Sublingual immunotherapy for cedar pollinosis possibly triggers eosinophilic esophagitis.

Sublingual immunotherapy (SLIT) is an effective and popular treatment for cedar pollinosis. Although SLIT can cause allergic side effects, eosinophilic esophagitis (EoE) is a lesser-known side effect of SLIT. A 26-year-old male with cedar pollinosis, wheat-dependent exercise-induced anaphylaxis, and food allergies to bananas and avocados presented with persistent throat itching, difficulty swallowing, heartburn, and anterior chest pain 8 days after starting SLIT for cedar pollinosis. Laboratory examination showed remarkably elevated eosinophils, and esophagogastroduodenoscopy revealed linear furrows in the entire esophagus. Histological examination of an esophageal biopsy specimen revealed high eosinophil levels. The patient was strongly suspected with EoE triggered by SLIT. The patient was advised to switch from the swallow to the spit method for SLIT, and the symptoms associated with SLIT-triggered EoE were reduced after switching to the spit method. This case highlights the importance of recognizing SLIT-triggered EoE as a potential side effect of SLIT for cedar pollinosis, especially with the increasing use of SLIT in clinical practice. EoE can occur within a month after initiating SLIT in patients with multiple allergic conditions, as observed in our case. Furthermore, the spit method should be recommended for patients who experience SLIT-triggered EoE before discontinuing SLIT.

Recurrent Syncope in a Case with Mediastinal Lymphoma.

An 83-year-old man suddenly lost consciousness, and his blood pressure dropped. Results of blood analysis were within normal range. A chest radiograph showed enlargement of the left mediastinum. Computed tomographic scan of the chest showed a large mass surrounding the left common carotid artery in the left upper mediastinum. Histology revealed a large B-cell lymphoma. A Holter ECG showed transient sinus bradycardia and atrioventricular block. The power spectrum revealed increase in power of high frequency, suggesting that general vagal activity might be related to bradycardia. Evaluation of autonomic system from high frequency and low frequency components may be useful in examining the mechanisms of sudden bradycardia and/or hypotension of unknown origin.

Sclerosing mucoepidermoid carcinoma of the salivary glands: report of three cases with special concern to the counterpart accompanied by eosinophilia.

Sclerosing mucoepidermoid carcinoma (SMC) is described as a "sclerosing variant" of mucoepidermoid carcinoma, and it is characterized by dense fibrosis and sclerosis of the stroma. SMC with eosinophilia (SMCE) is another and more rare subtype characterized by eosinophilia in addition to the sclerotic stroma common to SMC. However, unlike SMC, SMCE is not listed in the current 4th edition of WHO classification. Here, we describe three cases: one SMC in the parotid gland, one SMCE in the submandibular gland and one SMCE in the minor salivary gland of the oral cavity. The patients included a 71-year-old Japanese male, a 74-year-old Japanese female, and an 81-year-old Japanese female. They each complained of mass formation and underwent surgical resection. Histologically, the tumors mainly consisted of squamous cells with scarce keratinization that formed irregular large and small nests along with cystic structures containing mucous cells against the background of sclerotic stroma. One oral SMCE showed fine nesting and trabecular invasion. The two SMCEs included dense aggregates of eosinophils as well as more prominent lymphoid infiltration. Fluorescence in situ hybridization for MAML2 confirmed split signals in SMC, but not in SMCE.

Ki-67 index value and progesterone receptor status can predict prognosis and suitable treatment in node-negative breast cancer patients with estrogen receptor-positive and HER2-negative tumors.

Gene profiling has identified at least 4 breast cancer subtypes, including Luminal A, Luminal B, HER2-enriched and basal-like, and immunohistochemistry is used as a guide to determine these subtypes. In the present study, patients with ER-positive, HER2-negative and negative nodes were classified into 4 groups according to the PgR and the Ki-67 status and were retrospectively examined. The analysis was based on the clinicopathological findings, and includes the recurrence score (RS) and disease-free survival (DFS) rates. Patients with invasive breast cancer (n=1866) were classified as LA (high PgR/low Ki-67), LB-1 (high PgR/high Ki-67), LB-2 (low PgR/high Ki-67), and LB-3 (low PgR/low Ki-67). In addition, 41 of the cases underwent a 21-gene expression assay. The data revealed that T1 tumors were more prevalent in the LA group and rare in the LB-2 group. Furthermore, nuclear grade 3 and p53 overexpression was revealed to be significantly correlated with LB-2. In terms of prognosis, LA had a significantly more favorable DFS; however, no differences were observed in the LB-3 group. LB-2 had a significantly worse DFS in all cases, and in the cases administered with endocrine therapy alone. Chemotherapy in combination with endocrine therapy was administered to cases with a higher risk of recurrence. In the LB-2 group, there was no difference in the DFS rates between the cases with endocrine therapy and chemo-endocrine therapy. These findings suggest that chemotherapy could improve the DFS in the LB-2 group. In addition, the majority of cases with LA, LB-3 and LB-1 had a RS of ≤25 and the majority of the LB-2 cases had a RS of >25. The patients with LA and LB-3 had a favorable DFS even in the group that received endocrine therapy alone. LB-2 was significantly correlated with a higher degree of malignancy and benefited from chemotherapy. These data suggest that the PgR and the Ki-67 status are effective in predicting prognosis, and for deciding on the most effective treatment strategy in patients with breast cancer.

A case of sclerosing angiomatoid nodular transformation:the correlation between imaging and pathological findings.

A 53-year-old woman was referred to our hospital with a 40-mm splenic tumor, which was detected incidentally on abdominal computed tomography during hospitalization for pyelonephritis. The tumor was hypointense on T2-weighted imaging and gradually enhanced on dynamic study. The tumor increased in size over a six-month period. Since we could not exclude splenic malignancy, we performed laparoscopic partial splenectomy. Histological examination revealed multiple angiomatoid nodules with three distinct vessel types. Pathologically, the tumor was diagnosed as a sclerosing angiomatoid nodular transformation (SANT). We then examined the correlation between the imaging and pathological findings, and performed a review of previous reports, concluding that contrast-enhanced MRI was the most useful modality for diagnosing SANT.

[Diffuse large B-cell lymphoma developed newly after 9-year remission of a follicular lymphoma].

Follicular lymphoma (FL) occasionally transforms into diffuse large B-cell lymphoma (DLBCL). This is generally associated with a poor prognosis, necessitating more potent chemotherapy as salvage treatment. However, de novo DLBCL, but not DLBCL transformed from FL, can be treated as primary DLBCL. We encountered a 63-year-old woman who developed DLBCL after a 9-year remission following treatment of FL. To differentiate DLBCL transformed from FL and de novo DLBCL, VDJ gene rearrangements in IgH were examined by PCR using biopsy specimens from both lymphomas. The results revealed the two lymphomas to be different clones. Thus, she was diagnosed with primary DLBCL. Therefore, routine chemotherapy and radiation therapy were conducted for the primary DLBCL with a limited stage, achieving complete remission. Treatment based on the clonality assessment of VDJ gene rearrangements is potentially useful for treating late relapse of B-cell lymphoma according to the pathological conditions of patients.

A Comparison of the Hot Spot and the Average Cancer Cell Counting Methods and the Optimal Cutoff Point of the Ki-67 Index for Luminal Type Breast Cancer.

OBJECTIVE: In this case-control study, we investigated the most suitable cell counting area and the optimal cutoff point of the Ki-67 index. METHODS: Thirty recurrent cases were selected among hormone receptor (HR)-positive/HER2-negative breast cancer patients. As controls, 90 nonrecurrent cases were randomly selected by allotting 3 controls to each recurrent case based on the following criteria: age, nodal status, tumor size, and adjuvant endocrine therapy alone. Both the hot spot and the average area of the tumor were evaluated on a Ki-67 immunostaining slide. RESULTS: The median Ki-67 index value at the hot spot and average area were 25.0 and 14.5%, respectively. Irrespective of the area counted, the Ki-67 index value was significantly higher in all of the recurrent cases (p < 0.0001). The multivariate analysis revealed that the Ki-67 index value of 20% at the hot spot was the most suitable cutoff point for predicting recurrence. Moreover, higher x0394;Ki-67 index value (the difference between the hot spot and the average area, ≥10%) and lower progesterone receptor expression (<20%) were significantly correlated with recurrence. CONCLUSION: A higher Ki-67 index value at the hot spot strongly correlated with recurrence, and the optimal cutoff point was found to be 20%.

The importance of tissue handling of surgically removed breast cancer for an accurate assessment of the Ki-67 index.

AIM: Insufficient attention for the Ki-67 immunohistochemistry has been given to the importance of tissue handling for surgical breast cancer specimens. We sought to investigate the effect of fixation status on the Ki-67. METHODS: We examined the effect of fixative, time to and duration of fixation using surgical specimens, and finally, compared the paired Ki-67 index in the tumour between core needle and surgical specimen. RESULTS: The Ki-67 was significantly higher when 10% neutral buffered formalin was used (p=0.0276). Insufficient fixation caused a drastic reduction in the Ki-67 index (p=0.0177), but not significant in oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Sixteen hours delayed time to fixation also caused a reduction of the Ki-67 (p=0.0284), but not significant in ER. Prolonged fixation significantly led to a gradual reduction in the Ki-67 in a time-dependent manner, but not in both ER and HER2. Finally, cutting the tumour before fixation improved fixation status and consequently caused an increased level of the Ki-67 index (p=0.0181), which resulted in a strong correlation of the Ki-67 between core needle and surgical specimen (r=0.8595). CONCLUSIONS: Tissue handling of surgical specimen is critical for assessing the Ki-67 compared with ER and HER2. We should pay more attention to tissue fixation status for the standard assessment of the Ki-67 index.

Evaluation of an Optimal Cut-Off Point for the Ki-67 Index as a Prognostic Factor in Primary Breast Cancer: A Retrospective Study.

The Ki-67 index is an important biomarker for indicating the proliferation of cancer cells and is considered to be an effective prognostic factor for breast cancer. However, a standard cut-off point for the Ki-67 index has not yet been established. Therefore, the aim of this retrospective study was to determine an optimal cut-off point in order to establish it as a more accurate prognostic factor. Immunohistochemical analysis of the Ki-67 index was performed on 4329 patients with primary breast cancer from August 1987 to March 2012. Out of this sample, there were 3186 consecutive cases from September 1997 with simultaneous evaluations of ER, PgR and HER2 status. Cox's proportional hazard model was used to perform univariate and multivariate analyses of the factors related to OS. The hazard ratios (HR) and the p values were then compared to determine the optimal cut-off point for the Ki-67 index. The median Ki-67 index value was 20.5% (mean value 26.2%). The univariate analysis revealed that there was a statistically significant negative correlation with DFS and OS and the multivariate analysis revealed that the Ki-67 index value was a significant factor for DFS and OS. The top seven cut-off points were then carefully chosen based on the results of the univariate analysis using the lowest p-values and the highest HR as the main selection criteria. The multivariate analysis of the factors for OS showed that the cut-off point of 20% had the highest HR in all of the cases. However, the cutoff point of 20% was only a significant factor for OS in the Luminal/HER2- subtype. There was no correlation between the Ki-67 index value and OS in any of the other subtypes. These data indicate that the optimal cut-off point of 20% is the most effective prognostic factor for Luminal/HER2- breast cancer.

Survival time according to the year of recurrence and subtype in recurrent breast cancer.

BACKGROUND: Survival for patients with recurrent breast cancer has improved over time due to the introduction of modern systemic therapy. The aim of this study was to determine the impact of subtype and the year of recurrence on the survival times of recurrent breast cancer. METHODS: Between 1979 and 2013, 813 patients who underwent initial treatment for primary breast cancer experienced recurrence. They were divided into two groups based on the year of recurrence; before 2000 and after 2001. Survival after recurrence was compared between these groups based on following criteria; subtypes, disease free interval (DFI), and dominant recurrent site. The median follow-up period after recurrence was 4.3 years. RESULTS: Survival improved significantly in the after 2001 group, and a significant improvement in survival was only seen in the HER2-enriched subtype. Multivariate analysis revealed that DFI, ER, HER2 status, dominant recurrent site and the Ki-67 index value were significant prognostic factors. In the HER2-enriched subtype, the year of recurrence, DFI and dominant recurrent site were significant independent factors. In the other subtypes, these factors were not correlated with survival. CONCLUSION: Our study revealed that the survival rate of patients with only the HER2-enriched subtype significantly improved after recurrence. To prolong the survival time after recurrence of both luminal and triple negative subtypes, the development of novel targeting therapies to overcome refractory recurrent breast cancer is extremely important.

Efficacy of intraoperative entire-circumferential frozen section analysis of lumpectomy margins during breast-conserving surgery for breast cancer.

BACKGROUND: Intraoperative frozen section analysis of the surgical margins during breast-conserving surgery (BCS) for breast cancer can reliably achieve clear surgical margins and prevent re-operations. The aim of this study was to assess intraoperative entire-circumferential frozen section analysis (IEFSA) of the lumpectomy margins during BCS. METHODS: A total of 1029 patients who underwent BCS with IEFSA between June 2007 and July 2013 were available for assessment. The inner surfaces of the shaved lumpectomy margins were examined as frozen sections during BCS. The margins were defined as positive when the cancer cells were present within 5 mm from the edge of the outermost margins of the specimens. RESULTS: Out of 1029 patients, 312 patients (30.3 %) had positive margins after the initial lumpectomy and underwent additional resections during BCS. Fourteen patients (1.4 %) underwent mastectomy following the results of additional resections during the first surgery. Of 1015 patients who completed BCS, 60 patients (5.9 %) were found to have positive margins in the final pathology. One patient (0.1 %) underwent re-operation after BCS while the residual diseases of the other 59 patients were judged to be minimal. Of the 312 patients who were judged to have positive margins after the initial lumpectomy with IEFSA, 53 patients (16.9 %) were found to have negative margins in the final pathology. At a median follow-up time of 54.1 months, one patient (0.1 %) had a recurrence of breast cancer in the preserved breast. CONCLUSION: IEFSA is useful for preventing the need for re-operation and local recurrence after BCS.

Prognostic significance of Ki-67 index value at the primary breast tumor in recurrent breast cancer.

The Ki-67 index value is a prognostic factor in primary breast cancer and is a proliferation marker that also distinguishes between luminal type A and type B breast cancer. Moreover, a change in Ki-67 index values due to treatment and recurrence is considered to be important in treating breast cancer. In this study, we investigated whether the baseline Ki-67 value in the primary tumor is useful as a prognostic factor following disease recurrence. Immunohistochemical analysis of the Ki-67 index was performed on 4,701 patients with primary breast cancer from 1987 until March, 2013. Among these patients, there were 666 consecutive cases exhibiting recurrence after primary surgery. The fraction of proliferating cells was based on a count of at least 500 tumor cells in the area including the hot spot. The Ki-67 values were divided into 3 groups, namely <20, ≥20 and ≥50%. The investigated items included estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), tumor size, nodal status for the primary tumor, recurrence site (soft tissue, bone and viscera) and disease-free interval (DFI). The Cox's proportional hazard model was used to perform univariate and multivariate analyses of the factors associated with overall survival (OS) following recurrence. The median follow-up period was 65.9 months in the surviving group. The median Ki-67 value at baseline was 20% in all the cases and 27% in the recurrent cases. The Ki-67 values were low (24%) in patients with bone metastasis and significantly higher in patients with liver or brain metastasis (38 and 55%, respectively). Moreover, DFI was found to be inversely correlated with the Ki-67 values. Univariate analysis was performed to identify the prognostic factors for OS after recurrence. The significant factors included tumor size, lymph node status, ER, PgR, DFI, recurrence site and Ki-67 index value. Among these factors, a multivariate analysis identified the Ki-67 index value in the primary tumor as an independent significant factor, particularly in luminal type tumors. The Ki-67 index value in the primary tumor was a significant prognostic factor for OS after disease recurrence. It is, therefore, important to take the Ki-67 index value into consideration for the treatment and follow-up of breast cancer patients.

Definition of p53 overexpression and its association with the clinicopathological features in luminal/HER2-negative breast cancer.

AIMS: A suitable cut-off value for p53 overexpression and its usefulness as a prognostic factor in luminal/HER2-negative breast cancer were evaluated. PATIENTS AND METHODS: A retrospective analysis of 1,987 patients with luminal/HER2-negative breast cancer who underwent surgery between 2001 and 2009 was performed. RESULTS: p53 expression ≥50% was present in 9% of the patients. Moreover, these patients had significantly lower estrogen/progesterone receptor-positive rates, higher Ki-67 values, larger tumors, disease-positive nodes, higher nuclear grade, and shorter disease-free survival than patients with p53 expression <50% (p<0.0001). Therefore, status of p53-positive cells ≥50% was classified as p53 overexpression. These findings indicate that p53 overexpression is associated with unfavorable characteristics and prognosis. CONCLUSION: The suitable cut-off value for p53 overexpression was determined to be 50%, and p53 overexpression appears to be a significant prognostic factor in patients with luminal/HER2-negative breast cancer.

Evaluation of factors related to late recurrence--later than 10 years after the initial treatment--in primary breast cancer.

BACKGROUND: Breast cancer is associated with a relatively good prognosis. Prognostic factors examined to date are related to early recurrence while those related to late recurrence and their countermeasures remain unclear. Therefore, we examined the factors related to late recurrence. PATIENTS AND METHODS: From January 1980 to August 2012, 4,774 patients who underwent primary treatment and estrogen (ER) and progesterone receptor (PgR) assessment were enrolled in this study. The patients were divided into two groups, those with a follow-up period <10 years and those without any recurrence at 10 years but who continued follow-up examinations. Recurrence occurred in 711 patients followed up for <10 years and in 51 patients for ≥10 years. RESULTS: The overall 10-year cumulative disease-free survival rate was 79.5%, and the recurrence rate at ≥10 years was 5.8%. A multivariate analysis revealed that the factors related to late recurrence were PgR positivity and positive nodes. This result differed from that for early recurrence in terms of ER/PgR, Ki-67 index and p53 overexpression. CONCLUSION: PgR positivity and lymph node metastases significantly correlated with late recurrence. Therefore, it is important to evaluate appropriate measures such as treatment period and treatment regimen for hormone-sensitive patients.

Central nervous system lymphoma newly developed 12 years after remission of an ocular adnexal lymphoma.

Recurrence of non-Hodgkin's lymphoma more than 5 years after the initial diagnosis is rare. When late relapse occurs, it is difficult to determine whether it is a true recurrence or a new lesion. We experienced a case of an 81-year-old woman who developed central nervous system (CNS) lymphoma 12 years after remission of ocular adnexal lymphoma. Both showed the histology of diffuse large B-cell lymphoma. To elucidate whether the CNS lymphoma was clonally related to the first lymphoma, rearrangement of the immunoglobulin heavy chain genes of each lymphoma was studied using a polymerase chain reaction-based method. The results revealed that the sizes of the amplified products of the rearranged regions from the two lymphomas were different. This suggested different clonal origins of the lymphomas. It is clinically important to determine the origin of a second neoplasm because patients with a clonally related second lymphoma are usually treated with more intensive regimens, while those with a clonally unrelated lymphoma receive standard first-line therapy. The present case shows that, in the case of recurrent non-Hodgkin's lymphoma, not only histological confirmation but also genetic assessment is important to clarify the origin of the second lymphoma.

Predictive significance of the proportion of ER-positive or PgR-positive tumor cells in response to neoadjuvant chemotherapy for operable HER2-negative breast cancer.

Estrogen receptor (ER) and progesterone receptor (PgR) status are predictive factors for the clinical and pathological response to neoadjuvant chemotherapy for operable breast cancer. However, it remains unclear as to how the proportion of ER-positive or PgR-positive tumor cells affects the response to neoadjuvant chemotherapy. We examined the correlation of the proportion of ER-positive or PgR-positive tumor cells with the clinical and pathological response to neoadjuvant chemotherapy for operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer. From April 2002 to October 2010, 103 patients received neoadjuvant chemotherapy containing epirubicin and taxane in our clinic. A clinical response was observed in 86 (83%) patients, and a pathological complete response (pCR) was observed in 16 (16%) patients. Fourteen (30%) of 46 patients with ER-negative tumors achieved pCR and 15 (26%) of 57 patients with PgR-negative tumors achieved pCR. Patients with more than 30% ER-positive tumor cells or more than 1% PgR-positive tumor cells did not achieve pCR. No significant correlation was observed between pCR and the menopausal status, tumor size, grade and Ki-67 expression. In univariate analysis, pCR was associated with the ER status (p=0.001), PgR status (p=0.0001) and chemotherapy regimens (p=0.03). Multivariate analysis revealed that ER and PgR status were significant factors for pCR, and patients with ER-negative tumors were 18.6 times more likely to achieve pCR than those with greater than or equal to 30% ER-positive tumor cells (p=0.006; 95% confidence interval 2.3-149.9). We demonstrated a predictive significance of the proportion of ER-positive or PgR-positive tumor cells in the response to neoadjuvant chemotherapy for operable HER2-negative breast cancer. ER-negativity (<1%) was a significant predictive factor for achieving pCR in multivariate analysis. Conversely, patients with more than 30% ER-positive tumor cells or more than 1% PgR-positive tumor cells may not achieve pCR.

Mucocele-like tumor associated with ductal carcinoma in situ diagnosed as mucinous carcinoma by fine-needle aspiration cytology: report of a case.

Mucocele-like tumors (MLTs) of the breast are rare, with only 11 cases reported from Japan and 35 cases from other countries. MLTs of the breast were first described by Rosen in 1986. They are believed to be related to atypical ductal hyperplasia, ductal carcinoma, or mucinous carcinoma. It is difficult to diagnose this tumor preoperatively, and especially difficult to differentiate between benign and malignant forms. We report a case of MLT associated with ductal carcinoma in situ, which was initially diagnosed as fibroadenoma by mammography and ultrasonography, and as mucinous carcinoma by fine-needle aspiration cytology. We discuss the characteristic findings of imaging and the appropriate clinical treatment of this tumor. The characteristic image first signals the possibility of this tumor, following which the diagnosis can be confirmed by pathological examination of a fully excised tumor specimen. Breast-conserving surgery is recommended because of the low risk of high-grade malignancy, even when malignancy is confirmed, and lymph node dissection may be avoided.

Clinical Significance of CK19 Negative Breast Cancer.

Analysis of sentinel lymph nodes (SLNs) by means of One-Step Nucleic Acid Amplification (OSNA) is gaining widespread use as a quick and accurate method. This assay detects the expression level of cytokeratin 19 (CK19) which is present in some but not all breast tumors. In this study, the clinical significance of negative CK19 was investigated in 219 cases of primary breast cancer. In 179 patients with clinically negative nodes, OSNA and imprint smear cytology of SLN were performed simultaneously. The OSNA revealed a node-positive rate of 24.6%. Negative CK19 correlated significantly with negative ER/PgR and higher Ki-67 values, and marginally with higher nuclear grade and p53 overexpression. The triple negative subtype showed lower CK19 expression. OSNA revealed that one of the negative CK19 cases was actually a false negative but this was corrected with the use of the imprint smear cytology. In conclusion, CK19 negativity reflected the aggressiveness of primary breast cancer. OSNA assay used to analyze SLN was useful, but there is a possibility that it will mistakenly detect false negatives in CK19 negative tumors. Therefore, in tumors with negative CK19, the imprint smear cytology may be more useful in cases with macrometastasis.