Genetic analysis of low-grade adenosquamous carcinoma of the breast progressing to high-grade metaplastic carcinoma.

PURPOSE: Low-grade adenosquamous carcinoma (LGASC) is a rare type of metaplastic carcinoma of the breast (MBC) with an indolent clinical course. A few LGASC cases with high-grade transformation have been reported; however, the genetics underlying malignant progression of LGASC remain unclear. METHODS: We performed whole-genome sequencing analysis on five MBCs from four patients, including one case with matching primary LGASC and a lymph node metastatic tumor consisting of high-grade MBC with a predominant metaplastic squamous cell carcinoma component (MSC) that progressed from LGASC and three cases of independent de novo MSC. RESULTS: Unlike de novo MSC, LGASC and its associated MSC showed no TP53 mutation and tended to contain fewer structural variants than de novo MSC. Both LGASC and its associated MSC harbored the common GNAS c.C2530T:p.Arg844Cys mutation, which was more frequently detected in the cancer cell fraction of MSC. MSC associated with LGASC showed additional pathogenic deletions of multiple tumor-suppressor genes, such as KMT2D and BTG1. Copy number analysis revealed potential 18q loss of heterozygosity in both LGASC and associated MSC. The frequency of SMAD4::DCC fusion due to deletions increased with progression to MSC; however, chimeric proteins were not detected. SMAD4 protein expression was already decreased at the LGASC stage due to unknown mechanisms. CONCLUSION: Not only LGASC but also its associated high-grade MBC may be genetically different from de novo high-grade MBC. Progression from LGASC to high-grade MBC may involve the concentration of driver mutations caused by clonal selection and inactivation of tumor-suppressor genes.

Signet-ring Cell Carcinoma Component as an Indicator of Anaplastic Lymphoma Kinase Mutations in Colorectal Cancer.

OBJECTIVES: Molecular profiling of marker mutations has become an essential aspect in the treatment planning for colorectal cancer (CRC). Anaplastic lymphoma kinase (ALK) mutations could be used as markers in CRC molecular profiling. However, the extremely low frequency of these mutations makes their confirmation in all patients inefficient. Thus, to determine whether ALK positivity could be indicated by morphological features, we have analyzed ALK positivity in CRC tissues with a signet-ring cell carcinoma (SRCC) component. METHODS: We screened cases of patients who underwent CRC surgical resection at the Department of Gastrointestinal Surgery of the Kanagawa Cancer Center between January 2015 and December 2019. The selected samples were then assessed immunohistochemically using an antibody against p80 ALK. RESULTS: In total, we were able to retrieve 29 cases of CRC with the SRCC component from the database; however, 5 cases were excluded owing to the absence of formalin-fixed paraffin-embedded tissue sections or the absence of the SRCC component when the tissues were observed. In the immunohistochemical analysis, two cases showed diffused positive immunoreactivity for ALK and were defined as ALK-positive CRC. Thus, the ALK positivity rate in CRC with SRCC was determined to be 8.3%. CONCLUSIONS: This present study sheds light on the morphological features of ALK-positive CRC. Our findings could contribute to the effective screening and improvement of front-line therapy for CRC.

Machine learning-based image analysis for accelerating the diagnosis of complicated preneoplastic and neoplastic ductal lesions in breast biopsy tissues.

PURPOSE: Diagnosis of breast preneoplastic and neoplastic lesions is difficult due to their similar morphology in breast biopsy specimens. To diagnose these lesions, pathologists perform immunohistochemical analysis and consult with expert breast pathologists. These additional examinations are time-consuming and expensive. Artificial intelligence (AI)-based image analysis has recently improved, and may help in ordinal pathological diagnosis. Here, we showed the significance of machine learning-based image analysis of breast preneoplastic and neoplastic lesions for facilitating high-throughput diagnosis. METHODS: Images were obtained from normal mammary glands, hyperplastic lesions, preneoplastic lesions and neoplastic lesions, such as usual ductal hyperplasia (UDH), columnar cell lesion (CCL), ductal carcinoma in situ (DCIS), and DCIS with comedo necrosis (comedo DCIS) in breast biopsy specimens. The original enhanced convoluted neural network (CNN) system was used for analyzing the pathological images. RESULTS: The AI-based image analysis provided the following area under the curve values (AUC): normal lesion versus DCIS, 0.9902; DCIS versus comedo DCIS, 0.9942; normal lesion versus CCL, 0.9786; and UDH versus DCIS, 1.000. Multiple comparison analysis showed precision and recall scores similar to those of single comparison analysis. Based on the gradient-weighted class activation mapping (Grad-CAM) used to visualize the important regions reflecting the result of CNN analysis, the ratio of stromal tissue in the whole weighted area was significantly higher in UDH and CCL than that in DCIS. CONCLUSIONS: These analyses may provide a more accurate and rapid pathological diagnosis of patients. Moreover, Grad-CAM identifies uncharted important histological characteristics for newer pathological findings and targets of research for understanding diseases.

Comprehensive molecular analysis of genomic profiles and PD-L1 expression in lung adenocarcinoma with a high-grade fetal adenocarcinoma component.

BACKGROUND: Fetal adenocarcinoma of the lung is a rare variant of lung adenocarcinoma and is subcategorized into low-grade and high-grade (H-FLAC) fetal adenocarcinoma. We previously reported poor prognosis in pulmonary adenocarcinomas with an H-FLAC component; however, the genetic abnormalities involved in H-FLAC remain unclear. Therefore, this study aimed to elucidate molecular abnormalities as potential therapeutic targets for H-FLACs. METHODS: We performed immunohistochemical analysis and comprehensive genetic analyses using whole-exome sequencing in 16 lung cancer samples with an H-FLAC component. DNA was extracted from formalin-fixed paraffin-embedded tissues after macrodissection of the H-FLAC component. RESULTS: Cancer-related mutations were identified in TP53 (7/16 cases), KMT2C (6/16 cases), KRAS (4/16 cases), NF1 (3/16 cases), STK11 (3/16 cases), CTNNB1 (2/16 cases), and EGFR (1/16 cases). A high tumor mutation burden of ≥10 mutations per megabase was observed in 3/16 cases. A high microsatellite instability was not detected in any case. Based on the cosine similarity with the Catalogue of Somatic Mutations in Cancer mutational signatures, H-FLACs were hierarchically clustered into three types: common adenocarcinoma-like (five cases), surfactant-deficient (ten cases), and signatures 2 and 13-related (one case). All common adenocarcinoma-like cases presented thyroid transcription factor-1 (TTF-1) expression, whereas surfactant-deficient cases often presented loss of TTF-1 and surfactant protein expression and included cases with mutations in the surfactant system genes NKX2-1 and SFTPC. H-FLACs displayed low programmed death ligand-1 (PD-L1) expression (1-49% of tumor cells) in 5/16 cases, and no case displayed high PD-L1 expression (≥50% of tumor cells). CONCLUSIONS: This study indicates that lung cancers with an H-FLAC component rarely harbor currently targetable driver gene mutations for lung cancer but display a high frequency of KMT2C mutations. The microsatellite instability, tumor mutation burden, and PD-L1 expression status suggest a poor response to immune checkpoint therapy.

Quality Control of Breast Cancer Surgery Samples: Introducing Time Stamp Checking.

Background: Analytical information obtained from clinical tissue samples has recently become more important due to recent advancements in the clinical practice of medicine, for example, gene panel testing. However, acquiring and managing the sample quality, which greatly influences the analyses, are not sufficient and hence requires immediate attention. We introduced time stamp (TS) recording and documentation using the Standard PREanalytical Code (SPREC) for breast cancer surgery samples to monitor and control their quality. Materials and Methods: The TS recording used SPREC for quality control of each sample by recording seven factors: type of sample, type of collection, warm ischemia time (WIT), cold ischemia time (CIT), fixation type, fixation time (FT), and long-term storage. The responsibilities to record each factor were assigned among group members (breast surgeons, anesthesiologists, pathologists, operating room nurses, and medical technologists in pathology). Results: Records based on SPREC were recorded for 393 surgical cases of first-time breast cancer patients performed at the Kanagawa Cancer Center from May 2018 to April 2019. The vascular clamp time was defined as when skin flap formation was completed, regardless of the surgical procedure. An anesthesiologist recorded the vascular clamp time and sample collection time, and the pathologist recorded the fixation start time and fixation end time. WIT was 23 (3-116) minutes (breast-conserving surgery, 11 [3-38] minutes; mastectomy, 26 [5-116] minutes; and nipple-sparing mastectomy, 39 [31-43] minutes), CIT was 37 (3-1052) minutes, and FT was 43 (17-115) hours. The median CIT and FT were significantly shortened after introducing the TS system, and the variabilities were reduced. Conclusion: A TS system for quality control of breast cancer surgical sample functions well due to the establishment of highly versatile WIT and a working group consisting of multiple members of different occupations who shared roles.

Rapidly progressed neuroendocrine carcinoma in the extrahepatic bile duct: a case report and review of the literature.

BACKGROUND: Neuroendocrine carcinoma (NEC) originating from the extrahepatic bile duct (EHBD) is very rare but is known for its aggressiveness and poor prognosis. We herein report a case of rapidly progressed NEC in the extrahepatic bile duct. CASE PRESENTATION: An 84-year-old man was referred to our facility with obstructive jaundice and abdominal pain. Imaging studies revealed an irregular filling defect in the middle bile duct by endoscopic retrograde cholangiopancreatography and an enhanced wall thickening from the middle to distal portion by enhanced computed tomography. The patient was initially diagnosed with extrahepatic cholangiocarcinoma by a bile duct biopsy and underwent pancreatoduodenectomy with lymph node dissection. The pathological findings showed an NEC with an adenosquamous carcinoma component in the extrahepatic bile duct with lymph node metastases. The patient experienced multiple liver metastases 1 month after surgery and died 3 months after surgery. Due to the rapid progression of his disease, his general condition deteriorated, and he was unable to receive any additional treatments, such as chemotherapy. CONCLUSION: As shown in our case, NEC of the EHBD has an extremely poor prognosis and can sometimes progress rapidly. Multimodality treatment should be considered, even in cases of locoregional disease.

EZH2 and MMSET Were Identified as Potentially Useful Therapeutic Targets in Metaplastic Breast Carcinoma.

BACKGROUND/AIM: Metaplastic breast carcinoma (MBC) is a rare malignancy, which is often triple-negative for the hormone receptors and human epidermal growth factor receptor 2, and thus, does not benefit from targeted therapy. In this study, we examined the expression of methylation and demethylation enzymes by immunostaining MBC and the adjacent normal tissues or triple-negative ductal carcinoma (TNDC), and identified alterations that may be used as therapeutic targets. MATERIALS AND METHODS: We retrospectively studied surgical specimens from 15 patients who underwent surgery for MBC at Kanagawa Cancer Center between 2005 and 2016, and similarly from 14 patients with TNDC. The frequencies of high methylation/demethylation enzyme expression were compared among them. RESULTS: The frequencies of high enhancer of zeste homolog 2 (EZH2) and multiple myeloma SET domain (MMSET) expression were significantly higher in both MBC and TNDC than in normal tissue. CONCLUSION: EZH2 and MMSET may be useful therapeutic targets in MBC.

Diagnosis, Pathological Findings, and Clinical Management of Gangliocytic Paraganglioma: A Systematic Review.

Background: Although gangliocytic paraganglioma (GP) is considered a rare benign neuroendocrine tumor, cases of mortality have been reported. Occasionally, GP is misdiagnosed as neuroendocrine tumor G1, which is associated with a poorer prognosis than GP. To avoid such misdiagnoses, it is important to understand the clinicopathological characteristics of GP. Thus, herein, we discuss the current literature on the clinicopathological characteristics of GP. Methods: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed and Japana Centra Revuo Medicina searches were used to identify papers describing GP. Inclusion criteria included confirmation of epithelioid, spindle-shaped, and ganglion-like cells in the main article and/or figures and whether the paper was cited in other studies of GP. Data were collected on age, sex, site of the primary lesion, tumor size, treatment, prognosis, lymph node metastasis (LNM), depth of tumor invasion, rate of preoperative diagnosis, and clinical symptoms. Results: In total, 162 papers containing 263 cases of GP met the criteria. The mean age at diagnosis was 53.5 years. The male-to-female ratio was 157:104. The mean tumor size was 25.7 mm. The predominant site of the primary tumor was the duodenum (89.7%). The most common clinical sign of GP was gastrointestinal bleeding (47.9%). Other signs and symptoms of GP included abdominal pain (44.7%), anemia (20.3%), incidental findings (12.9%), nausea (6.9%), weight loss (5.5%), general fatigue (5.1%), jaundice (4.6%), and incidental autopsy findings (5.1%). LNM was observed in 11.4% of patients. Liver metastasis was observed in 1.1% of patients. Depth of tumor invasion (penetrating beyond the submucosal layer or sphincter of Oddi) was by far the most significant risk factor for LNM in patients with GP. This suggests, along with histological heterogeneity, that GP may have hamartomatous characteristics. Furthermore, immunohistochemical expression of progesterone receptor and pancreatic polypeptide were useful in distinguishing between GP and neuroendocrine tumor G1, even in small biopsy specimens. Conclusions: We reveal the clinicopathological characteristics of GP, including risk factors for LNM, differential diagnostic approaches, and improvements in the clinical management of this tumor.In addition, GP may have hamartomatous characteristics.

Pulmonary adenocarcinoma with high-grade fetal adenocarcinoma component has a poor prognosis, comparable to that of micropapillary adenocarcinoma.

Fetal adenocarcinoma is a rare variant of lung adenocarcinoma, which is subcategorized into low-grade and high-grade forms. High-grade fetal adenocarcinoma confers worse prognosis than low-grade fetal adenocarcinoma, but the prognostic differences between high-grade fetal adenocarcinoma and conventional lung adenocarcinoma are unknown. We reviewed tissue sections of 3719 cases of surgically resected primary lung cancers and found 53 lung cancers with a high-grade fetal adenocarcinoma component. We analyzed their clinicopathological and immunohistochemical features, and performed a prognostic analysis of adenocarcinomas with the fetal-type component. We further analyzed the prognostic differences between adenocarcinomas with the fetal-type component and conventional adenocarcinomas without the fetal-type component. Lung cancers with the fetal-type component predominantly occurred in elderly men with a smoking history. Twenty-nine patients had stage I disease, 13 patients had stage II, and 11 patients had stage III. The fetal-type histology was combined with conventional-type adenocarcinoma (41 cases), squamous cell carcinoma (5 cases), large cell neuroendocrine carcinoma (5 cases), enteric adenocarcinoma (2 cases), and small cell carcinoma (1 case). The fetal-type component showed immunopositivity for α-fetoprotein (39%), glypican-3 (37%), and SALL4 (17%). The 5-year overall survivals of fetal-type-predominant and fetal-type-nonpredominant patients were 44 and 56%, respectively (P = 0.962). The 5-year overall survivals of lepidic-, acinar-, papillary-, solid-, and micropapillary-predominant adenocarcinomas, invasive mucinous adenocarcinomas, and adenocarcinomas with the fetal-type component were 94, 82, 77, 69, 57, 83, and 41%, respectively (P < 0.001). Univariate and multivariate analyses showed that adenocarcinomas with the fetal-type component had a significantly lower overall survival rate than the other histological subtypes, except for the micropapillary-predominant subtype. Our study demonstrated that adenocarcinomas with the fetal-type component had a poor prognosis that was comparable to that of micropapillary adenocarcinoma. The presence of the high-grade fetal adenocarcinoma component in lung adenocarcinomas is an important prognostic marker.

Risk factors associated with the progression and metastases of hindgut neuroendocrine tumors: a retrospective study.

BACKGROUND: The worldwide incidence of neuroendocrine tumors (NETs) has increased remarkably, with the hindgut being the second most common site for such tumors. However, the mechanisms underlying progression and metastasis of hindgut NETs are unclear. A retrospective study was conducted to elucidate these mechanisms. METHODS: Clinicopathological data of cases of hindgut NET between April 1996 and September 2015 were analyzed, retrospectively. Patients with neuroendocrine carcinoma were excluded. Formalin-fixed paraffin-embedded tissues of hindgut NET cases were subjected to detailed morphometric and immunohistochemical analyses. Statistical analyses were performed using the non-parametric Mann-Whitney U test, Spearman's correlation coefficient, and chi-squared test. Multivariate logistic regression analysis was conducted as appropriate for the data set. RESULTS: Fifty-six hindgut NET cases were considered. Microvessel density and lymphatic microvessel density were identified as significant risk factors for venous and lymphatic invasion. There was a positive correlation between microvessel density and the maximum tumor diameter. Multivariate logistic regression analysis revealed that the maximum tumor diameter alone was an independent predictor of lymph node metastasis, whereas lymphovascular invasion and MVD was not the predictor of lymph node metastasis. There were no significant correlations between the Ki-67 labeling index and any of the parameters evaluated including age, sex, the maximum tumor diameter, venous invasion, lymphatic invasion, microvessel density, lymphatic microvessel density, and lymph node metastasis. CONCLUSIONS: Angiogenic mechanisms may play important roles in the progression of hindgut NET. Otherwise, the maximum tumor diameter alone was an independent predictor of lymph node metastasis in hindgut NETs. Moreover, our study raises the question of whether the presence of lymphovascular invasion, in endoscopically obtained hindgut NET tissues, is an absolute indication for additional surgery or not.

Chronic lymphocytic leukemia/small lymphocytic lymphoma with t (2;18) (p12;q21) accompanied by a cutaneous nodule with histological features of diffuse large B-cell lymphoma.

A 73-year-old woman presented a 3-year history of indolent enlargement of cutaneous tumor nodules. Peripheral blood flow cytometry revealed thrombocytopenia (platelets; 85,000/µl) and the presence of an abnormal, small B lymphocyte population (CD5+, CD10-, CD20+, CD22+, CD23dim, FMC7+, SmIgλ+, and SmIgκ-; 4,000/µl). Skin biopsy indicated infiltration of CD5+, CD10-, CD20+, BCL2+, BCL6+, and cyclin D1- atypical large B-cells, suggesting diffuse large B-cell lymphoma. Cytogenetic analysis of the peripheral blood revealed a complex karyotype [t (2;18) (p12;q21) and +12]. Fluorescence in situ hybridization detected the presence of BCL2 split signal and the absence of IGH/CCND1 fusion signal. Cervical lymph node biopsy indicated a pseudofollicular pattern. The sequence of immunoglobulin heavy chain variable region from the peripheral blood and the skin tumor contained the same mutated pattern, and therefore, confirmed clonality. Because the patient's clinical course and skin tumor were indolent, the possibility of Richter syndrome was discarded, and the final diagnosis was chronic lymphocytic leukemia/small lymphocytic lymphoma, Rai stage IV and Binet stage C. The patient achieved complete remission after 4 cycles of a fludarabine plus rituximab regimen, without disease progression since >1 year of treatment.

Non-functioning parathyroid carcinoma: a case report.

BACKGROUND: Non-functioning parathyroid carcinoma is a rare disease that is difficult to distinguish from other diseases based on the lack of hyperparathyroidism. This is a report of non-functioning parathyroid carcinoma diagnosed by reverse transcription polymerase chain reaction (RT-PCR) targeting parathyroid hormone (PTH) messenger RNA. CASE PRESENTATION: The patient is a 67-year-old male who visited our hospital for the chief complaint of hoarseness. A 5-cm mass was observed in the right lobe of the thyroid gland, and poorly differentiated thyroid carcinoma was suspected according to the fine-needle biopsy results. The laboratory data for thyroid functions, thyroglobulin, anti-thyroglobulin antibodies, calcium, phosphorus, and intact-PTH were all within the normal range. Right recurrent nerve paralysis was observed preoperatively. The patient was diagnosed with poorly differentiated thyroid carcinoma, and total thyroidectomy and central node dissection with partial resection of the right recurrent nerve and esophageal muscle were performed. The pathological findings revealed atypical cells containing clear cells in solid and alveolar structures with broad fibrosis. Mitosis, focal coagulative necrosis, and vascular and capsular invasions were observed. A slightly positive PTH immunohistochemical stain was noted, whereas the RT-PCR results were positive. We finally diagnosed this tumor as non-functioning PTC. No distant metastasis occurred, and the patient is still alive. CONCLUSIONS: This is a report of a patient with non-functioning parathyroid carcinoma, which is clinically very rare. We diagnosed this tumor as non-functioning parathyroid carcinoma using RT-PCR for PTH mRNA.

Clinicopathological and prognostic significance of Ki-67 immunohistochemical expression of distant metastatic lesions in patients with metastatic breast cancer.

BACKGROUND: Surgical biopsy of metastatic lesions followed by pathological confirmation for the investigation of biomarkers is occasionally proposed as an effective strategy in the treatment of metastatic breast cancer. However, few reports have examined Ki-67 immunohistochemical expression in distant metastatic lesions of breast cancer patients. This study aimed to investigate the clinicopathological significance of subtypes and Ki-67 immunohistochemical expression in metastatic breast cancer lesions. METHODS: We retrospectively studied surgical specimens of primary breast cancer tumors and their corresponding metastatic lesions from patients (n = 68) who underwent surgery for primary breast cancer tumors between December 1977 and March 2013. Tissue microarrays were constructed using primary and metastatic lesions, and were stained with antibodies against estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. We also examined the clinicopathological characteristics and outcome measures of patients with metastatic breast cancer using primary and paired metastatic lesions. RESULTS: Compared with the primary lesions, there was no significant difference in subtypes in the metastatic lesions according to metastatic sites. Metastatic lesions of the brain, viscera, and bone exhibited slightly higher levels of Ki-67 immunohistochemical expression compared with primary lesions. A Cox proportional hazards model using multivariate analysis demonstrated that high Ki-67 immunohistochemical expression in distant metastatic lesions was associated with poorer overall survival outcomes after biopsy of recurrence lesion (hazard ratio 2.307; 95% confidence interval 1.207-4.407, P = 0.011). CONCLUSIONS: High Ki-67 immunohistochemical expression levels in distant metastatic lesions were independently associated with poorer overall survival outcomes after biopsy of recurrence lesion in breast cancer patients.

Expression of enhancer of zeste homolog 2 correlates with survival outcome in patients with metastatic breast cancer: exploratory study using primary and paired metastatic lesions.

BACKGROUND: In metastatic breast cancer, the status of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as the Ki-67 index sometimes change between primary and metastatic lesions. However, the change in expression levels of enhancer of zeste homolog 2 (EZH2) between primary and metastatic lesions has not been determined in metastatic breast cancer. METHODS: Ninety-six metastatic breast cancer patients had biopsies or resections of metastatic lesions between September 1990 and February 2014 at the Kanagawa Cancer Center. We evaluated ER, PR, HER2, Ki-67, and EZH2 in primary lesions and their corresponding metastatic lesions using immunohistochemistry. We examined the change in expression of EZH2 between primary and metastatic lesions, the correlation between the expression of EZH2 and the expression of other biomarkers, and the relationship between EZH2 expression and patient outcome in metastatic breast cancer. RESULTS: EZH2 expression was significantly higher in metastatic lesions compared with primary lesions. EZH2 expression was highly correlated with Ki-67 expression in primary and metastatic lesions. High-level expression of EZH2 was associated with poorer disease-free survival (DFS) outcomes in patients with primary lesions (P < 0.001); however, high-level expression of EZH2 was not associated with poorer DFS outcomes in patients with metastatic lesions (P = 0.063). High-level expression of EZH2 was associated with poorer overall survival (OS) postoperatively in patients with primary (P = 0.001) or metastatic lesions (P = 0.005). High-level expression of EZH2 was associated with poorer OS outcomes after recurrence in patients with metastatic lesions (P = 0.014); however, high-level expression of EZH2 was not associated with poorer OS outcomes after recurrence in patients with primary lesions (P = 0.096). High-level expression of EZH2 in metastatic lesions was independently associated with poorer OS outcomes after recurrence. CONCLUSIONS: EZH2 expression was significantly increased in metastatic lesions compared with primary lesions. High-level expression of EZH2 in metastatic lesions was associated with poorer OS outcomes after primary surgery and recurrence.

The clinicopathological significance of angiogenesis in hindgut neuroendocrine tumors obtained via an endoscopic procedure.

BACKGROUND: As the World Health Organization grading system for gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) may not always correlate with tumor progression, it is imperative that other independent predictors of tumor progression be established. To identify such predictors, we conducted a retrospective histopathological study of hindgut NETs, obtained from endoscopic procedures, and used statistical analyses to evaluate predictive factors. METHODS: We first obtained clinicopathological data of cases of hindgut NETs. Tissue sections from tumor samples were prepared and subjected to pathological examination. In particular, we calculated the microvessel density (MVD) and lymphatic microvessel density (LMVD) values, and performed appropriate statistical analyses. RESULTS: A total of 42 cases of hindgut NETs were selected for the study, 41 from the rectum and 1 from the sigmoid colon. Based on the Ki-67 labeling index, 34 cases were classified as NET G1 tumors and 8 as NET G2 tumors. MVD values ranged from 1.4/mm2 to 73.9/mm2 and LMVD values from 0/mm2 to 22.9/mm2. MVD and LMVD were identified as risk factors for venous and lymphatic invasion of hindgut NETs. Moreover, MVD positively correlated with the maximum diameter of the tumor. CONCLUSIONS: Tumor progression of NETs may cause angiogenesis and lymphangiogenesis, via an unknown mechanism, as well as lymphovascular invasion. Angiogenesis likely plays an important role in occurrence and progression in the initial phase of hindgut NETs.

Metastatic large cell neuroendocrine carcinoma of the lung arising from the uterus: A pitfall in lung cancer diagnosis.

A 41-year-old female smoker presented with a vaginal mass. Gynecological examination showed a mass filling the uterine corpus, cervix, and vagina. A total abdominal hysterectomy was performed. Macroscopic findings included a large fragile mass involving the uterine cavity, cervix, and vagina. Histology revealed atypical ducts admixed with solid components consisting of large atypical cells. The initial pathological diagnosis was grade 3 endometrioid adenocarcinoma. The patient was designated as stage II according to the 2008 International Federation of Gynecology and Obstetrics (FIGO) staging. Two years later, two nodules were found in the upper lobe of the left lung, and the patient underwent an upper lobectomy. The masses, which exhibited solid and organoid growth patterns of large atypical cells, had histological characteristics of large cell neuroendocrine carcinoma (LCNEC) of the lung. However, the tumor was immunohistochemically positive for neuroendocrine markers, such as synaptophysin in addition to estrogen receptor and progesterone receptor, and the tumor was negative for thyroid transcription factor-1. These immunohistochemical results were almost identical to those of the solid portions of the uterine carcinoma. The final diagnosis was LCNEC combined with endometrioid adenocarcinoma of the uterine corpus and lung metastasis of the LCNEC component of the endometrial carcinoma. LCNEC often arises in the lung, but it rarely arises in other organs. Some patients with metastatic components exhibited only a LCNEC pattern although the primary tumor was a mixed carcinoma consisting of LCNEC and other histology, like the present case. LCNEC is often poorly differentiated, especially in extrapulmonary primary organ LCNEC. Therefore, pathologists should consider metastatic carcinoma when they encounter lung LCNEC in a patient with a preceding extrapulmonary carcinoma composed of a poorly differentiated component or LCNEC component, and they should clarify tumor immunohistochemical characteristics to confirm the diagnosis.

Duodenal Rare Neuroendocrine Tumor: Clinicopathological Characteristics of Patients with Gangliocytic Paraganglioma.

Gangliocytic paraganglioma (GP) has been regarded as a rare benign tumor that commonly arises from the second part of the duodenum. As GP does not exhibit either prominent mitotic activity or Ki-67 immunoreactivity, it is often misdiagnosed as neuroendocrine tumor (NET) G1. However, the prognosis might be better in patients with GP than in those with NET G1. Therefore, it is important to differentiate GP from NET G1. Moreover, our previous study indicated that GP accounts for a substantial, constant percentage of duodenal NETs. In the present article, we describe up-to-date data on the clinicopathological characteristics of GP and on the immunohistochemical findings that can help differentiate GP from NET G1, as largely revealed in our new and larger literature survey and recent multi-institutional retrospective study. Furthermore, we would like to refer to differential diagnosis and clinical management of this tumor and provide intriguing information about the risk factors for lymph node metastasis on GP.

Adenomyoepithelioma with carcinoma of the breast: A report of two cases and a review of the literature.

We herein described two cases of adenomyoepithelioma (AME) with carcinoma of the breast. Both of them were Japanese women, and they presented with a mass in their breast. Post-operative specimens revealed encapsulated and well-circumscribed tumors with local invasion, necrosis, cytological atypia, and a high mitotic rate. In immunohistochemistry, coincidentally with the loose adhesion pattern of myoepithelial cells in both cases, the intensities of E-cadherin and beta-catenin were much weaker in myoepithelial than luminal epithelial cells, with almost negative finding of beta-catenin in one case. We first found deletion of CDH1 and polysomy of CEP16 in myoepithelial cells by double color-fluorescence in situ hybridization. The two cases have been followed up for 5-8 years, and both remained free from local recurrence and distant metastases. We also presented an overview of 47 cases of AME with carcinoma in English-language literatures.

Impact of Expression Levels of Platinum-uptake Transporters Copper Transporter 1 and Organic Cation Transporter 2 on Resistance to Anthracycline/Taxane-based Chemotherapy in Triple-negative Breast Cancer.

Adding platinum drugs to anthracycline/taxane (ANC-Tax)-based neoadjuvant chemotherapy (NAC) improves pathological complete response (pCR) rates in triple-negative breast cancer (TNBC). Copper transporter 1 (CTR1) and organic cation transporter 2 (OCT2) critically affect the uptake and cytotoxicity of platinum drugs. We immunohistochemically determined CTR1 and OCT2 levels in pre-chemotherapy biopsies from 105 patients with HER2-negative breast cancer treated with ANC-Tax-based NAC. In the TNBC group, Ki-67(high) [pathological good response (pGR), P = 0.04] was associated with response, whereas CTR1(high) (non-pGR, P = 0.03), OCT2(high) (non-pGR, P = 0.01; non-pCR, P = 0.03), and combined CTR1(high) and/or OCT2(high) (non-pGR, P = 0.005; non-pCR, P = 0.003) were associated with non-response. In multivariate analysis, Ki-67(high) was an independent factor for pGR and CTR1 for non-pGR. Combined CTR1/OCT2 was a strong independent factor for non-pGR. However, no variables were associated with response in luminal BC. These results indicate that platinum uptake transporters are predominantly expressed in ANC-Tax-resistant TNBCs, which implies that advantage associated with adding platinum drugs may depend on high drug uptake.