PITX2 as a Sensitive and Specific Marker of Midgut Neuroendocrine Tumors: Results from a Cohort of 1157 Primary Neuroendocrine Neoplasms.

As neuroendocrine tumors (NETs) often present as metastatic lesions, immunohistochemical assignment to a site of origin is one of the most important tasks in their pathologic assessment. Because a fraction of NETs eludes the typical expression profiles of their primary localization, additional sensitive and specific markers are required to improve diagnostic certainty. We investigated the expression of the transcription factor Pituitary Homeobox 2 (PITX2) in a large-scale cohort of 909 NET and 248 neuroendocrine carcinomas (NEC) according to the immunoreactive score (IRS) and correlated PITX2 expression groups with general tumor groups and primary localization. PITX2 expression (all expression groups) was highly sensitive (98.1%) for midgut-derived NET, but not perfectly specific, as non-midgut NET (especially pulmonary/duodenal) were quite frequently weak or moderately positive. The specificity rose to 99.5% for a midgut origin of NET if only a strong PITX2 expression was considered, which was found in only 0.5% (one pancreatic/one pulmonary) of non-midgut NET. In metastases of midgut-derived NET, PITX2 was expressed in all cases (87.5% strong, 12.5% moderate), whereas CDX2 was negative or only weakly expressed in 31.3% of the metastases. In NEC, a fraction of cases (14%) showed a weak or moderate PITX2 expression, which was not associated with a specific tumor localization. Our study independently validates PITX2 as a very sensitive and specific immunohistochemical marker of midgut-derived NET in a very large collective of neuroendocrine neoplasms. Therefore, our data argue toward implementation into diagnostic panels applied for NET as a firstline midgut marker.

Neuroendocrine tumor G3 of bronchopulmonary origin and its classification.

Neuroendocrine tumors (NET) with high proliferative activity (Ki-67 index >20% and/or mitotic counts >2 mm2 ) are defined as NET G3 in the 2019 World Health Organization (WHO) classification of digestive system neuroendocrine neoplasms (NENs). NETs G3 occur mostly in the pancreas, colon, rectum, and stomach and only rarely in the small intestine and the appendix. In the bronchopulmonary system, similar tumors have also been recognized and were mostly classified as atypical carcinoid (AC) or large cell neuroendocrine carcinoma. Bronchopulmonary NENs that were classified as NETs G3 are characterized by histological and immunohistochemical similarities with carcinoids/NETs, and a clinical course that is more aggressive than with ACs and similar to that of neuroendocrine carcinomas. The morphomolecular and clinical features of bronchopulmonary neoplasms with a high proliferative activity were reviewed and a future classification system that is applicable for both digestive and bronchopulmonary NETs is proposed.

[Ductal adenocarcinoma of the pancreas: subtypes and molecular pathology]. / Das duktale Adenokarzinom des Pankreas: Subtypen und Molekularpathologie.

Ductal adenocarcinoma is the most common tumor of the pancreas. Although relatively rare, it poses one of the greatest oncological challenges because of its poor prognosis, which has so far only slightly improved. Progress has been made in the more precise classification and standardization of the morphological assessment. In the current WHO classification, prognostically relevant subtypes are clearly delimited among themselves and from ductal adenocarcinoma not otherwise specified (NOS). In the recent TNM classification, a size-based T­category was introduced. Diagnostically, the histological assessment of the resection specimen is relatively easy; on the other hand, assessment of the fine-needle biopsy from the primary tumor or a liver metastasis is still difficult. The molecular stratification of ductal adenocarcinoma and the other pancreatic neoplasms has made great progress. This not only defined the genetics of tumor entities, but also identified the prognosis and biology of tumor groups on the basis of RNA expression patterns. The range of treatment could be expanded by targeted molecular therapies (especially for patients with BRCA1/2 germline mutations, NTRK- or NRG1-fusions, or oncogenic BRAF and PIK3CA mutations as well as tumors with microsatellite instability (MSI)), even if targeted therapies are currently only available for a minority of patients (<10%).

Quantitative digital image analysis of somatostatin receptor 2 immunohistochemistry in pancreatic neuroendocrine tumors.

Immunohistochemical analysis of somatostatin receptor 2 (SSTR2) provides important information regarding the potential therapeutic efficacy of somatostatin analogues (SSAs) in patients with neuroendocrine tumors. HER2 scoring has been proposed to interpret SSTR2 immunoreactivity but their reproducibility was relatively low because of its intrinsic subjective nature. Digital image analysis (DIA) has recently been proposed as an objective and more precise method of evaluating immunoreactivity. Therefore, in this study, we used DIA for analyzing SSTR2 immunoreactivity in pancreatic neuroendocrine tumors (PanNETs) to obtain its H score and "(%) strong positive cells" and compared the results with those of manually obtained HER2 scores. Membranous SSTR2 immunoreactivity evaluated by DIA was calculated by two scales as: "Membrane Optical Density" and "Minimum Membrane Completeness". PanNETs with HER2 score of > 2 demonstrated the highest concordance with results of "(%) strong positive cells" obtained by DIA when "Minimum Membrane Completeness" was tentatively set at 80%. The SSTR2 immunoreactivity, evaluated based on all scoring systems, was different between grades G1 and G2 in insulinoma but not in non-functional PanNETs. DIA provided reproducible results of SSTR2 immunoreactivity in PanNETs and yielded important information as to the potential application of SSAs.

Classification and Prognostic Stratification of Bronchopulmonary Neuroendocrine Neoplasms.

The accuracy and reproducibility of the World Health Organization (WHO) 2015 classification of bronchopulmonary neuroendocrine neoplasms (BP-NENs) is disputed. The aim of this study is to classify and grade BP-NENs using the WHO 2019 classification of digestive system NENs (DiS-NEN-WHO 2019), and to analyze its accuracy and prognostic impact. Two BP-NEN cohorts from Japan and Germany, 393 tumors (88% surgically resected), were reviewed and the clinicopathological data of the resected tumors (n = 301) correlated to patients' disease-free survival (DFS). The DiS-NEN-WHO 2019 stratified the 350 tumors into 91 (26%) neuroendocrine tumors (NET) G1, 52 (15%) NET G2, 15 (4%) NET G3, and 192 (55%) neuroendocrine carcinomas (NEC). NECs, but not NETs, were immunohistochemically characterized by abnormal p53 (100%) and retinoblastoma 1 (83%) expression. The Ki67 index, which was on average 4 times higher than mitotic count (p < 0.0001), was prognostically more accurate than the mitotic count. NET G3 patients had a worse outcome than NET G1 (p < 0.01) and NET G2 patients (p = 0.02), respectively. No prognostic difference was detected between NET G3 and NEC patients after 5 year DFS. It is concluded that stratifying BP-NEN patients according to the DiS-NEN-WHO 2019 classification results in 3 prognostically well-defined NET groups, if grading is solely based on Ki67 index. Mitotic count alone may underestimate malignant potential of NETs.

Annexin A1 Expression Capacity as a Determinant for Disease Severity in Crohn's Disease.

INTRODUCTION: Crohn's disease (CD) is characterized by relapsing intestinal inflammation. The anti-inflammatory protein annexin A1 (ANXA1) has been linked to inflammatory processes in the gut. OBJECTIVE: To examine ANXA1 expression patterns in the inflamed intestine of patients with CD and associate ANXA1 expression capacity with disease characteristics. METHODS: Surgical specimens of patients with CD operated between 2003 and 2015 were examined. Immunohistochemistry and immunofluorescence were performed to delineate ANXA1 expression. Those with pronounced ANXA1 expression were included in further analysis by qPCR. ANXA1 mRNA expression ratio of the inflamed to non-inflamed tissue was determined and defined as expression capacity of the tissue. Depending on their expression capacity, patients were divided into 2 groups (ANXA1-low vs. ANXA1-high), which were associated with clinical characteristics. RESULTS: Immunohistochemical ANXA1 expression was localized in inflamed regions of the intestine. In immunofluorescence, ANXA1 costained with myeloperoxidase as neutrophil marker, CD4 and CD8 as T cell marker but not CD20 as B cell marker or CD68 as macrophage marker. In qPCR, ANXA1 mRNA expression was upregulated by 20-fold in inflamed to noninflamed tissues. Patients with higher intrinsic ANXA1 expression capacity had significantly less severity of inflammation. Furthermore, the ANXA1-high group had significantly more locally restricted disease (p = 0.0070), more stricturating disease (p = 0.0037), and was less frequently treated by preoperative steroid therapy (p = 0.030). CONCLUSIONS: ANXA1 expression was strongly associated with intestinal inflammation and expressed in T cells and neutrophils of the CD tissues. Patients with higher intrinsic ANXA1 expression capacity of the inflamed tissue presented milder inflammatory changes and indolent clinical course.

Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20.

The clinicopathological features of lung neuroendocrine neoplasms (NEN) with a high proliferative index at the border area between atypical carcinoid and neuroendocrine carcinoma have not been investigated so far. The aim of this study was, therefore, to search for lung NENs which are well differentiated but show Ki67 values that overlap with those of poorly differentiated (PD)-NENs. Resected lung NENs from 244 Japanese patients were reviewed, and Ki67 indices were assessed in all tumors. The data were then correlated to clinicopathological parameters and patient outcome. Among 59 (24%) well-differentiated (WD)-NENs and 185 (76%) lung PD-NENs, 7 were defined as WD-NENs with Ki67 indices > 20%. The Ki67 indices of these tumors (mean 29%, range 24-36) were significantly lower than those of PD-NENs (mean 74%, range 34-99). All WD-NENs with Ki67 > 20% lacked abnormal p53 and loss of retinoblastoma 1 (Rb1) expression. In contrast, many PD-NENs expressed p53 (48%) and showed loss of Rb1 (86%). The 2- and 5-year disease-free survival rates in WD-NEN patients with Ki67 > 20% were lower than those of WD-NEN patients with Ki67 ≤20% (p < 0.01 for disease-free and overall survival). No statistical differences were detected between outcome of WD-NEN patients with Ki67 > 20% and those of PD-NEN. It is concluded that WD-NEN patients with Ki67 > 20% share the morphological and immunohistochemical features of WD-NEN patients with Ki67 ≤20%, but they have a worse prognosis, suggesting that this tumor group requires particular attention in future classifications and probably new therapeutic regimes.

SOX2 and Rb1 in esophageal small-cell carcinoma: their possible involvement in pathogenesis.

Clinicopathological features and pathogenesis of esophageal small-cell carcinoma remain unclear. We hypothesized common cellular origin and pathogenesis in small-cell carcinoma of esophagus and lung associated with SOX2 overexpression and loss of Rb1. Expression of squamous-basal markers (CK5/6 and p40), glandular markers (CK18 and CEA), SOX2, and Rb1 were evaluated in 15 esophageal small-cell carcinomas, 46 poorly differentiated squamous cell carcinomas, and 88 small-cell lung carcinoma, as well as 16 embryonic esophagus. Esophageal small-cell carcinoma expressed higher levels of glandular markers and lower levels of squamous-basal markers than poorly differentiated squamous cell carcinoma. No significant differences were observed in immunohistochemistry profiles between small-cell carcinoma of the esophagus and the lung. SOX2 expression was high in esophageal small-cell carcinoma (70%±33% of nuclei), small-cell lung carcinoma (70%±26%), and the embryonic esophagus (75%±4%), and it was significantly lower in poorly differentiated squamous cell carcinoma (29%±28%). Rb1 expression was significantly lower in esophageal small-cell carcinoma (0.3%±1%), small-cell lung carcinoma (2%±6%), and the embryonic esophagus (7%±5%), and it was significantly higher in poorly differentiated squamous cell carcinoma (51%±24%). The immunohistochemistry profiles of small-cell carcinoma of the esophagus and the lung are highly similar. The loss of Rb1 function is a key contributor to the pathogenesis of both neoplasms. In addition, SOX2 overexpression observed in esophageal and lung small-cell carcinoma as well as in the embryonic esophagus indicated that esophageal small-cell carcinoma may arise from embryonic-like stem cells in the esophageal epithelium. The two distinct differentiation patterns (neuroendocrine and glandular) of esophageal small-cell carcinoma further support the fact that SOX2 has a pivotal role in the differentiation of pluripotent stem cells into esophageal small-cell carcinoma cells.

The Risk Factors for Metastasis in Non-Ampullary Duodenal Neuroendocrine Tumors Measuring 20 mm or Less in Diameter.

BACKGROUND/AIMS: The treatment strategy for non-ampullary duodenal neuroendocrine tumors (NAD-NETs) ≤20 mm in diameter has not been established. In this study, we aimed to evaluate the detailed characteristics of NAD-NETs ≤20 mm in diameter to clarify the risk factors of subsequent metastasis. METHODS: The patients with NAD-NETs ≤20 mm in diameter who had been treated at 12 institutions between 1992 and 2013 were enrolled. Clinical records were retrieved, and histopathological findings of all cases were centrally reviewed by 2 pathologists. RESULTS: We studied 49 patients with a mean follow-up period of 66.5 months. Thirty-five patients were initially treated with endoscopic resection (ER), and 14 with surgery. A univariate analysis revealed the ORs and 95% CIs of the risk factors for metastasis were lymphovascular invasion (12.5 [2.01-77.9]), multiple tumors (9.75 [1.46-65.4]), a tumor size of 11-20 mm (6.67 [1.21-36.6]), and World Health Organization grade G2 (7.13 [1.16-43.9]). Five-year overall and disease-specific survival rates were 86.1 and 97.2%, respectively. CONCLUSION: This is the first study to demonstrate the risk factors of metastasis in NAD-NETs ≤20 mm in diameter. These findings may be helpful for determining the appropriate therapeutic approach and the clinical strategy of treatment following ER.

Peritumoral apparent diffusion coefficients for prediction of lymphovascular invasion in clinically node-negative invasive breast cancer.

OBJECTIVES: To evaluate whether visual assessment of T2-weighted imaging (T2WI) or an apparent diffusion coefficient (ADC) could predict lymphovascular invasion (LVI) status in cases with clinically node-negative invasive breast cancer. MATERIALS AND METHODS: One hundred and thirty-six patients with 136 lesions underwent MRI. Visual assessment of T2WI, tumour-ADC, peritumoral maximum-ADC and the peritumour-tumour ADC ratio (the ratio between them) were compared with LVI status of surgical specimens. RESULTS: No significant relationship was found between LVI and T2WI. Tumour-ADC was significantly lower in the LVI-positive (n = 77, 896 ± 148 × 10(-6) mm(2)/s) than the LVI-negative group (n = 59, 1002 ± 163 × 10(-6) mm(2)/s; p < 0.0001). Peritumoral maximum-ADC was significantly higher in the LVI-positive (1805 ± 355 × 10(-6) mm(2)/s) than the LVI-negative group (1625 ± 346 × 10(-6) mm(2)/s; p = 0.0003). Peritumour-tumour ADC ratio was significantly higher in the LVI-positive (2.05 ± 0.46) than the LVI-negative group (1.65 ± 0.40; p < 0.0001). Receiver operating characteristic curve analysis revealed that the area under the curve (AUC) of the peritumour-tumour ADC ratio was the highest (0.81). The most effective threshold for the peritumour-tumour ADC ratio was 1.84, and the sensitivity, specificity, positive predictive value and negative predictive value were 77% (59/77), 76% (45/59), 81% (59/73) and 71% (45/63), respectively. CONCLUSIONS: We suggest that the peritumour-tumour ADC ratio can assist in predicting LVI status on preoperative imaging. KEY POINTS: • Tumour ADC was significantly lower in LVI-positive than LVI-negative breast cancer. • Peritumoral maximum-ADC was significantly higher in LVI-positive than LVI-negative breast cancer. • Peritumour-tumour ADC ratio was significantly higher in LVI-positive breast cancer. • Diagnostic performance of the peritumour-tumour ADC ratio was highest for positive LVI. • Peritumour-tumour ADC ratio showed higher diagnostic ability in postmenopausal than premenopausal patients.

A case of pulmonary adenocarcinoma harboring osteoclast-like giant cells: Its evaluation by immunohistochemical and genetic analyses.

Tumors harboring osteoclast-like giant cells (OGCs) at extraosseous site are extremely rare. These rare tumors have been detected most frequently in the pancreas and few pulmonary tumors harboring OGCs have been previously reported. In addition, the genetic profiles of these tumors have remained virtually unknown. Therefore, we report a case of pulmonary adenocarcinoma harboring OGCs in which k-ras mutation and immunohistochemical study of proteins associated with OGCs were examined. The case was a 70-year-old man, who demonstrated a pulmonary mass associated with unusual radiological features. Histopathologically, three different cell types, mucinous adenocarcinoma cell, OGC and mononuclear cell were detected. OGCs were immunohistochemically negative for epithelial markers and positive for histiocytic markers but mononuclear cells were immunopositive for epithelial markers. In addition, both mononuclear and adenocarcinoma cells had the same k-ras mutation profiles and mononuclear cells were immunohistochemically positive for macrophage colony-stimulating factor (M-CSF), one of the factors associated with OGC differentiation. Therefore, mononuclear cells were considered to be derived from neoplastic epithelium and OGCs could represent non-neoplastic cells. In addition, M-CSF locally produced could promote the differentiation of OGCs.

Progesterone Receptor Isoforms A and B in Pancreatic Neuroendocrine Tumor.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients. METHODS: Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP-1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters. RESULTS: CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher-grade PNETs (p = 0.035). CONCLUSION: The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs.

Microvessel density in hepatocellular carcinoma: Prognostic significance and review of the previous published work.

AIM: Assessment of the microvessel density (MVD) may yield important information leading to an effective antiangiogenic treatment for hepatocellular carcinoma (HCC). METHODS: The intratumoral MVD of 136 HCC patients was retrospectively evaluated using CD34. The correlation between the MVD and clinicopathological findings was assessed. In addition, the prognostic factors influencing the 2-year disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: The MVD of each tumor size group (<2, 2-5 and >5 cm) was 196 ± 51, 181 ± 63 and 147 ± 69. The MVD of each histological grade (well-, moderately and poorly differentiated) was 200 ± 56, 184 ± 61 and 114 ± 55. The optimum cut-off values of the MVD for the 2-year DFS and OS were 118.3 and 112.7, respectively. For the 2-year DFS, high tumor marker levels (α-fetoprotein >100 ng/mL and protein induced by vitamin K absence/antagonist-II >100 mAU/mL), poorly differentiated hepatocellular carcinoma (HCC), a high Ki-67 index (>20%), a large tumor size (>5 cm), vascular invasion, high tumor-node-metastasis (TNM) stage (III/IV) and a low MVD were the significant unfavorable prognostic factors. For the OS, a high Ki-67 index, a large tumor size, vascular invasion, high TNM stage and a low MVD were the significant risk factors for death. By the multivariate analysis, a low MVD was identified as an independent predictor of the 2-year DFS as well as the OS. CONCLUSION: A low MVD can be used to predict an unfavorable prognosis in HCC patients.

G-cell hyperplasia of the stomach induces ECL-cell proliferation in the pyloric glands in a paracrinal manner.

An inhibitory mechanism toward gastrin hypersecretion is significantly different between G-cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G-cell, d-cell and ECL-cell density in a case of G-cell hyperplasia. The 70-year-old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600 pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G-cells in the pyloric glands was quantified on the surgical specimens and G-cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL-cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G-cell density. Somatostatin immunoreactive cells (D-cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G-cell hyperplasia could induce ECL-cell proliferation in a paracrinal manner. In addition, relatively non-prominent endocrinological features in the G-cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL-cells in the pyloric glands.

Precise preoperative localization of prostate cancer employing 12-core needle biopsy with a tissue-marking method for effective surgical strategy.

Prostate needle biopsy plays a pivotal role not only in the diagnosis but also the management of patients with prostate cancer. Prostate cancer is often multifocal and diagnosis of the lesion could therefore be difficult with diagnostic imaging only; thus, multiple core biopsies are taken from several different regions of the prostate. In current practice, 10- or 12-core needle biopsy is considered the clinical standard. Several techniques have been reported to improve the orientation of the specimens, but tissue marking, which could theoretically provide important information on the location of the lesion in the prostate, has been rarely reported. Therefore, in this study, we evaluated the clinical significance of systematic 12-core needle biopsy with tissue marking for preoperative prediction of lesion sites and clinicopathological features of patients. We evaluated 93 patients who underwent 12-core prostate biopsy and subsequent radical prostatectomy. We correlated the biopsy results to the prostate sites in which biopsies were performed and prognostic factors of the patients, especially the degree of extraprostatic extension (EPE) obtained in surgical specimens. Among 253 cancer foci detected in 93 prostatectomy specimens, 168 (66.4%) foci were detected by biopsy. All patients had proven cancer. EPE-positive cancers were associated with a larger number of positive cores, larger tumor length, and higher percentage of cancer tissue in the corresponding cores. Systematic 12-core prostate biopsy with tissue marking is useful for preoperative detection of cancer foci and provides valuable information that enables effective surgical strategies.

Review of renal cell carcinoma with rhabdoid features with focus on clinical and pathobiological aspects.

Rhabdoid morphology in renal cell carcinoma (RCC) may, like sarcomatoid change, be perceived as a type of dedifferentiation, and is a poor prognostic factor. Histologically, rhabdoid neoplastic cells are round to polygonal cells with globular eosinophilic cytoplasmic inclusions and eccentric vesicular nuclei and enlarged nucleoli. All types of RCC, including clear cell, papillary, chromophobe, collecting duct carcinoma, renal medullary carcinoma, acquired cystic disease-associated RCC, ALK-positive renal cancer and unclassified RCC, may display a variably prominent rhabdoid phenotype. Immunohistochemically, the cytoplasm of rhabdoid cells shows positivity for vimentin and/or cytokeratin. Ultrastructurally, cytoplasmic whorls/aggregates of intermediate filaments correspond to light microscopically observed inclusions. Genetically, a previous report suggests that combined loss of BAP1 and PBRM1 may be associated with rhabdoid morphology. As with sarcomatoid change, pathologists should describe, estimate and state the proportion of tumor cells with a rhabdoid phenotype in the routine pathology report of RCC.

The usefulness of endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of pancreatic neuroendocrine tumors based on the World Health Organization classification.

BACKGROUND: We assessed the controversial topic of using 22-gauge needles in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for the diagnosis and evaluation of Ki67 labeling indices (Ki67LI) of pancreatic neuroendocrine tumors (pNET). METHODS: Thirty-eight patients with pNET who underwent EUS-FNA between January 1, 2008 and December 31, 2012 were enrolled in this study. When available, the Ki67LI and WHO classifications obtained by EUS-FNA and surgical resection were compared. RESULTS: EUS-FNA with a 22-gauge needle acquired sufficient histological sample to correctly diagnose pNET in 35 cases (92.1%). Both EUS-FNA and surgical histological specimens were available for 19 cases, and grading classes of the 2 procedures were consistent in 17 cases (89.5%) according to the WHO classification based on the Ki67LI. Tumor size was associated with a difference in the Ki67LI between the 2 procedures, although the Ki67LI was almost completely consistent for tumors less than 18 mm in size. CONCLUSIONS: EUS-FNA with a 22-gauge needle is a safe and highly accurate technique for the diagnosis of pNET. There was a clear correlation between the Ki67LI of histological specimens acquired by EUS-FNA and surgery. EUS-FNA with a 22-gauge needle is useful to predict the WHO classification of pNET.

Oncocytic adrenocortical neoplasm arising from adrenal rest in the broad ligament of the uterus.

Oncocytic adrenocortical neoplasm is characterized by abundant eosinophilic cytoplasm containing mitochondria, occasional nuclear atypia and diffuse growth pattern. Oncocytic adrenocortical neoplasm arising in adrenal rest is, however, extremely rare. We report a case of oncocytic adrenocortical neoplasm arising in adrenal rest of the broad ligament with associated marked lipomatous metaplasia. A well circumscribed tumor was accidentally detected in the pelvic cavity of a 29 year old Japanese woman, adjacent to the broad ligament of the uterus. The tumor was composed of large eosinophilic cells associated with diffuse growth pattern and abundant mature adipose tissue admixed with foci of clear cells. Both steroidgenic factor 1 (SF-1) and alpha-inhibin were immunohistochemically positive in tumor cells. Abundant mitochondria detected by immunohistochemical and electron microscopic examination confirmed the diagnosis of oncocytic adrenocortical neoplasm. The absence of necrosis, capsular and vascular invasion as well as the low mitotic index indicated the benign potential of this tumor. The tumor cells were also positive for dehydroepiandrosteron-sulfotransferase (DHEA-ST), 17ß-hydroxysteroid dehydrogenase type 5 (17ß-HSD5), 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and steroid 17α-hydroxylase (P450-c17), suggesting a possible production of testosterone of this tumor. This is the first reported case of oncocytic adrenocortical adenoma arising in adrenal rest of the broad ligament.

Renal epithelioid angiomyolipoma with malignant features: Histological evaluation and novel immunohistochemical findings.

Renal epithelioid angiomyolipoma (EAML) is a potentially malignant tumor type whose characteristics and biomarkers predictive of malignant behavior have not been elucidated. Here, we report three cases of renal EAML with malignant features but without histories of tuberous sclerosis complex. Case 1 involved a 29-year-old man with a 12-cm solid mass in the right kidney who underwent radical right nephrectomy. Case 2 involved a 22-year-old woman with a retroperitoneal mass who underwent radical right nephrectomy and retroperitoneal tumorectomy. Local recurrence was detected 7 years post-surgery. Case 3 involved a 23-year-old man with a 14-cm solid mass in the left kidney who underwent radical left nephrectomy. Microscopically, the tumors in all cases demonstrated proliferation of epithelioid cells with atypia, mitotic activity, necrosis, hemorrhage, and vascular invasion. Epithelioid cells in all cases were immunohistochemically positive for melanocytic and myoid markers and weakly positive for E-cadherin and ß-catenin. Immunohistochemistry revealed activation of the mammalian target of rapamycin pathway. Here, we report the morphological and immunohistochemical features of clinically or histologically malignant renal EAML.