymus. Only eight cases of ectopic hyperfunctioning parathyroid tumors in the middle mediastinum have been reported. We experienced two cases of either persistent or recurrent hyperparathyroidism in which abnormal parathyroid tissue was located in the aorticopulmonary window. One of the patients had a parathyroid adenoma and the other had metastatic lesions of parathyroid carcinoma. In both cases, thallium scanning proved useful in identifying the lesions while computed tomography scan was effective for mediastinal three-dimensional localization. In one case, single photon emission computed tomography imaging with thallium proved beneficial for both identification and localization of the middle mediastinal lesion. The surgical approach used in both cases was different. In one case, left thoracotomy was performed, after which the ligamentum arteriosum was divided, and an adenoma anterior to the left main bronchus and posterior to the left pulmonary artery removed. In the other case, two metastatic tumors of parathyroid carcinoma anterior to the right main bronchus and posterior to the right pulmonary artery were resected through a median sternotomy and opening of the pericardium.

A case of malignant fibrous histiocytoma after breast conserving therapy for breast cancer

A 45-year-old woman with malignant fibrous histiocytoma (MFH) of the breast following breast conserving therapy (BCT) is described.She noticed a lump in her left breast 52 months after BCT for breast cancer. The lump was excised and nodular fasciitis was initially diagnosed. However, the tumor recurred locally 4 times in the next 18 months. MFH was finally diagnosed.This case is considered to be radiation-induced sarcoma. The risk of radiation-induced sarcoma after BCT seems to be very low, however careful follow-up is necessary.

A case of mucinous carcinoma of the breast in which needle tract seeding was diagnosed by preoperative diagnostic imaging

Herein we report a 62-year-old woman with an excisable breast tumor in whom needle tract seeding was suspected during preoperative ultrasound and magnetic resonance imaging (MRI). A tumor of the right breast was observed during initial examination, and she was referred to our hospital after fine-needle aspiration cytology led to diagnosis of breast cancer, even though core needle biopsy results were negative. Mammography showed a high-density mass with a portion of the margin exhibiting very fine serrations. Ultrasonography revealed a circular mass with a border that was indistinct in some regions, and a hypoechoic band that extended from the tumor toward the skin. A mass was observed on MRI, with a linear enhancement extending on the skin side, and needle tract seeding was suspected. Fine-needle aspiration cytology revealed malignancy, and the histological appearance was consistent with mucinous carcinoma. T1cN0M0 stage I breast cancer was diagnosed, and wide excision and sentinel lymph node biopsy were performed. The skin directly above the tumor was concurrently excised to remove the biopsy puncture site. Histopathological diagnosis confirmed mucinous carcinoma, with the tumor observed to extend linearly into the subcutaneous adipose tissue in a pattern corresponding to the biopsy puncture site. The stump of the excised breast was negative for cancer cells. The possibility of tumor seeding must be considered during fine-needle aspiration cytology and biopsy. As demonstrated in this case, diagnosis of such seeding through preoperative imaging may enable extraction of the entire lesion, including the needle tract.

Primary Malignant Lymphoma of the Breast: Mammographic and Ultrasonographic Findings.

Malignant lymphoma rarely involves the breast. We describe four cases of primary breast lymphoma encountered in our institution from 1979 through 1996, focusing on mammographic and ultrasonographic findings. The lymphomas were demonstrated by mammography as a well-defined mass in one case, an ill-defined mass in two cases and as diffuse increased opacity in one case. No desmoplastic change or calcification was noted. In 3 cases ultrasonography was used, revealing hypoechoic masses with (1 case) or without (2 case) posterior enhancement. During the past two years, 45 of 197 cancers (23%) were demonstrated as a mass without desmoplastic change or calcification by mammography and ultrasonography at our institution. It can be difficult to distinguish malignant lymphoma from more common diseases of the breast, such as carcinoma, by mammography and ultrasonography.

Clinical Outcome of Reconstruction With Tissue Expanders for Patients With Breast Cancer and Mastectomy

BACKGROUND Because the number of patients with breast cancer who have reconstruction after mastectomy is increasing, we analyzed the outcomes of reconstruction with tissue expanders (TEs). PATIENTS AND METHODS From 2004 to 2009, 133 patients with unilateral primary breast cancer who required mastectomy concurrent with reconstruction using TEs (TE group) and 308 patients with breast cancer who underwent mastectomy without reconstruction (MT group) were examined. RESULTS The median follow-up period was 47 months versus 44 months (TE group vs. MT group, respectively). The median age was 46 years in the TE group and 58 years in the MT group (P < .0001). The rate of hormone receptor positivity in the TE group was significantly higher than in the MT group (P = .0123). The incidence of local recurrence, time to detection of local recurrence, and size of tumor in local recurrence in the TE group and the MT group were 3.8% versus 1.6% (P = .1560), 17.2 months versus 12.4 months (P = .9166), and 1.9 cm versus 2.4 cm (P = .6742), respectively. In the TE versus the MT groups, relapse-free survival (RFS) and overall survival (OS) at 45 months were 89.0% versus 87.9% (P = .8706) and 93.9% versus 94.2% (P = .9947), respectively. The incidence of infection was significantly higher in the TE group than in the MT group-14.3 % versus 2.9%, respectively (P < .0001). CONCLUSION Compared with mastectomy alone, immediate reconstruction with TEs did not impair prognosis or contribute to a delay in detection of local recurrence, although the incidence of surgical site infection in the TE group was significantly higher than in the MT group.

A Case of Granulocyte-Colony Stimulating Factor-Producing Spindle Cell Carcinoma of the Breast.

This is the first report to describe a very rare case of spindle cell carcinoma of the breast that produced granulocyte-colony stimulating factor (G-CSF). Removal of the tumor induced an immediate decrease in the white blood cell count and fever. In addition, immunohistochemistry for G-CSF provided proof of G-CSF expression of this breast carcinoma. Patients with G-CSFeproducing tumors usually have a poor prognosis, just as do those with spindle cell carcinoma of the breast. Consequently, our patient rapidly developed distant metastases. A G-CSFeproducing tumor should be considered, including in the breast, when a patient with cancer shows continuous leukocytosis and hyperthermia without a focus of infection.

Disease progression of metastatic breast cancer by first relapse site after definitive radiotherapy.

36 Background: Bone metastasis as initial distant relapse is commonly considered to have better prognosis than other sites in metastatic breast cancer. To elucidate true clinical course of metastatic disease, it is essential that we prospectively manage patients since primary setting. METHODS Overall, 3,417 patients with breast cancer treated with mastectomy (n = 379, 11.1%) or breast-conserving surgery (n = 3,029, 88.6%) followed by definitive radiotherapy at two institutions in Center of Tokyo between 1980 and 2014 were included in the study. Information on all patients was prospectively collected and rigorously-controlled. Initial metastatic relapse sites included bone, brain, and other (mainly visceral). Intrinsic subtypes of tumor were classified as luminal A, luminal-human epidermal growth factor receptor 2 (HER2), luminal B, triple negative, and HER2 identified by routine immunohistochemistry and histological grade. Cumulative incidence rates of overall survival (OS) for each affected site after metastatic relapse were estimated according to Kaplan-Meier method. RESULTS Median follow-up time for living patients was 113 months. A total of 370 patients experienced metastatic progression as first relapse event. Median duration of OS after initial metastatic relapse was 69 month in all subtypes. No difference was seen in OS among five subtypes after initial bone or brain relapse. Meanwhile, OS of luminal subtypes after initial other-site relapse was better than that of triple negative and HER2 subtypes (P = .003). Notably, OS rates of bone and non-bone/brain metastasis groups as initial relapse site were almost identical (P= .626). CONCLUSIONS We find no difference in mortality after metastatic relapse between bone and other site except for brain metastasis as initial relapse in breast cancer patients following definitive radiotherapy in our cohort without primary metastatic setting. Careful consideration is needed for initial distant relapse regardless of which site is involved. However, prognosis of metastatic breast cancer after definitive radiotherapy is favorable based on real world data, attributable mainly to improved systemic therapy and modern multidisciplinary approach.

Abstract P3-10-01: Randomized phase III trial of taxanes versus S-1 as first-line chemotherapy for metastatic breast cancer (SELECT BC: CSPOR- MBC01)

Background: Treatment goals of metastatic breast cancer (MBC) are to prolong survival and improve health-related quality of life (HRQOL). Current standard first-line chemotherapy for MBC are the taxanes or anthracyclines; however treatment-related adverse events greatly reduce HRQOL. S-1 is an oral 5-fluorouracil derivative, and phase II trials showed good clinical efficacy and tolerability. We conducted a phase III randomized controlled trial to establish non-inferiority of S-1 in overall survival (OS) and superiority in HRQOL to taxanes, when given as first-line chemotherapy for MBC. Methods: Patients with HER2-negative non-life-threatening MBC, naive to chemotherapy for metastatic disease, were randomly assigned to the taxane or S-1 groups. In the taxane group, patients received docetaxel 60-75mg/m2 q3w, paclitaxel 80-100mg/m2 q1w, or paclitaxel 175 mg/m2 q3w according to institutional policy. In the S-1 group, patients received S-1 40–60 mg twice daily based on body surface area using a 28 days on;14 days off regimen. Treatment was repeated until tumor progression or for at least 6 cycles (taxane) or 4 cycles (S-1). After failure of the first-line protocol therapy, another cytotoxic agent was administered, based on the investigator’s discretion. HRQOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, the Patient Neurotoxicity Questionnaire (PNQ) and the EQ-5D at baseline and 3, 6, 12 months after the start of the treatment. The primary endpoint was OS. Secondary endpoints were time to treatment failure (TTF), adverse events, and HRQOL. Results: A total of 618 women were enrolled. After a median follow-up of 34.6 months, median OS was 37.2 months in the taxane group (n=309) and 35.0 months in the S-1 group (n=309) (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.86–1.27, non-inferiority test p=0.015). Median TTF was 8.9 months in the taxane group and 8.0 months in the S-1 group (HR 1.10, 95% CI 0.93–1.30, p=0.022). The incidence of the following grade 3-4 adverse events, allergic reaction, edema and sensory neuropathy, were statistically significantly more frequent in the taxane group (p=0.038, 0.0013 and 0.0077, respectively). Hematologic and non hematologic toxicities except above did not differ significantly between the two groups. The results of the EORTC QLQ-C30 under study treatment indicated that the S-1 was better than the taxanes in global health status/QOL (p=0.044), physical functioning (p=0.002), role functioning (p=0.002), emotional functioning (p=0.004), cognitive functioning (p=0.026), social functioning (p Conclusions: This study clearly demonstrated that S-1 was superior to taxanes in terms of HRQOL and toxicity, without compromising the prolonged OS. S-1 should be considered as a new standard for first-line chemotherapy for MBC. We are conducting another similar trial (UMIN000005449) that compares first-line anthracycline with S-1 in terms of OS and HRQOL. Citation Format: Takanori Watanabe, Kojiro Shimozuma, Kentaro Imi, Hiroyoshi Doihara, Hiromitsu Akabane, Hiroaki Ueo, Shinji Ohno, Masahiro Kashiwaba, Atsushi Fukuuchi, Kenichi Watanabe, Michiko Tsuneizumi, Hirotsugu Isaka, Yukari Uemura, Yasuo Ohashi, Hirofumi Mukai. Randomized phase III trial of taxanes versus S-1 as first-line chemotherapy for metastatic breast cancer (SELECT BC: CSPOR- MBC01) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-01.

Secondary cancers after breast-conserving therapy in Tokyo database.

139 Background: The more patients overcome early breast cancer and become cancer survivors as a result of modern sophisticated approach, the more secondary cancers inevitably arise. The second malignancies after breast conserving therapy (BCT) are well-known sticky dilemma because of additional anxiety and need for medical care for longer-time. However, it is unclear whether secondary cancers negatively affect prognosis of breast cancer survivors. METHODS We performed a retrospective study of long-term cancer survivors after BCT for locoregional invasive or noninvasive breast cancer diagnosed between 1982 and mid-2012. Actuarial rates of overall (OS) and cause-specific survival (CSS) were calculated by using the Kaplan-Meier method. We compared between-group differences using the log-rank test. RESULTS Eight hundred sixty patients (32%) were followed-up for more than 10 years. At a median follow-up of 90 months, 146 patients had developed a second malignancy. The greatest increases in risk were for leukemia (Standardized incidence ratio (SIR): 4.24 (1.52-8.31)), ovarian cancer (SIR: 4.12 (2.40-6.31)), reno-ureteral cancer (SIR: 3.18 (1.14-6.23)), endometrial cancer (SIR: 2.48 (1.27-4.08)), and pancreatic cancer (SIR: 2.32 (1.11-3.99)). No increased risk was observed for other gastrointestinal and genitourinary cancer, malignant melanoma, lymphoma, thyroid or head and neck cancer. Overall 10-year cumulative incidence of OS without secondary cancer was 93.3%, and 10-year cumulative incidence of OS with secondary cancer was 81.5%. (p<0.001)Overall 10-year cumulative incidence of CSS without secondary cancer was 94.2%, and 10-year cumulative incidence of CSS with secondary cancer was 92.8%. (p=0.749). This likelihood of survival disadvantage is similar to that with ipsilateral breast tumor recurrecnce. CONCLUSIONS Secondary cancers after BCT negatively impact on OS. Given the life-threatening nature to cancer survivors, lifetime caution such as smoking cessation, alcohol intake abstention, weight control, physical activity, and other healthy lifestyle must be paid.