The Diagnostic Utility of IDH2 R172 Immunohistochemistry in Tall Cell Carcinoma With Reversed Polarity of the Breast.

Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic type of low-grade breast cancer, consisting of tall columnar cells with reversed nuclear polarity and characterized by frequent IDH2 mutations. We herein report 3 cases of TCCRP with sequencing analyses of the IDH2 gene and immunohistochemical examination using monoclonal antibodies (11C8B1) against IDH2 R172. IDH2 R172 mutations were detected in all 3 resected tumors (R172S in 2 tumors and R172T in 1 tumor), and the presence of these mutations was confirmed by IDH2 R172 immunohistochemistry. Tumor cells of TCCRP showed strong and diffuse staining for the antibody against IDH2 R172. In 1 case, tumor tissue from 2 core needle biopsy samples collected on different days were also immunohistochemically positive for IDH2 R172. These results indicate that IDH2 R172 immunohistochemistry is suitable for the detection of TCCRP in both resection and biopsy samples. In addition, a literature review revealed that R172S and R172T account for 76% of IDH2 mutations in TCCRP, suggesting that 11C8B1, which reacts with R172S and R172T, was likely most sensitive for IDH2 -mutated TCCRP among many available antibodies for IDH2 R172. Furthermore, the combination of 2 or more antibodies against IDH2 R172 could be more effective for detecting TCCRP mutation. However, it is important to note that IDH2 R172 immunohistochemistry is not absolute, because IDH2 wild type is found in a small proportion (10%) of cases, and a few cases of IDH2 -mutated TCCRP may harbor rare subtypes of R172 that are not covered by available antibodies.

Important cytological findings for distinction between follicular variant and conventional papillary thyroid carcinoma, including noninvasive follicular thyroid tumors with papillary-like nuclear features.

We studied cytological specimens of conventional papillary thyroid carcinoma (PTC), follicular variant papillary thyroid carcinoma (FVPTC), and noninvasive follicular thyroid tumor with papillary-like nuclear features (NIFTP) (formerly noninvasive FVPTC) to identify useful cytological parameters for their differentiation. Cytological findings of invasive FVPTC and NIFTP were very similar to each other but differed from those of conventional PTC. Intranuclear cytoplasmic inclusions, true papillary cell clusters, monolayered cell sheets, ropy colloids, multinucleate giant cells, psammoma bodies, and cystic background were the observed characteristic features of conventional PTC. Microfollicular cell clusters and dense globules of colloids were characteristic features of invasive FVPTC and NIFTP. Scoring the eight parameters (intranuclear cytoplasmic inclusions, nuclear grooves, powdery chromatin, true papillary cell clusters, ropy colloids, multinucleate giant cells, psammoma bodies, and cystic background) readily distinguished NIFTP from conventional PTC, but could not distinguish NIFTP from invasive FVPTC. The average total score of NIFTP, invasive FVPTC, and conventional PTC were 2.60 ± 0.55, 2.63 ± 0.62, and 4.57 ± 0.99, respectively. The difference between conventional PTC and NIFTP or invasive FVPTC was statistically significant (p < 0.001, Student's t-test). Individuals with more than three of the identified parameters likely harbor conventional PTC, rather than NIFTP. In this way, 87.5% (112/128) of conventional PTCs could be differentiated from NIFTP, and definitively diagnosed as malignant by cytology.

Diagnostic accuracy of fine-needle aspiration cytology of the breast in Japan: report from the Working Group on the Accuracy of Breast Fine-Needle Aspiration Cytology of the Japanese Society of Clinical Cytology.

The Working Group of the Japanese Society of Clinical Cytology was assembled to assess the current status of breast cytology in Japan by conducting a large-scale survey regarding the accuracy of fine-needle aspiration biopsy (FNAB) in Japan. We collected data and investigated the status of breast cytological diagnosis at 12 different cooperating facilities in Japan, and re-evaluated their false-negative and false-positive cases. Among 30,535 individuals who underwent a breast cytological examination, analyses were conducted on 10,890 individuals (35.7%) in whom cytological diagnoses were confirmed by histology. Among these patients, the cytological diagnosis had an inadequate rate of 17.7%, an indeterminate rate of 7.8%, a positive predictive value of 'malignancy suspected' cells of 92.4%, an absolute sensitivity of 76.7%, a complete sensitivity of 96.7%, a specificity of 84.3%, a positive predictive value of 'malignant' cells of 99.5%, a false-negative value of 3.31%, a false-positive value of 0.25% and an accuracy rate of 88.0%. Subsequently, 297 false-negative and 23 false-positive cases were re-evaluated and several factors were characterized (i.e. histological type, tumor size and misread points). This survey collected data from a large number of cases for breast FNAB. Based on our survey, the accuracy of FNAB in Japan was relatively high compared with the goal of assessment of diagnostic accuracy. However, there were some false-negative and false-positive cases. Improvements in accuracy resulting from the learning points in the present study will lead to more useful and reliable diagnostic tools in clinical practice.

Evaluation of inadequate, indeterminate, false-negative and false-positive cases in cytological examination for breast cancer according to histological type.

BACKGROUND: We previously investigated the current status of breast cytology cancer screening at seven institutes in our area of southern Fukuoka Prefecture, and found some differences in diagnostic accuracy among the institutions. In the present study, we evaluated the cases involved and noted possible reasons for their original cytological classification as inadequate, indeterminate, false-negative and false-positive according to histological type. METHODS: We evaluated the histological findings in 5693 individuals who underwent cytological examination for breast cancer (including inadequate, indeterminate, false-negative and false-positive cases), to determine the most common histological types and/or features in these settings and the usefulness/limitations of cytological examination for the diagnosis of breast cancer. RESULTS: Among 1152 cytologically inadequate cases, histology revealed that 75/173 (43.6%) cases were benign, including mastopathy (fibrocystic disease) in 38.6%, fibroadenoma in 24.0% and papilloma in 5.3%. Ninety-five of 173 (54.9%) cases were histologically malignant, with scirrhous growing type, invasive ductal carcinoma (SIDC) being significantly more frequent (49.5%) than papillotubular growing type (Papi-tub) (P < 0.0001), solid-tubular growing type (P = 0.0001) and ductal carcinoma in situ (DCIS) (P = 0.0001). Among 458 indeterminate cases, 54/139 (38.8%) were histologically benign (mastopathy, 30.0%; fibroadenoma, 27.8%; papilloma, 26.0%) and 73/139 (52.5%) were malignant, with SIDC being the most frequent malignant tumor (37.0%). Among 52 false-negative cases, SIDC was significantly more frequent (42.3%) than DCIS (P = 0.0049) and Papi-tub (P = 0.001). There were three false-positive cases, with one each of fibroadenoma, epidermal cyst and papilloma. CONCLUSIONS: The inadequate, indeterminate, false-negative and false-positive cases showed similar histological types, notably SIDC for malignant tumors, and mastopathy, fibroadenoma and papilloma for benign cases. We need to pay particular attention to the collection and assessment of aspirates for these histological types of breast disease. In particular, several inadequate, indeterminate and false-negative cases with samples collected by aspiration were diagnosed as SIDC. These findings should encourage the use of needle biopsy rather than aspiration when this histological type is identified on imaging. Namely, good communication between clinicians and pathological staff, and triple assessment (i.e., clinical, pathological and radiological assessment), are important for accurate diagnosis of aspiration samples. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7349809170055423.

Comparison of the accuracy of breast cytological diagnosis at seven institutions in southern Fukuoka Prefecture, Japan.

OBJECTIVE: Cytological examination is inexpensive and relatively simple to carry out and deserves utilization in breast cancer screening. We investigated the status of cytological diagnosis at seven facilities in southern Fukuoka Prefecture, Japan. METHODS: We collected data on the criteria for cytological judgments and status of breast cytological diagnosis at seven different facilities in this region. RESULTS: Among 5693 individuals who underwent breast cytological examination, analyses were conducted on 1250 individuals (22.0%) in whom cytological diagnoses were confirmed by histological diagnoses. Among these patients, cytological diagnosis had an absolute sensitivity of 71.9%, a specificity of 76.0%, a false-negative value of 6.7% and a false-positive value of 0.08%. At three facilities with relatively large numbers of cases (>300), excluding a facility for specialized breast disease, similar trends of high complete sensitivity (94.3, 95.6 and 97.1%, respectively) and low absolute sensitivity (60.4, 74.8 and 57.2%, respectively) were found. No false-negative or false-positive cases were seen in individual facilities with relatively low numbers of cases (<150). CONCLUSIONS: The accuracy of cytological diagnosis at the facilities we surveyed was relatively high compared with the goals of assessment of diagnostic accuracy. However, the performance was dependent on the facility type, i.e. number of cases, staff involved and whether it was specialized or not, making the diagnosis specific for this region. We recommend that management of the accuracy of cytological diagnosis be undertaken jointly by multiple facilities to establish systems in Japan that lead to more useful diagnostic tools.

Diagnostic utility of EUS-guided FNA in patients with gastric submucosal tumors.

BACKGROUND: Submucosal tumors (SMTs) comprise both benign and malignant lesions, and most of the gastric lesions tend to be malignant. The addition of EUS-guided FNA (EUS-FNA) has the potential to improve this distinction, but published series are limited. OBJECTIVE: To evaluate the yield of EUS-FNA in gastric SMTs with referral to a criterion standard final diagnosis. DESIGN: Retrospective study. SETTING: Tertiary-care referral center. PATIENTS: This study involved 141 consecutive patients with gastric SMTs, who underwent EUS-FNA from January 2000 to December 2008. Immunohistochemical staining with c-kit, CD34, actin, and S-100 antibodies was done if a spindle cell tumor was found. Based on FNA sample adequacy, and whether a specific diagnosis could be established, EUS-FNA results were categorized as diagnostic, suggestive, or nondiagnostic. The criterion standards for final diagnosis were the surgical histopathological results or the follow-up course for malignant, inoperable cases. INTERVENTION: EUS-FNA. MAIN OUTCOME MEASUREMENTS: Diagnostic yield of EUS-FNA and factors related to sampling adequacy for cytological and immunohistochemical evaluation. RESULTS: A total of 141 patients (52% female, mean age 56.7 years) underwent EUS-FNA (range 1-5 passes). The overall results of EUS-FNA were diagnostic, suggestive, and nondiagnostic in 43.3%, 39%, and 17.7% of cases, respectively. Adequate specimens were obtained in 83% of cases, and 69 cases (48.9%) had a definitive final diagnosis. The most common gastric SMT was GI stromal tumor (59.5%). EUS-FNA results were 95.6% accurate (95% confidence interval [CI], 87.5%-99%) for the final diagnosis and 94.2% (95% CI, 85.6%-98.1%) accurate for differentiating potentially malignant lesions. A heterogeneous echo pattern was the only independent predictor for sampling adequacy (adjusted odds ratio 6.15; P = .002). There were no procedure-related complications. LIMITATIONS: Possibility of selection bias. CONCLUSION: EUS-FNA is an accurate method for diagnosis of gastric SMTs and for differentiating malignant lesions.

Usefulness of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for undiagnosed intra-abdominal lymphadenopathy.

BACKGROUND: The differentiation between benign and malignant abdominal lymph nodes is difficult, especially if no primary site is evident or if cancer resection was remote in time. The aim of this study was to evaluate the yield of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in patients with undiagnosed intra-abdominal lymphadenopathy. METHODS: Fifty-seven consecutive patients with undiagnosed abdominal lymphadenopathy who were registered in our EUS-FNA database from January 1997 to December 2007 were reviewed. EUS-FNA was carried out using a 22-G needle. The final pathological diagnosis was based on the cytopathological, histological, and immunohistochemical (IHC) findings. RESULTS: Adequate specimens were obtained in 93% cases. The final diagnoses included local recurrence of malignancy after resection (n = 16), lymphoma (n = 12), and benign/reactive changes (n = 17). The sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy of EUS-FNA were 94, 100, 100, 90 and 96%, respectively. In addition, it was also possible to classify lymphoma subtypes in 83% of cases. No complications occurred during the procedures. CONCLUSIONS: EUS-FNA is clinically very useful for establishing the diagnosis of abdominal lymphadenopathy of unknown cause and can provide sufficient tissue for IHC and subtyping of lymphomas.

Rare pancreatic neoplasms: the utility of endoscopic ultrasound-guided fine-needle aspiration-a large single center study.

BACKGROUND: Tumors other than ductal adenocarcinomas constitute 10%-15% of all pancreatic tumors. We describe the performance and pitfalls of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for diagnosis of these rare pancreatic tumors and their characteristic cytopathological features. METHODS: The records of 455 pancreatic fine-needle aspiration procedures done between March 1997 and August 2006 at Aichi Cancer Center, Nagoya, Japan, were reviewed. Besides cytology, aspirated material was routinely submitted in formalin for cell-block analysis. The reference standard for final diagnosis was surgical pathology from resected specimens. RESULTS: Twenty-eight rare (nonductal adenocarcinomas) pancreatic tumors were identified. Overall, EUS-FNA with the results of cytology, cell-block processing, and immunohistochemistry could correctly diagnose the type of neoplasm in 19 (67.9%) cases. EUS-FNA could distinguish benign from malignant rare tumors with a sensitivity of 69.2%, a specificity of 100%, positive predictive value of 100%, negative predictive value of 79.0%, and accuracy of 85.7%. None of three malignant pancreatic endocrine neoplasms could be diagnosed as malignant. An adequate core tissue sample could be obtained in 21 cases (75.0%) and provide a histopathological diagnosis in 19 (67.9%) cases. EUS-FNA could change the presumptive diagnosis in 11 (39.3%) cases. Specific immunochemical studies were useful adjuncts to the diagnosis. No major or minor complication was noted in any patient. CONCLUSIONS: Pancreatic neoplasms other than ductal adenocarcinomas have diverse imaging and histopathological features. EUS-FNA is accurate and safe for their identification.

Immunocytochemical detection using CDX2: An aid for discerning tumor involvement in ascites cytology.

BACKGROUND: Although ascites cytology is important for therapeutic strategies, it is difficult to distinguish cancer infiltration from reactive mesothelial proliferation in some patients. In this study, the authors applied CDX2 immunocytochemistry to improve diagnostic accuracy. METHODS: The authors examined the distribution of CDX2 expression in carcinoma specimens using paraffin-embedded tissues from various organs from 549 cancer patients. CDX2 immunostaining was applied to the 116 ascites specimens. RESULTS: CDX2 expression was detected in a restricted range of cancers, with the vast majority of them originating from the gastrointestinal tract and pancreas. When applied to ascites specimens, no positive reactions were detected in any of the 81 cytology-negative and molecular genetic analysis-negative specimens. By contrast, 28 of 35 specimens diagnosed as suspicious for malignancy or malignancy showed a positive reaction. Furthermore, the authors found that a nuclear-positive reaction was easily evaluated, even with a high level of background staining, and single cancer cells in 10(6) normal cells could be detected. CONCLUSION: Results suggest that CDX2 is a specific and sensitive marker to detect gastrointestinal and pancreatic malignancies in ascites cytology.

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB): past, present, and future.

Endoscopic ultrasound (EUS) is a combination of endoscopy and intraluminal ultrasonography. EUS also enables ultrasonographic images of high resolution to be obtained. However, whether a lesion is malignant or benign cannot be diagnosed solely from the findings of EUS. Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) was developed to enhance the diagnostic capabilities of EUS by providing additional pathological findings. Though more than 10 years have passed since EUS-FNAB was first used for pancreatic disease, EUS FNAB has not been widely accepted in Japan. This may be due to the technical difficulties, relatively low sensitivity for the detection of malignancies, and Japanese gastroenterologists' and surgeons' inherent conservative way of thinking. We describe here a short history of EUS-FNAB, with details of technical tips, current indications and contraindications, diagnostic accuracy, and complications. The clinical utility of EUS-FNAB has been gradually understood and EUS-FNAB procedures have been increasing in number in Japan. So in the near future, EUS followed by EUS-FNAB will be routinely performed in the same manner as gastrointestinal endoscopy, followed by biopsy under direct vision. Also, therapeutic EUS procedures, such as EUS-guided celiac plexus neurolysis, pancreatic tumor ablation, drainage of pancreatic pseudocysts, and the development of an anastomosis may become feasible as less invasive and safer techniques than those used at present.

Differential diagnosis of pancreatic cancer and focal pancreatitis by using EUS-guided FNA.

BACKGROUND: Despite advances in diagnostic imaging techniques, the differentiation between pancreatic cancer and focal pancreatitis remains difficult. This study evaluated the effectiveness of EUS-guided FNA in the differential diagnosis between pancreatic cancer and focal pancreatitis, with particular reference to detection of the K-ras point mutation. METHODS: The study included 62 consecutive patients with pancreatic ductal cancer and 15 patients with focal pancreatitis demonstrated as a pancreatic mass lesion by EUS. RESULTS: Sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of cytopathologic diagnosis were 82%, 100%, 86%, 100%, and 58%, respectively. Sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of histopathologic diagnosis were 44%, 100%, 55%, 100%, and 32%, respectively. The K-ras point mutation was found in 74% of pancreatic cancers and 0% of focal pancreatitis lesions. No complication of EUS-guided FNA was observed. CONCLUSIONS: EUS-guided FNA is useful for the differential diagnosis of pancreatic mass lesions caused by pancreatic cancer and focal pancreatitis. Analysis for the K-ras point mutation in specimens obtained by EUS-guided FNA may enhance diagnostic accuracy in indeterminate cases.

Endoscopic ultrasound-guided fine-needle aspiration biopsy for the diagnosis of gastrointestinal stromal tumors in the stomach.

BACKGROUND: For the diagnosis of gastric submucosal tumors (SMTs), endoscopic ultrasound (EUS) alone does not reveal the complete pathology, such as the degree of malignancy, and EUS-guided fine-needle aspiration biopsy (EUS-FNAB) has been reported to be more useful. Recently, most cases initially diagnosed as leiomyosarcomas have received further study with immunohistochemical staining and have been given the new diagnosis of gastrointestinal stromal tumors (GISTs). The degree of malignancy of GISTs differs widely in clinical aspects. In this study, we examined whether EUS-FNAB was useful in diagnosing GISTs and differentiating their degrees of malignancy. METHODS: From January 1997 to March 2002, 21 cases of gastric GISTs were diagnosed from the immunohistochemical staining of specimens resected at Aichi Cancer Center Hospital. Of these 21 patients, 14 (5 with high-grade malignancy and 9 with low-grade malignancy) underwent EUS-FNAB preoperatively, and were examined further: their EUS-FNAB specimens were submitted for additional immunohistochemical testing. RESULTS: The EUS-FNAB specimens from all patients were positive for c-kit and CD34 immunohistochemical testing, coinciding with the staining results of the resected specimens. The MIB-1 labeling indices in specimens of high-grade malignancy were significantly higher than those of low-grade malignancy. If we assumed that a tumor with an MIB-1 labeling index of more than 5% was a high-grade malignancy, the diagnostic accuracy was 85.7%. CONCLUSIONS: The EUS-FNAB procedure is a useful tool for diagnosing GISTs of the stomach with immunohistochemical staining. When used with MIB-1 staining, the procedure may indicate GIST prognosis and influence decisions regarding therapeutic strategies.

HBME-1 immunostaining in thyroid tumors especially in follicular neoplasm.

It is generally known that even with permanent sections, the differential diagnosis between follicular adenoma and follicular carcinoma is often difficult to determine. It is not unusual to encounter patients diagnosed with benign follicular adenoma whose diagnoses have to be changed to malignancies because of recurrence or metastasis. As the monoclonal antibody HBME-1 produced by mesothelioma cells has been shown to have reactivity in thyroid carcinomas, we investigated the diagnostic usefulness of HBME-1 in follicular neoplasms. Immunohistochemical staining for HBME-1 was performed on 205 various thyroid tumors using the labeled streptavadin biotin peroxidase method. When hematoxylin-eosin (HE) staining was performed again for this study and all cases were examined in accordance with the WHO Histological Classifications 2nd Edition, 87.2% (54/62) of adenomatous goiter and 72.6% (45/62) of follicular adenoma were negative. On the other hand, 84.6% (33/39) of follicular carcinoma and 97.2% (35/36) of papillary carcinoma were positive. All anaplastic (2/2) and medullary (4/4) carcinoma were negative. Examination in follicular neoplasms had a sensitivity of 84.6%, specificity of 72.6%, positive predictive value of 66.0% and overall accuracy of 77.2%. Among the cases treated as follicular adenoma clinically, the diagnosis of 13 cases was changed to follicular carcinoma, and 6 cases to papillary carcinoma for this study. These cases showed strong HBME-1 positivity. Two of the follicular carcinoma cases experienced recurrence. We conclude that immunohistochemical staining with HBME-1 may be useful clinically to pick out cases with a high risk of recurrence in follicular carcinoma, and that benign adenoma cases need close follow-up.