Search

An 85-year-old man with a history of aortic dissection suddenly fainted, underwent cardiac heart arrest, and died. An autopsy was performed, but the cause of death was not grossly identified. Congo red staining detected amyloid deposits in systemic organs, including the heart, lungs, liver, and kidneys. Immunohistochemical (IHC) analysis revealed immunoglobulin (Ig) λ light chain (-λ) in systemic blood vessels and transthyretin (TTR) in the heart and lungs. Ig-λ was predominantly positive in the blood vessels of the lungs, while TTR was detected in the alveolar septum. In the heart, Ig-λ was positive in the endocardium and blood vessels, and TTR was positive in nodular deposits between cardiomyocytes. The concurrent deposition of Ig-λ and TTR in the heart was further substantiated by laser microdissection (LMD)-liquid chromatography-tandem mass spectrometry (LC-MS/MS) at each deposition site. Despite systemic deposition of Ig-λ, bone marrow biopsy findings were not diagnostic for multiple myeloma. In summary, we present an autopsy case of concurrent Ig-λ and TTR deposition as revealed by IHC and LC-MS/MS. When Congo red staining and IHC results are indeterminate due to the deposition of multiple amyloid proteins, LMD-LC-MS/MS is useful for determining the precursor protein.

Histiocytic sarcoma is a relatively new disease category and the gastrointestinal origin is sporadic. We report a case of a 74-year-old woman who underwent chemotherapy and proximal gastrectomy for extremely rare, advanced gastric histiocytic sarcoma. The resected specimen was subjected to numerous immunostainings to meet the diagnostic criteria of histiocytic sarcoma and was positive for the histiocyte markers' cluster of differentiation 68 and lysozyme. The markers of Langerhans cells, follicular dendritic cells, and myelocyte were all negative. Six reports of surgical resection of histiocytic sarcoma originating in the stomach exist, including our case. We reviewed the clinical course and the histological and immunohistochemical diagnostic features of surgically resected gastric histiocytic sarcoma.

Background: Non-palpable breast lesions represent about 25-35% of all breast cancers diagnosed in developed countries, according to findings based on the evolution of imaging modalities such as MRI, and the uses reliable biopsy techniques such as ultrasound-guided or stereo-guided vacuum assisted biopsy. Wire -guided localization (WGL), radio-guided localization (RGL), and SAVI SCOUT localization (SSL) have been presented as a surgical procedure for non-palpable breast lesion. The reported disadvantages of WGL are related to mechanical stimulation of wire plucking, kinking, and patient discomfort. RGL has issues regarding radioactive licensing, handling, and waste management, and the SSL system requires high start-up costs. To eliminate these problems, we verified the magnetically guided localization (MGL) method for breast lesion localization by means of the combinations of the magnetic probe TAKUMI (ISO13485, Matrix cell Research Institute Inc., Tokyo, Japan) and the guiding-marker system® (Hakko, Tokyo, JAPAN). The TAKUMI is a novel handheld magnetic probe with a permanent magnet and a Hall magnetic sensor for detecting magnetic substances. It was newly developed at the University of Tokyo under a grant from the Japan Agency for Medical Research and Development (AMED). The aim of this study was to evaluate the feasibility and safety of our MGL system. Method: Patients were enrolled in this multi-center, open-label trial from January 2019 to March 2019 at two University Hospitals. The inclusion criteria were age 20 or older female patients who had non-palpable breast lesions, for which breast-conserving surgery or tumor resection was performed. Patients who had a metal allergy, pregnancy, or inflammatory breast cancer were excluded. The guiding-marker system® consists of a stainless-steel hook (φ 0.28 × 10 mm) connected with a nylon thread and an a 21-gauge 10 cm long steel needle.The marker was inserted into the center of the target lesions using ultrasound guidance or stereo guidance within 4 days before surgery. The TAKUMI was used to determine whether the guiding marker was detectable or not before, during, and after the surgical resection of the specimen. The resection rate of the guiding marker, surgical margin status, and re-operation rates were evaluated as the primary outcomes, and the volume and weight of the excised specimen were evaluated as secondary outcomes. The study protocol of the evaluation of magnetic probe system for detecting of non-palpable lesions of the breast was approved by the Institutional Review Board of Nippon Medical School Foundation (CRB3180001) and was registered at https://jrct.niph.go.jp/re (protocol record jRCTs032180422). Written informed consent was obtained from all participants. Results: Forty-one patients were recruited into this study. Thirty-eight patients (92.6%) underwent breast-conserving surgery for breast cancer treatment, and 3 (7.3%) underwent tumor resection for biopsy purposes. All guiding markers were resected during the initial surgical operation. Three out of 38 breast cancer patients (7.9%) were diagnosed as margin positive in frozen section analysis; 2 (5.2%) underwent additional resection during the initial surgery due to the positive margin, and 1 (2.6%) underwent subsequent surgery due to the positive margin on final pathology. Eight patients (21%) underwent boost radiation therapy due to the close margin ( Citation Format: Tomoko Kurita, Kanae Taruno, Seigo Nakamura, Hiroyuki Takei, Katsutoshi Enokido, Takashi Kuwayama, Yoko Kanada, Sadako Akashi, Maki Nakai, Meishi Hankyo, Keiko Yanagihara, Takashi Sakatani, Kentaro Sakamaki, Akihiko Kuwahata, Masaki Sekino, Moriaki Kusakabe. Magnetic guided localization for non-palpable breast lesion: A multi-center open-label trial in Japan [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-17.

Background Non-functioning parathyroid carcinoma is an extremely rare malignancy among endocrine tumors. We report a case in which non-functional oxyphilic parathyroid carcinoma was diagnosed from clinical symptoms and pathological diagnosis. Case presentation The patient was a 42-year-old man with no medical or family history of note. He had presented to a local hospital with a neck mass 2 months earlier. Medullary thyroid carcinoma was diagnosed and he was referred to our department. A 3.5-cm mass was observed in the left thyroid lobe. Laboratory data for thyroid functions, thyroglobulin, anti-thyroglobulin antibodies, anti-thyroid peroxidase antibodies, serum calcium, and parathyroid hormone (PTH) were all within normal ranges. Ultrasonography revealed a 40-mm irregular, hypoechoic mass throughout the left thyroid lobe. Follicular thyroid tumor was suspected from fine-needle aspiration cytology. Left lobectomy was performed. Pathological features revealed a thick fibrous capsule around the tumor, and a thick fibrous band was observed inside the tumor. Both capsular invasions and vascular invasions were observed. Tumor cells were eosinophilic and displayed solid growth. Immunohistochemically, tumor cells were negative for thyroid transcription factor-1, negative for thyroglobulin, negative for chromogranin A (positive for normal parathyroid tissue within the nodule), positive for PTH, and positive for parafibromin. Ki-67 labeling index was 10%. Based on these findings, non-functional oxyphilic parathyroid carcinoma was diagnosed. One and a half years postoperatively, calcium and PTH were within normal ranges, and he has shown no evidence of recurrence or metastasis. Conclusions Non-functioning oxyphilic parathyroid carcinoma is an extremely rare malignancy, and definitive diagnosis is difficult to obtain preoperatively. Few reports have been made worldwide, and information on the long-term prognosis is scarce. Long-term surveillance by imaging is mandatory, since no indices that can be used as a marker for postoperative recurrence and metastasis have been identified.

Aims: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799–0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74–0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. Conclusions: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

Adding taxane to an anthracycline-based regimen improves survival in node-positive breast cancer patients, as shown by clinical trials and meta-analyses. However, no studies have analyzed the number of metastatic lymph nodes in patients with estrogen receptor (ER)-positive cancer. This study investigated whether adding a taxane to an anthracycline-based regimen improved prognosis in node-positive, ER-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients in a real-world setting. Using Japanese Breast Cancer Society registry data, we compared disease-free survival (DFS) of patients with ER-positive, HER2-negative breast cancer, excluding those receiving neoadjuvant chemotherapy, between those who received an anthracycline-based regimen followed by a taxane-based regimen (A + T) and those who received only an anthracycline-based regimen (A w/o T), stratified by lymph node status. A Cox proportional hazards model was used to evaluate DFS in both groups. There were 4566 eligible patients with ER-positive, HER2-negative breast cancer. During the median follow-up period of 60 months, there were 481 recurrences and 149 deaths. There was no significant difference in DFS between the A + T and A w/o T groups among patients with 1–3 positive nodes, while there was a significant difference among patients with ≥ 4 positive nodes. In patients with ER-positive, HER2-negative breast cancer, adding taxane to an anthracycline regimen did not improve DFS in patients with metastasis in 1–3 lymph nodes. We considered that the group without the addition of taxane might be present in patients with ER-positive, HER2-negative lymph node metastases.

BACKGROUND A retrospective study of the real-world use of neoadjuvant endocrine therapy (NET) is important for standardizing the role of NET in breast cancer care. METHODS In a consecutive series of women with operable breast cancer who received NET for ≥28 days, associations of NET objectives, NET outcomes, adjuvant chemotherapy use after NET, and survival with clinicopathological factors were examined. RESULTS NET objectives were reduction in surgical extent in 49 patients, avoidance of surgery in 31, and treatment until scheduled surgery in 8. The mean duration of NET was 349.5 (range, 34-1,923), 869.8 (range, 36-4,859), and 55.8 (range, 39-113) days, respectively, in these cohorts (success rate: 79.6%, 64.5%, and 100%, respectively), and the differences were significant. Among patients in the former two cohorts, progression-free survival was significantly better in patients with stage 0 or I disease, ductal carcinoma in situ or invasive ductal carcinoma, ≥71% estrogen receptor (ER) positivity, and the surgical extent reduction cohort than the other counterparts. Postoperative chemotherapy use was significantly associated with lymph node metastasis, a high Ki67 labeling index, lymphovascular invasion, and a high preoperative endocrine prognostic index at the time of surgery after NET. Better recurrence-free survival after surgery was significantly associated with high ER expression after NET or high progesterone receptor expression before or after NET. CONCLUSIONS NET can help reduce surgical extent or avoid surgery in women with early breast cancer, ductal carcinoma, or high ER expression. NET may also aid in decisions related to postoperative systemic therapy to improve survival.

Background The caudal type homeobox 2 transcription factor (CDX2) is a specific and sensitive marker for intestinal carcinoma, but usually not expressed in breast cancer. In CDX2-positive metastatic cancer of occult primary, the origin is highly suspicious of an enteric carcinoma. Case presentation A 50-year-old woman complained of enlarged lymph nodes (LNs) in the right axilla. Mammography and ultrasonography scans showed no abnormal findings in her breasts. Core needle biopsy (CNB) revealed metastatic adenocarcinoma. Immunohistochemical staining was positive for CDX2 intensely. The primary tumor was suspicious of intestinal adenocarcinoma. A dynamic contrast-enhanced magnetic resonance imaging scan revealed an accentuated lesion which was detected using a second-look ultrasound, and diagnosed invasive ductal carcinoma by CNB. A partial mastectomy of the right breast with level I and II axillary LN dissection was performed. A few cells of primary cancer were expressed CDX2 and estrogen receptor. The final pathological diagnosis was T1bN3aM0 stage IIIC. The fluorescent double staining showed that CDX2 simultaneously expressed on the Ki67 positive cells of metastatic tumors. The adjuvant treatment included chemotherapy and radiation, followed by tamoxifen administration. The patient survived without any recurrences over the following 36 months. Conclusions We report a rare case of CDX2-positive metastatic breast cancer in the axillary LNs. As some literatures reported vitamin D pathways induced cancer cell apoptosis and inhibition, these metastatic cells of our case might play the effort of autoregulation of inhibiting progression.

Objective The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen’s criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists. Methods We held slide conferences, where photomicrographs of haematoxylin–eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics. Results In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753). Conclusion Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ.

Breast cancer survival outcomes vary across different ethnic groups. We clarified the differences in clinicopathological and survival characteristics of breast cancer among Japanese, US residents with Japanese origin (USJ), and US residents with other origins (USO). Using Surveillance, Epidemiology, and End Results (SEER) 18 dataset and Japanese Breast Cancer Society (JBCS) registry, we included patients first diagnosed with breast cancer between 2004 and 2015. We categorized the patients into three groups based on the database and the recorded ethnicity: Japanese (all those from the JBCS registry), USJ (those from SEER with ethnicity: Japanese), and USO (those from SEER with ethnicity other than Japanese). Excluding patients diagnosed after 2012, stage 0, and 4 patients, we examined the overall survival (OS) and breast cancer-specific survival (BCSS) using the Kaplan–Meier method and Cox proportional hazards models, adjusting for age, sex, cancer stage, and hormone receptor (HR) status. We identified 7362 USJ, 701,751 USO, and 503,013 Japanese breast cancer patients. The proportion of HR-positive breast cancer was the highest among USJ (71%). OS was significantly longer among Japanese and USJ than USO (Hazard ratio 0.46; 95% Confidence Interval [CI] 0.45–0.47 for Japanese and 0.66 [95% CI 0.59–0.74] for USJ) after adjusting for baseline covariates. BCSS was also significantly higher in the two groups (HR 0.53 [95% CI 0.51–0.55] for Japanese and 0.53 [95% CI 0.52–0.74] for USJ). In stage I–III breast cancer, Japanese and US residents with Japanese origin experienced significantly longer survival than US residents with non-Japanese origins.

Aim Infants with fetal growth restriction (FGR) are at an increased risk of perinatal morbidity and mortality. The long noncoding RNA H19 gene is expressed abundantly in placental villi and recent studies suggest that it regulates FGR. However, the role of H19 in the FGR placenta remains unclear. This study aimed to clarify the relationship between H19 expression and FGR using normotensive placentas after 34 weeks of gestation. Methods Formalin-fixed paraffin-embedded tissues from human placentas collected from pregnancies resulting in small for gestational age (SGA) and appropriate for gestational age (AGA) newborns were used. The histopathological features of placenta tissues, such as villous stromal fibrosis, the numbers of terminal villi, villous vessels and cytotrophoblasts were analyzed using hematoxylin and eosin, Masson's trichrome staining and immunostaining. The localization and expression of H19 in the placentas were demonstrated by in situ hybridization and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively. Moreover, the expression levels of H19-regulated molecules such as IGF2 and decorin (DCN) were measured by RT-qPCR. Results Histopathological features of the placental villous were not different between placentas associated with SGA and AGA. H19 localized to the villous stroma, endothelial cells and cytotrophoblasts. Moreover, the expression level of H19 in SGA placentas was significantly lower than that in AGA placentas. The expression levels of IGF2 and DCN in SGA placentas tended to be lower than those in AGA placentas similarly to H19. Conclusion This study highlights the potential importance of regulatory events mediated by H19 in SGA placentas without histopathological abnormalities in late pregnancy.

Programmed death-ligand 1 (PD-L1) expression on immune cells (ICs) is a predictive marker for PD-L1 checkpoint blockade in patients with triple-negative breast cancer (TNBC). However, the level of PD-L1 expression and the percentage of cells that are PD-L1+ are continuous variables not dichotomous variables for tumor-infiltrating lymphocytes (TILs) and other cells. Multiplexed immunohistochemistry was applied to 31 archived surgical specimens from untreated TNBC patients. TIL levels were visually scored, and CD8+ T cells and PD-L1+ ICs were quantified using an automated multispectral imaging system. PD-L1 expression was assessed within a multiplexed context (CD8 combined spectral composite). The mean value of stromal TILs (i.e., the percentage of the stromal area with a dese mononuclear infiltrate) was 20%. The frequency of patients with PD-L1-positive tumor cells (TC) and ICs was 38.7% and 32.2%, respectively, with a significant association between them. TIL levels were correlated with CD8+ T cell infiltration in the stroma (Spearman r = 0.795, p

Accurate pre-operative localization of nonpalpable lesions plays a pivotal role in guiding breast-conserving surgery (BCS). In this multicenter feasibility study, nonpalpable breast lesions were localized using a handheld magnetic probe (TAKUMI) and a magnetic marker (Guiding-Marker System®). The magnetic marker was preoperatively placed within the target lesion under ultrasound or stereo-guidance. Additionally, a dye was injected subcutaneously to indicate the extent of the tumor excision. Surgeons checked for the marker within the lesion using a magnetic probe. The magnetic probe could detect the guiding marker and accurately localize the target lesion intraoperatively. All patients with breast cancer underwent wide excision with a safety margin of ≥5 mm. The presence of the guiding-marker within the resected specimen was the primary outcome and the pathological margin status and re-excision rate were the secondary outcomes. Eighty-seven patients with nonpalpable lesions who underwent BCS, from January to March of 2019 and from January to July of 2020, were recruited. The magnetic marker was detected in all resected specimens. The surgical margin was positive only in 5/82 (6.1%) patients, these patients underwent re-excision. This feasibility study demonstrated that the magnetic guiding localization system is useful for the detection and excision of nonpalpable breast lesions.

An 82-year-old woman who had been suffering from repeated obstructive jaundice for 7 years was referred to our hospital. Although endoscopic aspiration of the mucin in the common bile duct had been temporally effective, origin of the mucin production had not been detectable. The patient thus had been forced to be on long-term follow-up without curative resection. Endoscopic retrograde cholangioscopy on admission revealed massive mucin in the common bile duct. In addition, an anomalous bile duct located proximal to the gallbladder was identified. Since the lumen of the anomalous duct was irregular and the rest of biliary tree was completely free of suspicious lesions, the anomalous duct was judged to be the primary site. Surgical resection of the segment 4 and 5 of the liver combined with the extrahepatic biliary tract was performed. Pathological diagnosis was compatible to intraductal papillary neoplasm with high-grade intraepithelial dysplasia of the anomalous bile duct. The patient has been free from the disease for 6.5 years after resection. This is the first case of intraductal papillary neoplasm derived from an anomalous bile duct, which was resected after long-term conservative treatment. The present case suggested the slow growing character of natural history of the neoplasm.

BACKGROUND AND OBJECTIVES Emerging evidence suggests that the presence of atypical mitoses is associated with poor prognosis in some types of cancer, but its clinical significance remains uncertain. Here, we investigated the occurrence of atypical mitoses in breast cancers. METHODS Mitotic figures, including normal and atypical mitoses, were assessed in resected histological sections from 109 patients with invasive carcinoma of no special type (ICNST). Comparisons with clinicopathological features and biomarkers such as Ki67 and phosphohistone H3 (PHH3) were performed. RESULTS The total number of mitotic figures, including atypical mitoses, was higher in situ and invasive ductal carcinoma components than in normal ducts. Morphological characteristics of atypical mitoses included multipolar, lagged, ring, asymmetrical mitoses, and anaphase bridge. Patients with higher total mitoses and PHH3, and the presence of atypical mitoses showed reduced overall survival (OS), compared to those with lower total mitoses and PHH3, and without atypical mitoses (P = 0.03, 0.02, and

Objectives: Evaluation of Intraductal Components (ICs) of breast cancer, such as ductal extension or segmental distribution, is essential before surgery. Evaluation is mainly performed using contrast-enhanced MRI as its sensitivity and detectability are superior to those of contrast-enhanced CT. Dual Energy CT (DECT) has been shown to have a high contrast enhancement effect with high resolution in soft tissues such as breast tissue. Thus, we assessed the utility of DECT for evaluating an IC of breast cancer. Methods: Fifty-five patients with a biopsy-proven breast cancer have undergone contrast-enhanced DECT and MRI for preoperative investigation. We compared the imaging findings of both modalities and correlated them with the pathological outcome. Results: Pathologically, an IC of breast cancer was identified in 26 patients. Existence of an IC was identified in 32 patients on DECT and 35 patients on MRI. The sensitivity, specificity and accuracy for detecting an IC were 76.9%, 58.6% and 67.3% with DECT and were 73.1%, 44.8%, and 58.2% with MRI, respectively. Conclusions: The appearance of ICs on DECT was highly correlated with the pathological outcome. The advantages of DECT include high detectability of an IC, clinically acceptable image quality, imaging in the face-up position (consistent with the surgical position) and simultaneous assessment of distant metastasis without radiation dose penalty. Thus, DECT is a useful supporting modality for the detection of an IC of breast cancer.

Breast carcinoma with osteoclast-like giant cells (OGCs) is a rare disease characterized by the infiltration of OGCs in the tumor; however, cytological aspects of this tumor type remain elusive. We examined the cytological features in fine needle aspiration (FNA) biopsy smears obtained from 5 patients who were histologically diagnosed with breast carcinoma with OGCs. We compared FNA and clinicopathological findings with results from the published literature. Histological assessment of the resected samples showed that all tumors exhibited a histological grade 1 phenotype with a predominant cribriform architecture. Four patients were estrogen receptor positive, and 1 patient showed a triple negative phenotype. All patients survived without tumor recurrence. In the FNA smears, tumor cells were arranged in loosely cohesive clusters, characterized by varying degrees of OGCs infiltration and rare formation of solid tumor nests. Occasionally, 2- or 3-dimensional clusters of tumor cells were found, accompanied by OGCs at the peripheral regions. In all patients, tumor cells were small without severe nuclear atypia. None of the patients showed significant background necrosis. In summary, cytological features of breast carcinoma with OGCs are characterized by loose aggregates of low grade tumor cells, the presence of OGCs, and the absence of necrosis, all of which were consistent with features reported previously. This peculiar form of breast tumors should be included in the differential diagnosis, when physicians encounter FNA findings including low grade ductal carcinoma with the admixture of multinucleated giant cells or OGCs.

Rosai-Dorfman disease (RDD) is a benign histiocytic proliferative disorder characterized by the accumulation of histiocytes in lymph nodes and various other organs. RDD seldom involves the central nervous system, and cases of purely intracranial RDD are particularly rare. We report a case of purely intracranial RDD involving the brainstem that was diagnosed at autopsy. A 68-year-old woman visited our hospital because of visual disturbances and loss of energy. Magnetic resonance imaging revealed an obscure mass in the brainstem. Despite exhaustive work-ups, the etiology of the intracranial mass remained unclear. The patient died of respiratory depression, and an autopsy was performed for pathological investigation. Macroscopically, a pink pale mass 2.5 cm in diameter was found in the brainstem, with no attachment to the dura. Histologically, it was composed of histiocytic cells with incorporation of small lymphocytes (emperipolesis). Immunohistochemical staining revealed that the cells were positive for CD68 and S100 and negative for CD1a, consistent with a diagnosis of RDD. Purely intracranial RDD is extremely rare and considered benign. To date, nine cases (including ours) have been reported. To our knowledge, this is the first case of intracranial RDD with autopsy. Although generally considered benign, RDD involving the brainstem might be lethal.

We hypothesized that a reduction in the size of the lymph nodes after neoadjuvant therapy for locally advanced rectal carcinoma would be associated with decreased lymph node metastases and/or a better prognosis. Between March 2006 and April 2012, 71 patients with primary rectal cancer received neoadjuvant chemoradiation therapy (CRT). For all lymph nodes 5 mm or larger in size, the major and minor axes were measured on CT scan images, and the product was calculated. The lymph node size was determined before and after CRT. The patients were divided into three groups based on the lymph node size before and after treatment. Group A exhibited a reduction in size of 60 % or more, Group B a reduction of less than 60 % and Group C had no lymph node enlargement before treatment. The incidence of lymph node metastases on pathological examination was 15 % in Group A and 50 % in Group B (p = 0.006). The five-year disease-free survival in Group A was 84 % compared with 78 % in Group B (log rank p = 0.34). The five-year overall survival in Group A was 92 % compared with 74 % in Group B (log rank p = 0.088). A reduction in the size of enlarged lymph nodes after neoadjuvant therapy may be a useful prognostic factor for recurrence and survival.

A lack of consistent methods to evaluate Ki67 expression is problematic in terms of accurately predicting prognosis in breast cancer. Accordingly, this study aimed to identify the causes of discrepancies in Ki67 labeling index measurements by different observers under different conditions using breast cancer samples.This Japanese study group compared and assessed immunohistochemical (IHC) analysis of the Ki67 labeling index when measured by different pathologists. Six pathologists (pathologists A-F) in Japan participated in this ring study. One hundred and ten surgical cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative invasive breast cancer treated in 2007 were identified from the breast cancer database of Tokai University Hospital and were included in this study.For all 6 pathologists, the Ki67 labeling index were significantly different between grade 3 and grade 1 cases and between grade 3 and grade 2 cases, whereas the index tended to be different between grade 1 and grade 2 cases. Further, the Ki67 labeling indexes measured by the 6 pathologists were strongly correlated (ρ: 0.73-0.88). The IHC scores recorded by pathologist A were in moderate to good agreement with those recorded by the others in patients with a Ki67 labeling index of13.25 % and in those with a Ki67 labeling index of13.25 % (κ = 0.429-0.660). The Ki67 low and high concordance rates between pathologist A and the others were 0.452-0.778 and 0.862-0.979, respectively. The most pertinent reason for discrepancy in scores seemed to be the selection of the area for counting and the quality of nuclear staining.The Ki67 labeling index measured by 6 pathologists without method standardization was in fair to good agreement. We plan to undertake a second ring study, pending recommendations by the international Ki67 panel.

Aims: (i) Determine whether between-observer reproducibility for Ki67 when assessed on whole sections according to a standardized scoring protocol is adequate for clinical application. (ii) Compare between-observer reproducibility of Ki67 scores assessed on hot-spots to scores using a global method that averages across a tissue section. Background: The nuclear proliferation biomarker Ki67 has multiple potential roles in breast cancer, including aiding decisions based on prognosis, but unacceptable levels of between-laboratory variability have been observed. The International Ki67 in Breast Cancer Working Group has undertaken a systematic program to determine whether Ki67 measurement can be analytically validated and standardized across labs. In phase 1, variability in visual interpretation was identified as an important source of variability. Phases 2 and 3a showed that adherence to defined scoring methods substantially improved reproducibility in scoring tissue microarrays and core-cut biopsies. We now assess whether acceptable reproducibility can be achieved on whole sections. Methods: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 to assemble 4 sets of 30 stained tumor sections, circulated around 23 labs in 12 countries. Ki67 was scored by 2 methods by all labs: (a) global: 4 fields of 100 tumor cells each were selected to reflect observed heterogeneity in nuclear staining (b) hot-spot: the field with highest Ki67 percentage of tumor cells with nuclear staining was selected and up to 500 cells scored. Ki67 scores were log2-transformed for statistical analyses and back-transformed for presentation. The primary objective was to assess whether either method could achieve an intraclass correlation coefficient (ICC) significantly greater than 0.8, considered substantial to almost-perfect reproducibility. Secondary objectives were to assess which method had highest observed ICC and to assess whether observers identified the same “hot-spots”. Results: ICC for the global method was 0.87 (95%CI: 0.799-0.93), marginally meeting the prespecified success criterion. The ICC for the hot-spot method was 0.83 (95%CI: 0.74-0.90) and had a CI extending below the success criterion. Across the 23 labs, geometric mean value of the 30 scores ranged from 8.5 to 19.6 for the global method and from 12.8 to 30.3 for the hot-spot method. The overall mean (95% CI) of these values was 12.9 (11.9-14.0) and 20.9 (19.1-22.8), respectively. Visually, between-laboratory agreement in location of selected hot-spot varies between cases. The median times for scoring were 9 and 6 minutes for global and hot-spot methods respectively. Conclusions: The global method marginally met the prespecified criterion of success; it should now be evaluated for clinical validity in appropriate cohorts of cases. The hot-spot method was observed to have slightly less reproducibility between labs. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between labs further. (Supported by a grant from the Breast Cancer Research Foundation) Citation Format: Nielsen TO, Leung SCY, Zabaglo LA, Arun I, Badve SS, Bane AL, Bartlet JMS, Borgquist S, Chang MC, Dodson A, Ehinger A, Fineberg S, Focke CM, Gao D, Gown AM, Gutierrez C, Hugh JC, Kos Z, Lænkholm A-V, Mastropasqua MG, Moriya T, Nofech-Mozes S, Osborne CK, Penault-Llorca FM, Piper T, Sakatani T, Salgado R, Starczynski J, Sugie T, van der Vegt B, Viale G, Hayes DF, McShane LM, Dowsett M. Analytical validation of a standardized scoring protocol for Ki67 assessed on breast excision whole sections: An international multicenter collaboration [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-03-01.

Rearranged during transfection (RET) fusions have been newly identified in approximately 1% of patients with primary lung tumors. However, patient-derived lung cancer cell lines harboring RET fusions have not yet been established or identified, and therefore, the effectiveness of an RET inhibitor on lung tumors with endogenous RET fusion has not yet been studied. In this study, we report identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line LC-2/ad. LC-2/ad showed distinctive sensitivity to the RET inhibitor, vandetanib, among 39 non–small lung cancer cell lines. The xenograft tumor of LC-2/ad showed cribriform acinar structures, a morphologic feature of primary RET fusion–positive lung adenocarcinomas. LC-2/ad cells could provide useful resources to analyze molecular functions of RET-fusion protein and its response to RET inhibitors.

The effectiveness of neoadjuvant chemotherapy is evaluated on the basis of pathological responses and survival outcome, because achievement of a pathological complete response (pCR) is a good predictor of long-term survival. However, few studies have assessed the survival of breast cancer patients who received neoadjuvant chemotherapy including trastuzumab. The records of 161 breast cancer patients who received neoadjuvant chemotherapy between January 2006 and December 2011 were retrospectively reviewed. The patients were categorized into 4 subgroups on the basis of the status of the estrogen receptor (ER), the progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). HER2-positive patients received trastuzumab-based regimens. Pathological responses and survival were analyzed on the basis of breast cancer subtypes. The pCR results obtained were: luminal A and B (ER and/or PR-positive, HER2-negative), 6.3 % (5/79 cases); luminal–HER2 hybrid (ER and/or PR-positive, HER2-positive), 25.0 % (5/20 cases); HER2-enriched (ER and PR-negative, HER2-positive), 63.0 % (17/27 cases); and triple-negative (ER and PR-negative, HER2-negative), 25.7 % (9/35 cases). Achievement of pCR was a good predictor of disease-free survival in the HER2-enriched group. Overall survival of patients with pCR was slightly, but not significantly, better in the HER2-enriched and triple-negative subgroups. Responses and survival after neoadjuvant chemotherapy including trastuzumab of patients with HER2-positive tumors differed among disease subtypes. Our findings suggest that disease subtype is an important determinant of the efficacy of neoadjuvant chemotherapy.

e24123Background: Standardized evaluation of TIL is currently based on the extent of lymphocytic infiltration into the tumor stroma for breast cancer. However, the distributions of subpopulations a...

Epstein-Barr virus (EBV) associated lymphoproliferative disease (LPD) comprises a wide spectrum of clinical and pathological features [1]. This variety is most systematically categorized in post-transplant lymphoproliferative disorders (PTLD) [2], in which subtypes are ordered according to disease progression from reactive polyclonal proliferation to large cell lymphoma. However, whether this categorization is applicable to LPDs other than PTLD is not well explored. Here, we present a nontransplant case of EBV-LPD that initially presented as a polyclonal self-limiting proliferation and later transited to large cell lymphoma. This transition was associated with the progression of lung cancer and its therapy. Our case demonstrates that stepwise progression of LPD is a feature that can be observed in non-PTLD cases of EBV-LPD.

Extranodal non-Hodgkin's lymphoma (NHL) is a rare breast disease. Here we report three cases of primary NHL of the breast. The first patient was a 29-year-old woman with a firm mass in her right breast with ipsilateral axillary lymphadenopathy. An excisional biopsy revealed NHLs. Clinical stage was IIAE. The tumor and enlarged lymph nodes had successfully been treated following the combination therapy. The second patient was a 70-year-old women with an elastic hard mass in her left breast. An excisional biopsy revealed NHLs and clinical stage was 1AE. The tumor disappeared following the combination therapy. The third patient was a 67-year-old women with a hard mass in her left breast. Core needle biopsy revealed NHLs and clinical stage was 1AE. The tumor disappeared following chemotherapy. All patients are alive with no evidence of recurrence 4-8 years after the initial treatment. Although a standard treatment has yet to be established, an initial treatment with combination therapy without surgical intervention including axillary dissection appears to be appropriate for this rare disease.

Objective Mucinous carcinoma (MCA) may show neuroendocrine differentiation (ND), but the cytological features characteristic of ND remains elusive. We compared fine needle aspiration (FNA) findings of MCA between cases with high and low degrees of ND. Methods Histological sections of 37 MCA cases were immunohistochemically evaluated for expression of chromogranin A and synaptophysin, and were graded as 0 to 3+ degrees of ND. They were divided into low ND (grade 0 and 1+) and high ND (grade 2+ and 3+) groups. Pre-operative FNA samples of each group were assessed for cytological features. Results The mean age of the high ND group (n = 18) was higher than the low ND group (n = 19, P = 0.01). In FNA samples of the high ND group, 17 cases showed moderate to severe degrees of discohesiveness, but low ND cases mainly showed no or only mild discohesiveness (P < 0.001). Nine of the low ND cases displayed overlapped, cohesive cell clusters, whereas, in the high ND cases, the cells were arranged in a loose, flat and monolayered pattern (P = 0.045). Fourteen of the high ND cases had round nuclei, but oval nuclei were predominant in the low ND cases (P = 0.027). The nuclei were eccentrically located in 12 of the high ND cases but were centrally located in 14 of the low ND cases (P = 0.01). Conclusions Mucinous carcinoma with high ND may be diagnosed by the presence of discohesiveness, a flat, monolayered pattern, and round or eccentrically located nuclei. Features of ND in carcinomas in other organs, such as intracytoplasmic granules and coarse chromatin, may not be reliable cytological features of ND in MCA.

Suppression of apoptosis is important for carcinogenesis and tumor growth. Recent studies revealed that survivin not only inhibited apoptosis but also accelerated cancer cell proliferative activity. To investigate the prognostic role of expression of the antiapoptosis gene, survivin, in hepatocellular carcinoma (HCC), the authors analyzed the correlation between the expression pattern of survivin messenger RNA (mRNA) and clinicopathologic findings of patients. Tissues were obtained by surgical resection of livers from 51 patients with HCC and 6 patients without HCC. Expression of survivin mRNA was evaluated using reverse transcription-polymerase chain reaction in 51 tumors, 51 adjacent histologically noncancerous livers, and 6 normal livers. Survivin protein expression was evaluated using Western blotting, and apoptotic cancer cells were detected by immunostaining with polyclonal rabbit anti-single-stranded DNA. Survivin mRNA expression was detected in 21 of 51 (41%) tumors, 2 of 51 (4%) noncancerous livers, and none of the 6 normal livers. Survivin mRNA expression did not correlate with tumor size or stage of HCC. Percentage of apoptotic cancer cells of 30 survivin mRNA-negative tumors (5.2 +/- 3.4%) was significantly higher than that of 21 survivin mRNA-positive tumors (2.2 +/- 2.3%, P = 0.0019). The disease-free 5-year survival rate of 21 patients positive for survivin mRNA (19%) was significantly poorer than that of 30 patients negative for survivin mRNA (39%, P = 0.0148). Survivin mRNA was detected in 57% (17/30) patients with HCC recurrence but in only 19% (4/21) of patients without recurrence (P = 0.0072). These results indicated that survivin mRNA expression could be used as an independent prognostic factor for patients with HCC after hepatectomy.

Multicystic mesothelioma is a well recognized but rare serosal tumor which mainly arises from the peritoneum in women and is considered as a benign lesion. This is the second case report of pericardial multicystic mesothelioma, which took a fatal clinical course. A 63-year-old man presented with pitting edema, shortness of breath, and hoarseness. Radiological investigations revealed solid and cystic tumor of the pericardium which was continuously extending into the mediastinum and the liver. Pericardial biopsy showed micro-cystic tumor lined by single layer of mesothelial cells without atypia, and the diagnosis was multicystic mesothelioma. Curative surgery could not be performed, and three years and four months later, the patient died because of the direct compression of the heart by the tumor. At autopsy, the tumor was found to be directly extending into the right pleural cavity and the right lung, besides the mediastinum and the liver. Neither malignant transformation nor metastatic tumor was identified.

Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference0.6 and Maximum Absolute Deviation from reference1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.

A 29-year-old woman was admitted to our hospital with fever and abdominal pain. Abdominal echogram and CT revealed intra-abdominal lymphadenopathy. Seven days after the onset, she developed cervical lymphadenitis. Kikuchi-Fujimoto’s disease (KFD) was diagnosed on cervical lymph node biopsy. Although KFD with intra-abdominal lymphadenopathy is rare, it should be considered in young adults with intra-abdominal lymphadenitis. Because KFD is a benign, self-limiting disease, we suggest the use of a minimally invasive method of diagnosis such as superficial lymph node biopsy.

Hepatitis B infection of a liver allograft can have serious consequences including a negative influence on the probability of survival. Therefore, there is a need for very effective antiviral therapy for transplant recipients. In this article the early experience with nucleoside analogue antiviral agents, both to prevent and to treat hepatitis B in liver allografts, is reviewed. There are several important characteristics of these agents that are already apparent. Ganciclovir and famciclovir have limited efficacy in treating infections when they are used alone. These compounds might be beneficial if used after resistance develops to other drugs or when used in combination with other agents. Lamivudine is effective for about two-thirds of patients in preventing and treating hepatitis B infection in allografts. Hepatitis B immune globulin (HBIg) is known to increase the efficacy of lamivudine in preventing infection. A large study to further characterize this combination therapy is being organized. Resistance to famciclovir and lamivudine can occur if they are used alone for a long time. In order to lower the incidence of drug resistance, it may be necessary to utilize combinations of nucleoside analogues.

BACKGROUND This study examined the effect of tegafur, a depot of 5-fluorouracil, in human colorectal carcinomas in terms of apoptosis, cell proliferation, and expression of p53 gene and angiogenesis-related molecules. METHODS A total of 32 patients with colorectal carcinoma were divided into 2 groups; 20 patients received tegafur suppositories (TS) at 1 g/day for 14 days before surgery, and 12 patients did not receive any chemotherapy. Surgically removed specimens were examined immunohistochemically for Ki-67, CD34, p53, p21, Bax, vascular endothelial growth factor (VEGF), and thymidine phosphorylase (dThdPase). Apoptotic tumor cells were visualized by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick-end labeling (TUNEL) procedure. RESULTS The mean percentage of apoptotic index (AI) was 6.9 ± 1.2 in the 20 TS-treated tumors and 4.4 ± 1.0 in the 12 nontreated tumors (P < 0.001). In contrast, the mean percentage of Ki-67 labeling index (KI) became significantly lower in the former group (P < 0.05). The frequency of p21 expression was significantly higher in the TS-treated group than in the nontreated group (P < 0.05), whereas no difference was detected in p53 and Bax expression between the two groups. The mean intratumoral microvessel density was 47.8 ± 19.8 in the TS-treated tumors and 66.8 ± 16.5 in the nontreated tumors (P < 0.01). The frequency of dThdPase expression, but not of VEGF expression, became significantly lower with the TS treatment. p53 expression did not correlate with AI, KI, IMV density, or the expression of VEGF, p21, or Bax, except for dThdPase, which was significantly higher in the 18 p53 positive tumors (P < 0.05). CONCLUSIONS Preoperative TS treatment enhances apoptosis and suppresses angiogenesis of colorectal carcinomas in a p53-independent manner. Cancer 2000;88:1007–15. © 2000 American Cancer Society.

In cases of pT3 gastric cancer, even when standard histological staining reveals no evidence of metastases in the regional lymph nodes, patients still may die of postoperative recurrence of the tumor. An attempt was made in the present study to explain the unfavorable outcome of such patients by investigating the presence of occult cancer cells in lymph nodes by immunostaining of cytokeratin. Methods. We examined 2310 lymph nodes that had been removed from 83 patients with stage II gastric cancer (pT3, N0, M0). Two consecutive sections of 4 μm thick were prepared for simultaneous staining with hematoxylin and eosin and immunostaining with the CAM 5.2 monoclonal antibody against cytokeratin, respectively. Results. Evidence of occult involvement was found in 299 of 2310 (13%) lymph nodes and in 54 of 83 (65%) patients with pT3 gastric cancer. An analysis of survival demonstrated the limited 5-year survival of patients with occult involvement in their resected lymph nodes, as compared with that of patients without involvement (P < 0.01). Moreover, the patients in whom group 2 lymph nodes had occult cancer cells had a significantly poorer prognosis than those in whom occult involvement was limited to group 1 lymph nodes (P < 0.05). Conclusions. The accuracy of predictions of prognosis of patients with pT3 gastric cancer should be greatly enhanced if cytokeratin-specific immunostaining is performed in conjunction with routine histopathological examination of lymph nodes.

An extremely rare case of gastric cancer metastasized to the bilateral breasts is reported. A 46-year-old woman was admitted to the hospital because of a left breast tumor and back pain. There was a previous history of undergoing a gastrectomy for gastric cancer [ow (-), aw (+), P0, H0, n2, t2. mp, infγ, ly2, v0, stage IIIa, cure. B] on October 29, 1993, when the histopathologic type was poorly differentiated adenocarcinoma. The patient became having the back pain and left breast tumor since around May, 1996 and a bone scintigraphy revealed remarkable bone metastasis. In June, an 8.6×7.6cm elastic hard mass infiltrating into the skin and nipple in the entire left breast and left axillary lymph node metastases were palpated, when no tumor was present in the right breast. In October a 5.8×5.6cm tumor was also palpated in the right breast. Neither needle aspiration biopsy cytology nor incisional biopsy of the left breast could differentiate between signet ring cell carcinoma arisen from the breast and metastasis from the gastric cancer. So a left modi-fied radical mastectomy was performed. Histopathologic exploration of the resected material offered a suspicion of breast metastasis of the gastric cancer. In making the definite diagnosis, paradoxical concanavalin A staining, HIK 1083 staining and galactose-oxydase-Shiff reaction which revealed the same positive reactions as the gastric cancer tissue showed were useful. She died of lung metastasis and carcinomatous pleuritis 5 months after the mastectomy.

Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81–0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999–0.93) and hot-spot methods (0.84; 95% CI: 0.77–0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples.

Summary A case of elastofibroma occurring in the sigmoid colon of a 69 year-old woman is reported. The woman presented for survey of her gastrointestinal tract. Colonoscopy disclosed two polyps in the sigmoid colon, one of which was clinically considered to be recurrent adenoma. Histologically, the lesion had characteristic eosinophilic fibers and globules, termed elastofibroma fibers with hematoxylin and eosin stain. In addition, these elastinophilic materials were digested by elastase. Histological evaluation confirmed the diagnosis of elastofibroma. Our case might suggest that it is the result of long-term fibrosis after previous endoscopic resection of a sigmoid colonic adenoma.

We experienced severe uterine hemorrhage in a patientwith chronic myelomonocytic leukemia (CMMoL) due touterine inWltration of leukemic cells and early-stage endo-metrial carcinoma (EA). A 35-year-old premenopausalfemale developed intermittent genital hemorrhage, and shewas diagnosed as having endometrioid adenocarcinoma byendometrial biopsy. Three months later, her WBC countgradually increased to 31.6£ 10