Tokiko Ito

Clinical features of a new disease concept, IgG4-related thyroiditis

Objectives: Immunoglobulin (Ig)G4-related disease is a recently proposed systemic disorder that includes autoimmune pancreatitis (AIP), Mikulicz’s disease, and various other organ lesions. In the present retrospective study, we examined whether thyroid lesions should also be included in IgG4-related disease (Ig4-RD) under the new term IgG4-related thyroiditis. Method: We enrolled 114 patients with Ig4-RD, including 92 patients with AIP, 15 patients with Mikulicz’s disease, and seven patients with IgG4-related cholangitis, and analysed clinical findings, function, serum values of activity markers, computed tomography (CT) images, and histology of the thyroid gland. Results: Among the 22 patients (19%) in our cohort who were found to have hypothyroidism [thyroid stimulating hormone (TSH) > 4 mIU/L], 11 patients had clinical hypothyroidism [free thyroxine (FT4) < 1 ng/dL] and 11 patients had subclinical hypothyroidism (FT4 ≥ 1 ng/dL). Serum concentrations of IgG, IgG4, circulating immune complex (CIC), and β2-microglobulin (β2-MG) were significantly higher in the hypothyroidism group compared with the remaining 92 euthyroid patients, and serum C3 concentration was significantly lower. After prednisolone treatment, TSH values had decreased significantly (p = 0.005) in this group and FT4 values had increased significantly (p = 0.047). CT images showed that the thyroid glands of patients with clinical hypothyroidism had a significantly greater volume than those of the euthyroid and other groups. Pathological analysis of one resected thyroid gland disclosed a focused lesion with infiltration of lymphocytes and IgG4-bearing plasma cells and loss of thyroid follicles. Conclusions: Thyroid lesions associated with hypothyroidism can be considered as a new disease termed IgG4-related thyroiditis. Awareness of this condition should lead to appropriate corticosteroid treatment that may prevent progression to a fibrous state.

Multimodality therapeutic outcomes In anaplastic thyroid carcinoma: Improved survival in subgroups of patients with localized primary tumors

The aim of the present study was to investigate the role of a multimodality treatment for anaplastic thyroid carcinoma (ATC).

ENDOSCOPIC-ASSISTED SKIN-SPARING MASTECTOMY COMBINED WITH SENTINEL NODE BIOPSY

Breast‐conserving surgery (BCS) has been carried out as desirable choice for patients with early‐stage breast cancer. However, many patients obliged to abandon BCS because of tumours accompanied by extended intraductal components or multiple tumours. The purpose of this study was to develop a novel endoscopic‐assisted technique for skin‐sparing mastectomy (SSM) combined with sentinel node biopsy (SNB), followed by immediate breast reconstruction with mammary prosthesis. Between April 2000 and November 2006, 33 patients diagnosed with primary breast cancer underwent endoscopic‐assisted SSM. Immediate reconstruction with the mammary prosthesis was carried out in 30 of 33 patients. On postoperative histopathological diagnosis, 21 tumours were diagnosed as ductal carcinoma in situ or lobular carcinoma in situ. Twelve tumours were diagnosed as invasive carcinoma. Eight of 12 invasive carcinomas were accompanied by a wide spreading intraductal component. Two patients were diagnosed as having multicentric carcinomas, which made the standard breast‐conserving treatment difficult. After a mean follow‐up period of 51.2 months (range 16–86 months), neither locoregional recurrence nor distant metastasis has been detected. Thus, combining SSM and SNB with immediate reconstruction with the mammary prosthesis may offer the selected patients with early‐stage breast cancer favourable aesthetic results without incurring additional oncological risks. The procedure could be an alternative treatment option for patients with widely spreading intraductal component or multiple tumours.

CSLEX (Sialyl Lewis X) is a Useful Tumor Marker for Monitoring of Breast Cancer Patients

BACKGROUND CSLEX is a type II carbohydrate antigen that interacts with the CSLEX-1 monoclonal antibody. CSLEX in combination with carbohydrate antigen 15-3 may be more useful than Carcinoembryonic Antigen with carbohydrate antigen 15-3 as tumor markers for monitoring of breast cancer. METHODS The serum levels of tumor markers, including CSLEX, were measured in 480 consecutive breast cancer patients with or without metastasis who visited the outpatient clinic of the Division of Breast and Endocrine Surgery, Shinshu University Hospital, between April 2007 and September 2007. RESULTS Serum levels of each of the tumor markers correlated significantly with the status of metastasis (P < 0.01). Combinations of Carcinoembryonic Antigen and carbohydrate antigen 15-3, Carcinoembryonic Antigen and Nation Cancer Center-Stomach-439, Carcinoembryonic Antigen and CSLEX, carbohydrate antigen 15-3 and Nation Cancer Center-Stomach-439, and carbohydrate antigen 15-3 and CSLEX levels also correlated significantly with the status of metastasis (P < 0.01). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were almost the same for CSLEX and Nation Cancer Center-Stomach-439, which are both type II carbohydrate antigens. The cutoff indexes of serum CSLEX and Nation Cancer Center-Stomach-439 for detection of breast cancer metastasis were 38.8 ± 52.7-fold and 22.1 ± 27.8-fold, respectively (P = 0.16). CONCLUSIONS These data suggest that the diagnostic values of CSLEX and Nation Cancer Center-Stomach-439 are similar in single or combined use. However, the cutoff index of serum CSLEX tended to be higher than that of Nation Cancer Center-Stomach-439, which may make CSLEX more useful for detection of breast cancer metastasis.

A Case of Brain Metastases from Breast Cancer that Responded to Anastrozole Monotherapy

To the Editor: Brain metastases are less common in breast cancer patients than bone or visceral metastases; however, brain metastasis is one of the most critical metastatic lesions in the treatment of breast cancer because of the progressive neurological disability caused by the lesions and the lack of effective treatment as seen in visceral or bone metastasis (1,2). Treatments for brain metastases of breast cancer include corticosteroids, whole-brain radiation therapy, surgical resection, and stereotactic radiosurgery (1). However, after such treatment, median survival has been only slightly extended by several months. Generally, chemotherapy is not considered a useful strategy in the management of brain metastases because the tight junctions of the blood–brain barrier preclude the entry of most chemotherapeutic agents into the central nervous system (CNS) (3). With regard to endocrine therapy, there have been a certain number of reports of breast cancer patients with brain metastasis responding well to tamoxifen therapy (4–7), however, there have been only a few reports regarding the effects of aromatase inhibitors in the treatment of brain metastasis (8). In this study, we report a very rare case of brain metastases from hormone-sensitive breast cancer that responded well to the aromatase inhibitor, anastrozole for a prolonged period. A 73-year-old woman visited her family physician due to a common cold in June 2004. Chest roentgenogram showed multiple nodular shadows in bilateral lung fields. Her clinical history included right radical mastectomy for left breast cancer in 1985 at the age of 54. Based on her clinical history, the multiple nodular shadows in the lung were suspected to be metastases of breast carcinoma. Furthermore, positron emission tomography and computed tomography also revealed multiple metastases in her bones, lymph nodes, and subcutaneous tissues. Core needle biopsy of one of the subcutaneous tumors revealed that the cancer was estrogen receptor-positive, progesterone receptor (PgR)-positive, and human epidermal growth factor receptor type 2 (Her2)-negative. As systemic therapy for the recurrent breast cancer, anastrozole was administered at a dose of 1 mg ⁄ day. To prevent progression of bone metastases, 45 mg of pamidronate disodium was also administered every four weeks. Although she was neurologically asymptomatic, screening magnetic resonance imaging (MRI) of the brain revealed more than 20 metastatic lesions in her brain (Fig. 1). Although a radiologist recommended the patient undergo whole-brain radiation therapy (WBRT) to treat the multiple brain metastases, she refused due to fear of adverse events caused by the therapy. Consequently, she continued oral anastrozole therapy alone as systemic therapy for the multiple-organ metastatic breast cancer lesions, and intended to undergo radiation therapy of the lesions in the brain if they progressed further or became symptomatic. Two months after administration of anastrozole, marked decreases in levels of tumor markers, such as CEA, CA15-3, and NCC-ST439, were observed. Three months after the initiation of anastrozole, MRI of the brain revealed reductions in the metastatic tumors in her brain. Subsequently, 6 months after the initiation of anastrozole, MRI of the brain revealed gross reductions in the metastatic tumors in the brain (Fig. 2). Eight months after initiation of anastrozole, all except one of the metastatic lesions in the brain remained stable in size and she still was neurologically asymptomatic. However, she accepted radiation therapy for the brain metastases at this point because of the slight increase in size of one metastatic lesion. She preferred SRS to WBRT. Subsequently, SRS was applied to 10 metastatic regions in her brain. Thereafter, her metastatic cancer in the brain gradually reduced in size. As the multiple bone metastases progressed gradually, anastrozole was changed to exemestane for second line endocrine therapy in July 2005, and then Address correspondence and reprint requests to: Ken-ichi Ito, MD, PhD, Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan, or e-mail: kenito@shinshu-u.ac.jp

Alteration of Y-box binding protein-1 expression modifies the response to endocrine therapy in estrogen receptor-positive breast cancer

Y-box binding protein-1 (YB-1) plays an important role in tumor progression and drug resistance. This study examined whether YB-1 is involved in the alteration of response to endocrine therapy in estrogen receptor (ER)-positive breast cancer cells. MCF7 cells that stably expressed YB-1 (MCF7-YB-1) and vector control cells (MCF7-vector) were established. These cells were used to analyze the expression of the factors related to ER and growth factor receptor signaling pathways and responses to antiestrogens (tamoxifen and fulvestrant) and estrogen responsive element (ERE) activity. The effect of knocking down endogenous YB-1 expression was tested in wild-type MCF7 cells. In addition, the expression of YB-1 and the factors related to ER and growth factor receptor signaling pathways were evaluated in clinical breast cancers treated with preoperative chemotherapy. The expression of HER2, AIB1, p-Erk, and c-Myc was increased in MCF7-YB-1 cells. In contrast, knocking down of YB-1 decreased the expression of these factors but increased the expression of ERα in wild-type MCF7 cells. Furthermore, sensitivity to antiestrogens was decreased in the MCF7-YB-1 in comparison to that in MCF7-vector cells. The introduction of YB-1 into MCF7 cells inhibited apoptosis and cell cycle arrest at G1 phase induced by antiestrogens. In MCF7-YB-1 cells, the expression levels of p-Erk and c-Myc were continuously upregulated when cells were treated with either tamoxifen or fulvestrant. The ERE activity was reduced in MCF7-YB-1 cells in comparison to MCF7-vector cells, and the ERE activity in MCF7-YB-1 cells was inhibited by fulvestrant at a lower concentration than that which inhibited the ERE activity in MCF7-vector cells. In ER-positive clinical breast cancers treated with preoperative chemotherapy, significantly more number of specimens that showed increased or positive YB-1 expression after chemotherapy was positive for HER2 expression. These data suggest that alteration of YB-1 may modify the crosstalk between the ER pathway and HER2 pathway in ER-positive breast cancer cells, and consequently, may alter the response to endocrine therapy in ER-positive breast cancer cells.

Two cases of sarcoidosis discovered accidentally by positron emission tomography in patients with breast cancer.

To the Editor: Follow-up of women with breast cancer to detect recurrence and distant metastases is critical because earlier detection of recurrence can result in earlier and probably more efficient treatment. F-2-deoxy-2-florod-glucose (FDG) positron emission tomography (PET) provides information about the metabolic activity of tumors that can complement the anatomical information provided by other imaging modalities. Several studies have demonstrated that whole-body FDG-PET is superior to conventional imaging in detecting recurrent and metastatic disease from breast cancer (1–7). However, false positive results are sometimes encountered in FDG-PET due to interpretative pitfalls and the non-specificity of FDG. Here, we present two cases of advanced breast cancer that showed false positive results on FDG-PET due to sarcoidosis that developed during the period of follow-up of breast cancer.

Breast metastases of gastric signet-ring cell carcinoma: a report of two cases and review of the literature.

It is occasionally difficult to diagnose breast metastasis of gastric carcinoma because of its rarity. However, to appropriately treat patients with breast tumors without delay, it is important to distinguish metastatic cancer from primary breast cancer. We report two cases of breast metastasis of gastric carcinoma and review the literature. The first case was a 41-year-old female diagnosed with bilateral pelvic tumors who visited the outpatient clinic because of pain and enlargement of both breasts. Ultrasonography showed diffuse hypoechoic lesions, which were enhanced on gadolinium-enhanced magnetic resonance imaging in the bilateral mammary gland. Core needle biopsy of the right breast revealed signet-ring cells, which were also identified in the resected bilateral pelvic tumors. Subsequent upper gastrointestinal endoscopy revealed signet-ring cell carcinoma in the stomach, and the bilateral breast lesions were diagnosed as metastases of gastric carcinoma. The second case was a 34-year-old female diagnosed with cervical metastasis of signet-ring cell carcinoma who was referred to the breast cancer clinic because of a nodule in the left breast detected by computed tomography. Ultrasonography showed a hypoechoic nodule that was enhanced on gadolinium-enhanced magnetic resonance imaging. Because the pathologic findings for the left breast nodule were quite similar to those of gastric cancer and its cervical metastasis, the breast nodule was diagnosed as a metastasis of gastric carcinoma. When a breast tumor is suspected to have metastasized from a primary tumor in another organ, particularly if signet-ring cells are found, the possibility that gastric cancer is present should be considered.

A case of severe and recurrent painless thyroiditis requiring thyroidectomy.

Objective: To report a case of severe and recurrent painless thyroiditis requiring thyroidectomy. Clinical Presentation and Intervention: A 47-year-old man who presented with severe thyrotoxicosis was found to have extremely low radioactive iodine uptake, negative TSH receptor antibodies, and normal C-reactive protein; these findings suggested a diagnosis of painless thyroiditis. Due to the severity and recurrence of thyrotoxicosis, surgical resection of the thyroid gland was performed to prevent a thyrotoxic storm. Histological examination revealed typical lymphoid infiltration of the thyroid gland. Conclusion: This case illustrates that a patient with painless thyroiditis was successfully treated with surgery.

Lipid-rich carcinoma of the breast that is strongly positive for estrogen receptor: a case report and literature review.

Lipid-rich carcinoma (LRC) of the breast is a rare breast cancer variant that accounts for <1% of all breast malignancies. It has been reported that LRCs are negative for estrogen receptor. Here, we report a case of LRC of the breast that was strongly positive for estrogen receptor and treated with endocrine adjuvant therapy. A 52-year-old postmenopausal female noticed a lump in her right breast by self-examination and presented to our hospital. Physical examination revealed an elastic 30 mm ×20 mm hard mass in the upper medial part of her right breast. The findings obtained using ultrasonography, mammography, and contrast-enhanced magnetic resonance imaging suggested breast cancer. Core needle biopsy resulted in the diagnosis of invasive carcinoma. The patient underwent mastectomy and sentinel lymph node biopsy. Histopathologically, the tumor cells were abundant in foamy cytoplasm. Because the presence of marked cytoplasmic lipid droplets was confirmed by Sudan IV staining and electron microscopic examination of the tumor and the lipid droplets were negative for periodic acid–Schiff staining, the tumor was diagnosed as an LRC. Immunohistochemically, estrogen and progesterone receptors of the tumor were strongly positive, human epidermal growth factor receptor type 2 was negative, and the ratio of Ki-67-positive cells was ~30%. After surgery, the patient underwent combination chemotherapy with anthracycline, cyclophosphamide, and 5-fluorouracil, followed by docetaxel. Thereafter, the pateint was treated with letrozole and has remained well for 24 months with no signs of recurrence.