Dataset for reporting of the invasive carcinoma of the breast: recommendations from the International Collaboration on Cancer Reporting (ICCR).

BACKGROUND AND OBJECTIVES: Current national or regional guidelines for the pathology reporting on invasive breast cancer differ in certain aspects, resulting in divergent reporting practice and a lack of comparability of data. Here we report on a new international dataset for the pathology reporting of resection specimens with invasive cancer of the breast. The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organizations. METHODS AND RESULTS: The established ICCR process for dataset development was followed. An international expert panel consisting of breast pathologists, a surgeon, and an oncologist prepared a draft set of core and noncore data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalized and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for invasive cancer of the breast is intended to promote high-quality, standardized pathology reporting. Its widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve the management of invasive breast cancer patients.

A dedicated structured data set for reporting of invasive carcinoma of the breast in the setting of neoadjuvant therapy: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: The International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organisations, is an initiative aimed at providing a unified international approach to reporting cancer. ICCR recently published new data sets for the reporting of invasive breast carcinoma, surgically removed lymph nodes for breast tumours and ductal carcinoma in situ, variants of lobular carcinoma in situ and low-grade lesions. The data set in this paper addresses the neoadjuvant setting. The aim is to promote high-quality, standardised reporting of tumour response and residual disease after neoadjuvant treatment that can be used for subsequent management decisions for each patient. METHODS: The ICCR convened expert panels of breast pathologists with a representative surgeon and oncologist to critically review and discuss current evidence. Feedback from the international public consultation was critical in the development of this data set. RESULTS: The expert panel concluded that a dedicated data set was required for reporting of breast specimens post-neoadjuvant therapy with inclusion of data elements specific to the neoadjuvant setting as core or non-core elements. This data set proposes a practical approach for handling and reporting breast resection specimens following neoadjuvant therapy. The comments for each data element clarify terminology, discuss available evidence and highlight areas with limited evidence that need further study. This data set overlaps with, and should be used in conjunction with, the data sets for the reporting of invasive breast carcinoma and surgically removed lymph nodes from patients with breast tumours, as appropriate. Key issues specific to the neoadjuvant setting are included in this paper. The entire data set is freely available on the ICCR website. CONCLUSIONS: High-quality, standardised reporting of tumour response and residual disease after neoadjuvant treatment are critical for subsequent management decisions for each patient.

Pancreatic ductal adenocarcinoma with acinar-to-ductal metaplasia-like cancer cells shows increased cellular proliferation.

BACKGROUND/OBJECTIVES: Acinar-to-ductal metaplasia (ADM) has been shown to contribute to the development of pancreatic ductal adenocarcinoma (PDAC) in genetically engineered mouse models, but little is known about whether acinar cell plasticity contributes to carcinogenesis in human PDAC. We aimed to assess whether cancer cells that stain positive for amylase and CK19 (ADM-like cancer cells) are present in human resected PDAC and to investigate their role in tumor progression. METHODS: We immunohistochemically investigated the presence of ADM-like cancer cells, and compared the clinical and histological parameters of PDAC patients with and without ADM-like cancer cells. RESULTS: ADM-like cancer cells were detected in 16 of 60 (26.7%) PDAC specimens. Positive staining for anterior gradient protein 2 (AGR2) was observed in 14 of 16 (87.5%) PDAC specimens with ADM-like cancer cells. On the other hand, the intensity of AGR2 expression (negative, low/moderate or high) was lower in PDAC with ADM-like cancer cells (9/7) than in PDAC without these cells (11/33) (P = 0.032). The presence of ADM-like cancer cells was significantly correlated with increased cell proliferation (P = 0.012) and tended to be associated with MUC1 expression (P = 0.067). CONCLUSIONS: These results indicated that acinar cells may act as the origin of human PDAC, and that their presence may be useful for the stratification of human PDAC to predict prognosis.

Evaluation of the one-step nucleic acid amplification assay for detecting lymph node metastasis in patients with cervical and endometrial cancer: A multicenter prospective study.

OBJECTIVE: This multicenter study aimed to evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay in diagnosing lymph node metastasis (LNM) in patients with cervical and endometrial cancers. METHODS: Surgically removed LNs from patients with cervical and endometrial cancer were sectioned at 2-mm intervals along the short axis direction and alternately examined using the OSNA assay and conventional histopathological examination. Ultrastaging (200-µm LN sections) was performed for metastatic LNs using hematoxylin and eosin staining and immunostaining with an anti-CK19 antibody in cases where the OSNA assay and histopathological examination (performed using 2-mm LN sections) results showed discordance. RESULTS: A total of 437 LNs from 133 patients were included; 61 patients (14%) showed metastasis by histopathological examination, with a concordance rate of 0.979 (95% confidence interval [CI]: 0.961-0.991) with the OSNA assay. The sensitivity and specificity of the OSNA assay were 0.918 (95% CI: 0.819-0.973) and 0.989 (95% CI: 0.973-0.997), respectively. Discordance between the two methods was observed in nine LNs (2.1%), and allocation bias of metastatic foci was identified as the major cause of discordance. CONCLUSIONS: The OSNA assay showed equally accurate detection of LN metastasis as the histopathological examination. We suggest that the OSNA assay may be a useful tool for the rapid intraoperative diagnosis of LN metastasis in patients with cervical and endometrial cancers.

An extremely rare case of nonfunctioning parathyroid carcinoma occurring in a parathyroid adenoma.

A 53-year-old woman with a 4-month history of fatigue and somnolence was referred to her local doctor because of the worsening of her symptoms. Marked increases in her serum calcium (13.0 mg/dl) and intact-parathyroid hormone (175 pg/ml) were found, she was referred to our hospital. On physical examination, there was a palpable 3 cm mass in her right neck. Ultrasonography showed a 1.9 × 3.6 cm circumscribed hypoechoic lesion in the caudal right lobe of the thyroid gland. There was very mild 99mTc-sestamibi scintigraphic accumulation. Her preoperative diagnosis was primary hyperparathyroidism due to parathyroid carcinoma, and surgery was performed. The tumor weighed 6300 mg and did not invade the surrounding area. The pathology showed a mixture of small cells thought to be parathyroid adenomas and large, pleomorphic nuclei and fissionable carcinomas. Immunostaining showed that the adenoma portion was PTH-positive, chromogranin A-positive, p53-negative, PAX8-positive, PGP 9.5-negative with a Ki 67 labeling index (LI) of 2.2%. Whereas the carcinoma portion was PTH-negative, chromogranin A-negative, p53-positive, PAX8-positive, PGP 9.5-positive with a Ki67 LI of 39.6%, showing a nonfunctioning aspect and highly malignant. Postoperatively, the patient is alive without recurrence 9 years later without hypercalcemia or recurrence. A case of nonfunctioning parathyroid carcinoma in an extremely rare parathyroid adenoma is reported.

The Urinary Bladder is Rich in Glycosphingolipids Composed of Phytoceramides.

Glycosphingolipids (GSLs) are composed of a polar glycan chain and a hydrophobic tail known as ceramide. Together with variation in the glycan chain, ceramides exhibit tissue-specific structural variation in the long-chain base (LCB) and N-acyl chain moieties in terms of carbon chain length, degree of desaturation, and hydroxylation. Here, we report the structural variation in GSLs in the urinary bladders of mice and humans. Using TLC, we showed that the major GSLs are hexosylceramide, lactosylceramide, globotriaosylceramide, globotetraosylceramide, Neu5Ac-Gal-Glc-Ceramide, and Neu5Ac-Neu5Ac-Gal-Glc-Ceramide. Our LC-MS analysis indicated that phytoceramide structures with a 20-carbon LCB (4-hydroxyeicosasphinganine) and 2-hydroxy fatty acids are abundant in hexosylceramide and Neu5Ac-Gal-Glc-Ceramide in mice and humans. In addition, quantitative PCR demonstrated that DES2 and FA2H, which are responsible for the generation of 4-hydroxysphinganine and 2-hydroxy fatty acid, respectively, and SPTLC3 and SPTSSB, which are responsible for the generation of 20-carbon LCBs, showed significant expressions in the epithelial layer than in the subepithelial layer. Immunohistochemically, dihydroceramide:sphinganine C4-hydroxylase (DES2) was expressed exclusively in urothelial cells of the urinary bladder. Our findings suggest that these ceramide structures have an impact on membrane properties of the stretching and shrinking in transitional urothelial cells.

Pathological Study on the Expression of Vasohibins in Peripheral Artery Disease.

Vasohibin-2 (VASH2) is a gene that promotes local angiogenesis. The tubulin carboxypeptidase activity of vasohibin causes detyrosination of alpha-tubulin and may play an important role in the regulation of various phenomena. Pathological and therapeutic angiogenesis are involved in atherosclerotic lesions. This study aimed to investigate whether the expression of VASH2 is associated with peripheral artery disease (PAD) in relation to angiogenesis, tubulin detyrosination, and severity of atherosclerotic lesions. An analysis of femoral and tibial arteries obtained from 86 patients with PAD or abdominal aortic aneurysm (AAA) was performed. The expressions of cluster of differentiation 31, VASH1, VASH2, and detyrosinated alpha-tubulin (DT-tubulin) were examined by immunohistochemistry, and their association with PAD was analyzed. The counts of VASH2 in the tunica media and adventitia in the tibial artery were significantly higher than those in the femoral artery in the PAD (P = 0.005 and P = 0.008, respectively) and AAA (P = 0.002 and P < 0.001, respectively) groups. In the tunica media and adventitia, VASH2 was significantly correlated with DT-tubulin. There was no significant difference in the expression of VASH2 and DT-tubulin in medial smooth muscle cells (McNemar test, P > 0.999). This study revealed the possible involvements of VASH2 in atherosclerosis by two methods-one maybe related to the progression of atherosclerosis by inducing angiogenesis and the second may be related to the decrease in arterial elasticity by increasing DT-tubulin in medial smooth muscle cells.

Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome.

Mucopolysaccharidoses (MPS) are rare lysosomal storage disorders (LSD) characterized by the excessive accumulation of glycosaminoglycans (GAG). Conventional MPS, caused by inborn deficiencies of lysosomal enzymes involved in GAG degradation, display various multisystemic symptoms-including progressive neurological complications, ophthalmological disorders, hearing loss, gastrointestinal and hepatobiliary issues, cardiorespiratory problems, bone and joint abnormalities, dwarfism, and coarse facial features. Mucopolysaccharidosis-Plus Syndrome (MPSPS), an autosomal recessive disease caused by a mutation in the endo-lysosomal tethering protein VPS33A, shows additional renal and hematopoietic abnormalities ("Plus symptoms") uncommon in conventional MPS. Here, we analyze data from biochemical, histological, and physical examinations-particularly of blood counts and kidney function-to further characterize the clinical phenotype of MPSPS. A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow. High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction. Histological analyses of MPSPS kidneys similarly suggest the extensive destruction of glomerular structures by foamy podocytes. Height and weight did not significantly deviate from the average, but in some cases, growth began to decline at around six months or one year of age.

Sputum characteristics of patients with severe COVID-19: report of two cases with immunocytochemical detection of SARS-CoV-2 spike protein.

Patients with SARS-CoV-2 infection and with severe COVID-19 often have multiple coinfections, and their treatment is challenging. Here, we performed cytology analysis on sputum samples from two patients with severe COVID-19. The specimens were prepared using the rubbing method and stained with Papanicolaou stain. In both cases, several cells with frosted nuclei were observed, and the cytological findings per 100 cells were evaluated. The infected cells were mononuclear to multinuclear, showing chromatin aggregation at the nuclear margins, intranuclear inclusion bodies, eosinophilic cytoplasmic inclusion bodies, and mutual pressure exclusion of the nuclei. Immunocytochemical staining revealed that the cells were positive for AE1/AE3 and negative for CD68 expression, indicating their epithelial origin. Furthermore, infected cells with frosted nuclei were positive for surfactant protein A (SP-A) in Case 2, suggesting infection of type II alveolar pneumocytes or Clara cells. Moreover, in Case 2, the infected cells were positive for herpes simplex virus (HSV) I + II and SARS-CoV-2 spike protein, confirming double infection in these cells. In conclusion, sputum cytology is an important tool for determining the diversity of viral infection, and additional immunocytochemistry can be used for definitive diagnosis.

Comparison of Biparametric and Multiparametric MRI for Clinically Significant Prostate Cancer Detection With PI-RADS Version 2.1.

BACKGROUND: Biparametric MRI (bpMRI) without dynamic contrast-enhanced MRI (DCE-MRI) results in an elimination of adverse events, shortened examination time, and reduced costs, compared to multiparametric MRI (mpMRI). The ability of bpMRI to detect clinically significant prostate cancer (csPC) with the Prostate Imaging and Reporting Data System version 2.1 (PI-RADS v2.1) compared to standard mpMRI has not been studied extensively. PURPOSE: To compare the interobserver reliability and diagnostic performance for detecting csPC of bpMRI and mpMRI using PI-RADS v2.1. STUDY TYPE: Retrospective. POPULATION: In all, 103 patients with elevated prostate-specific antigen (PSA) levels who underwent mpMRI and subsequent MRI-ultrasonography fusion-guided prostate-targeted biopsy (MRGB) with or without prostatectomy. FIELD STRENGTH/SEQUENCES: T2 -weighted imaging (T2 WI), diffusion-weighted imaging (DWI), and DCE-MRI at 3T. ASSESSMENT: Three readers independently assessed each suspected PC lesion, assigning a score of 1-5 for T2 WI, a score of 1-5 for DWI, and positive and negative for DCE-MRI according to PI-RADS v2.1 and determined the overall PI-RADS assessment category of bpMRI (T2 WI and DWI) and mpMRI (T2 WI, DWI, and DCE-MRI). The reference standard was MRGB or prostatectomy-derived histopathology. STATISTICAL TESTING: Statistical analysis was performed using the kappa statistic and McNemar and Delong tests. RESULTS: Of the 165 suspected PC lesions in 103 patients, 81 were diagnosed with csPC and 84 with benign conditions. Interobserver variability of PI-RADS assessment category showed good agreement for bpMRI (kappa value = 0.642) and mpMRI (kappa value = 0.644). For three readers, the diagnostic sensitivity was significantly higher for mpMRI than for bpMRI (P < 0.001 to P = 0.016, respectively), whereas diagnostic specificity was significantly higher for bpMRI than for mpMRI (P < 0.001 each). For three readers, the area under the receiver operating characteristic curve (AUC) was higher for bpMRI than for mpMRI; however, the difference was significant only for Reader 1 and Reader 3 (Reader 1: 0.823 vs. 0.785, P = 0.035; Reader 2: 0.852 vs. 0.829, P = 0.099; and Reader 3: 0.828 vs. 0.773, P = 0.002). DATA CONCLUSION: For detecting csPC using PI-RADS v2.1, the interobserver reliability and diagnostic performance of bpMRI was comparable with those of mpMRI. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Coexistence of three nevus lipomatosus cutaneus superficialis with typical, cutaneous adenolipoma-like, and dermal spindle cell lipoma-like histopathological features in a patient.

We report an unique case of a patient who showed coexistence of three nevus lipomatosus cutaneus superficialis (NLCS) with typical, cutaneous adenolipoma (AL)-like, and dermal spindle cell lipoma (SCL)-like histopathological features. A 53-year-old woman presented with a 20-year history of skin-colored and slightly elevated nodules. These lesions were separately located on the lateral side (lesion 1) and medial side (lesion 2) of her left buttock and on her right thigh (lesion 3). Microscopically, all were ill-defined dermal lesions with some subcutaneous involvement and were mostly composed of mature adipocytes. The adipocytes formed small aggregates around blood vessels in the upper dermis. Lesions 1, 2, and 3 were diagnosed as NLCS, and additional features were recognized in lesions 2 and 3. Lesion 2 revealed eccrine glands and ducts amongst the lipomatous component, as seen in cutaneous AL. Lesion 3 had scattered CD34-positive spindle cells, which is representative of dermal SCL. These appearances were considered to be on the morphological spectrum of NLCS. In all three lesions, CD34-positive cells proliferated between the upper dermal blood vessels and their peripheral mature adipocytes. This pathological finding could be principal in NLCS and might be associated with its pathogenesis.

Cutaneous adenomyoepithelioma with histopathological heterogeneity: A case report.

Some skin adnexal tumors display both epithelial and myoepithelial cell populations and can be broadly categorized as biphasic tumors. These include apocrine hidrocystoma, mixed tumor, adenomyoepithelioma (AME), and adenoid cystic carcinoma (ACC). Myoepithelioma is the myoepithelial cell-predominant type in this category. Cutaneous AME is exceedingly rare and usually has a benign prognosis, but it is considered to have the potential for local recurrence and metastasis. We report the case of a 57-year-old man with a 1-year history of an ulcerated nodule on his scalp. Microscopically, it was a defined cutaneous nodule with a focal lobulated architecture, composed of epithelial cells forming ducts and myoepithelial cells distributed around the ducts. In addition to these findings of typical AME, the present case focally revealed atypical features, such as increased mitotic activity (7/10 high power fields), invasive growth, and necrosis. However, cytological atypia was not significant. We conclusively diagnosed cutaneous AME with atypical features, suggesting malignant potential. Moreover, areas showing appearances similar to apocrine hidrocystoma, mixed tumor, myoepithelioma, and ACC were focally observed. We present a unique case of cutaneous AME exhibiting histopathological heterogeneity. The recognition of morphological variation could be helpful in appropriately diagnosing and treating AME of the skin.

A case of total hysterectomy due to massive maternal bleeding immediately after fetoscopic laser surgery for twin-twin transfusion syndrome.

Twin-twin transfusion syndrome (TTTS) complicates approximately 10% of monochorionic twin pregnancies and is associated with almost 90% mortality if left untreated. Fetoscopic laser photocoagulation (FLP) is the first-line therapy for TTTS, and an overall twin survival rate of 75% and at least one survival rate of 90% have been established. We report a case of TTTS complicated with bleeding from the uterine wall by inserting the procedure after FLP. The patient consequently underwent emergency caesarean section. The bleeding was uncontrollable due to atonic bleeding and emergency hysterectomy was performed. To detect the possibility of amniotic fluid embolism (AFE), biochemical blood samples demonstrated that there was no inflow of fetal ingredients in blood vessels of uterine tissue. There was no evidence of damage to any specific vessels by histopathological staining. These findings indicated that the cause of massive bleeding was unlikely to have been AFE. It was concluded that atonic bleeding was likely caused by uncontrollable hemorrhage from an injury lesion where an endoscope had been inserted.

Automated assessment of Ki-67 in breast cancer: the utility of digital image analysis using virtual triple staining and whole slide imaging.

AIMS: Precise evaluation of proliferative activity is essential for the stratified treatment of luminal-type breast cancer (BC). Immunohistochemical staining of Ki-67 has been widely used to determine proliferative activity and is recognised to be a useful prognostic marker. However, there remains discussion concerning the methodology. We aimed to develop an automated and reliable Ki-67 assessment approach for invasive BC. MATERIALS AND RESULTS: A retrospective study was designed to include two cohorts consisting of 152 and 261 consecutive patients with luminal-type BC. Representative tissue blocks following surgery were collected, and three serial sections were stained automatically with Ki-67, pan-cytokeratin and p63. The whole slides were scanned digitally and aligned using VirtualTripleStaining - an extension to the VirtualDoubleStaining™ technique provided by Visiopharm software. The aligned files underwent automated invasive cancer detection, hot-spot identification and Ki-67 counting. The automated scores showed a significant positive correlation with the pathologists' scores (r = 0.82, P < 0.0001). Among selected patients with curative surgery and standard adjuvant therapies (n = 130), the digitally assessed low Ki-67 group (<20%) demonstrated a significantly better prognosis (breast cancer-specific survival, P = 0.030; hazard ratio = 0.038) than the high Ki-67 group. CONCLUSIONS: Digital image analysis yielded similar results to the scores determined by experienced pathologists. The prognostic utility was verified in our cohort, and an automated process is expected to have high reproducibility. Although some pitfalls were confirmed and thus need to be monitored by laboratory staff, the application could be utilised for the assessment of BC.

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions.

BACKGROUND: Next-generation sequencing (NGS) has shown that recurrent/metastatic breast cancer lesions may have additional genetic changes compared with the primary tumor. These additional changes may be related to tumor progression and/or drug resistance. However, breast cancer-targeted NGS is not still widely used in clinical practice to compare the genomic profiles of primary breast cancer and recurrent/metastatic lesions. METHODS: Triplet samples of genomic DNA were extracted from each patient's normal breast tissue, primary breast cancer, and recurrent/metastatic lesion(s). A DNA library was constructed using the QIAseq Human Breast Cancer Panel (93 genes, Qiagen) and then sequenced using MiSeq (Illumina). The Qiagen web portal was utilized for data analysis. RESULTS: Successful results for three or four samples (normal breast tissue, primary tumor, and at least one metastatic/recurrent lesion) were obtained for 11 of 35 breast cancer patients with recurrence/metastases (36 samples). We detected shared somatic mutations in all but one patient, who had a germline mutation in TP53. Additional mutations that were detected in recurrent/metastatic lesions compared with primary tumor were in genes including TP53 (three patients) and one case each of ATR, BLM, CBFB, EP300, ERBB2, MUC16, PBRM1, and PIK3CA. Actionable mutations and/or copy number variations (CNVs) were detected in 73% (8/11) of recurrent/metastatic breast cancer lesions. CONCLUSIONS: The QIAseq Human Breast Cancer Panel assay showed that recurrent/metastatic breast cancers sometimes acquired additional mutations and CNV. Such additional genomic changes could provide therapeutic target.

Primary endometrioid carcinoma of the uterosacral ligament arising from deep infiltrating endometriosis 6 years after bilateral salpingo-oophorectomy due to atypical proliferative endometrioid tumor of the ovary: a rare case report.

BACKGROUND: Endometriosis can potentially lead to the development of a malignant tumor. Most malignant tumors arising from the endometriosis originate from the ovarian endometrioma, whereas those arising from extragonadal lesions are rare. We report a rare case of endometrioid carcinoma that developed from deep infiltrating endometriosis in the uterosacral ligament 6 years after treatment for atypical proliferative endometrioid tumor of the ovary in a 48-year-old woman. CASE PRESENTATION: Six years ago, the patient underwent laparoscopic bilateral salpingo-oophorectomy for her right ovarian tumor with atypical proliferative (borderline) endometrioid tumor accompanied by ovarian endometrioma. The solid tumor in the cul-de-sac was detected during follow-up using magnetic resonance imaging. Positron emission tomography/computed tomography revealed an abnormal accumulation of 18F-fluorodeoxyglucose at the tumor site. Thus, tumor recurrence with borderline malignancy was suspected. The patient underwent diagnostic laparoscopy followed by hysterectomy and partial omentectomy. Retroperitoneal pelvic lymphadenectomy and para-aortic lymphadenectomy were also performed. The cul-de-sac tumor at the left uterosacral ligament was microscopically diagnosed as invasive endometrioid carcinoma arising from deep infiltrating endometriosis. The final diagnosis was primary stage IIB peritoneal carcinoma. The patient received six courses of monthly paclitaxel and carboplatin as adjuvant chemotherapy. The patient showed no evidence of recurrence for 2 years after the treatments. CONCLUSION: This study reports a rare case of metachronous endometriosis-related malignancy that developed 6 years after treatment for borderline ovarian tumor. If endometriosis lesions remain after bilateral salpingo-oophorectomy, the physician should keep the malignant nature of endometriosis in mind.

Multiplex PCR analysis of apocrine lesions shows frequent PI3K-AKT pathway mutations in both benign and malignant apocrine breast tumors.

Pathological diagnosis of intraductal apocrine lesions can be challenging, because even benign apocrine lesions often show atypical cytology, and immunohistochemistry is of little assistance. A new diagnostic method for apocrine lesions is desirable. The mutations present in apocrine lesions have not been well studied. We performed a MassARRAY multiplex polymerase chain reaction (PCR) study of benign and malignant apocrine lesions, which included 152 mutations of 18 genes. We found that four of 11 benign lesions showed AKT1 or PIK3CA mutations, one of four noninvasive apocrine carcinomas showed a FBX4 mutation, two of 15 invasive apocrine carcinomas showed a PIK3CA mutation, and one invasive apocrine carcinoma showed both PIK3CA and TP53 mutations. The mutation frequency did not differ significantly between benign and malignant lesions (p = 0.683). We demonstrated that both benign and malignant apocrine lesions may contain mutations of genes in the PI3K-AKT pathway, this pathway could be a good therapeutic target of these diseases.

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration.

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.

CD1d- and PJA2-related immune microenvironment differs between invasive breast carcinomas with and without a micropapillary feature.

BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is characterized by its unique morphology and frequent nodal metastasis. However, the mechanism for development of this unique subtype has not been clearly elucidated. The aim of this study was to obtain a better understanding of IMPC. METHODS: Using representative cases of mixed IMPC, mRNA expression in the micropapillary area and usual invasive area was compared. Then, immunohistochemical analyses for 294 cases (76 invasive carcinomas with a micropapillary feature [ICMF] and 218 invasive carcinomas without a micropapillary feature [ICNMF]) were conducted. Clinicopathological analyses were also studied. RESULTS: DNA microarray analyses for mixed IMPC showed that BC-1514 (C21orf118) was commonly upregulated in the micropapillary area. CAMK2N1, CD1d, PJA2, RPL5, SAMD13, TCF4, and TXNIP were commonly downregulated in the micropapillary area. Immunohistochemically, we confirmed that BC-1514 was more upregulated in ICMF than in ICNMF. CD1d and PJA2 were more downregulated in ICMF than ICNMF. All patients with cases of PJA2 overexpression survived without cancer recurrence during the follow-up period, although the differences for disease-free (p = 0.153) or overall survival (p = 0.272) were not significant. CONCLUSIONS: The CD1d- and PJA2-related tumour microenvironment might be crucial for IMPC. Further study of the immune microenvironment and micropapillary features is warranted.

Primary non-gestational uterine choriocarcinoma mimicking leiomyoma.

Uterine choriocarcinoma is a trophoblastic neoplasm that is most commonly gestational but can also be non-gestational in origin. However, primary non-gestational uterine choriocarcinoma is very rare, with only few cases having been reported. We report a case of a premenopausal woman who had initially been diagnosed with myoma delivery but who was discovered to have primary non-gestational uterine choriocarcinoma. This 46-year-old woman had no history of pregnancy. She was referred to our hospital for treatment of the myoma delivery. After tumor removal, histological examination led to the diagnosis of choriocarcinoma. The serum human chorionic gonadotropin level (207,300 mIU/mL) prior to surgery was abnormally high, and because the computed tomography scans additionally revealed lung metastasis, the patient was diagnosed with FIGO stage III choriocarcinoma. Due to the lack of pregnancy history and abstinence from sexual intercourse for >1 year, we performed short tandem repeat analysis, and diagnosed the patient with non-gestational choriocarcinoma. Despite treatments using multiple anticancer agents after the surgery, the patient died 1 year after starting the treatments. On this occasion, we report a very rare case of a premenopausal woman who was diagnosed with primary non-gestational uterine choriocarcinoma mimicking leiomayoma.