Endometrial cancer with a POLE mutation progresses frequently through the type I pathway despite its high-grade endometrioid morphology: a cohort study at a single institution in Japan.

POLE-mutated endometrial cancer (EC) frequently shows high-grade endometrioid histology, which represents heterogeneity in the dualistic classification of EC. This study aimed to assess the clinicopathology and pathogenesis of POLE-mutated EC due to the scarcity of related information for Asian women. POLE variants were sequenced in tissues of Japanese women with EC. The tumor mutation burden (TMB) was assessed in tissues with a POLE variant of unknown significance. In the POLE-mutated EC tissues, the immunostaining expression of CD8, hormonal receptors, and p53 was evaluated, and the POLE variants in cancer and atypical endometrial hyperplasia (AEH) lesions were assessed by laser-capture microdissection. POLE variants were identified in five patients (3.9%) with high-grade endometrioid carcinoma among 127 patients with EC (S459F in two tissues and P441P in three tissues with a high TMB). The five cancer tissues coexisted with normal endometrium and/or AEH. Both AEH and cancer cells showed hormonal receptor positivity and harbored the same POLE mutation. Two patients showed a subclonal overexpression pattern of p53 in cancer and AEH lesions. In conclusion, POLE-mutated EC progresses through the type I pathway, even though it frequently shows high-grade endometrioid morphology. The common POLE mutation sites in EC might vary among races.

Serum Prolactin Contributes to Enhancing Prolactin Receptor and pJAK2 in Type I Endometrial Cancer Cells in Young Women Without Insulin Resistance.

Elevated levels of serum prolactin and a high expression of prolactin receptor (PRLR) in cancer cells was recently identified in patients with endometrial cancer (EC). However, the impact of prolactin on EC remains unknown. The aim of this study was to elucidate the clinical and immunohistochemical characteristics of hyperprolactinemic patients with EC according to the pathogenetic types, type I and type II. EC patients were retrospectively divided into a high prolactin (HP) group and a low prolactin (LP) group by a serum prolactin level of 20 ng/mL and were compared between 2 groups. The expression of PRLR, phosphorylated Janus-kinase 2 (pJAK2), estrogen receptor-α, progesterone receptor, and PTEN in cancer tissue were evaluated by immunohistochemistry. Ninety-nine patients were identified. In the type I group, HP group was significantly younger (45.2 vs. 52.2, P=0.028) and their insulin resistance was significantly lower (1.6 vs. 2.5, P=0.033) than those in LP group, and the expression of PRLR and pJAK2 in the HP group was significantly higher than that in the LP group (immunoreactive score: 6.8 vs. 3.9, P=0.003; 5.7 vs. 2.6, P<0.001, respectively). In the type 2 group, there were no differences between all the term. In the type I group, the rate of loss of PTEN in the HP group was significantly lower than the LP group (25.0% vs. 60.7%, P=0.024). Prolactin-PRLR signaling may play a crucial role for the progression of type I EC without involving the PTEN mutation in young hyperprolactinemic women without insulin resistance.

Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-ß signaling in chronic kidney disease.

Renal fibrosis is a common pathological consequence of chronic kidney disease (CKD) with tissue fibrosis closely associated with chronic inflammation in numerous pathologies. However, molecular mechanisms underlying that association, particularly in the kidney, remain unclear. Here, we determine whether there is a molecular link between chronic inflammation and tissue fibrosis in CKD progression. Histological analysis of human kidneys indicated abundant expression of angiopoietin-like protein 2 (ANGPTL2) in renal tubule epithelial cells during progression of renal fibrosis. Numerous ANGPTL2-positive renal tubule epithelial cells colocalized with cells positive for transforming growth factor (TGF)-ß1, a critical mediator of tissue fibrosis. Analysis of M1 collecting duct cells in culture showed that TGF-ß1 increases ANGPTL2 expression by attenuating its repression through microRNA-221. Conversely, ANGPTL2 increased TGF-ß1 expression through α5ß1 integrin-mediated activation of extracellular signal-regulated kinase. Furthermore, ANGPTL2 deficiency in a mouse unilateral ureteral obstruction model significantly reduced renal fibrosis by decreasing TGF-ß1 signal amplification in kidney. Thus, ANGPTL2 and TGF-ß1 positively regulate each other as renal fibrosis progresses. Our study provides insight into molecular mechanisms underlying chronic inflammation and tissue fibrosis and identifies potential therapeutic targets for CKD treatment.

Prediction of sentinel lymph node status using single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging of breast cancer.

PURPOSE: Single-photon emission computed tomography (SPECT)/computed tomography (CT) improves the anatomical identification of sentinel lymph nodes (SNs). We aimed to evaluate the possibility of predicting the SN status using SPECT/CT. METHODS: SN mapping using a SPECT/CT system was performed in 381 cases of clinically node-negative, operable invasive breast cancer. We evaluated and compared the values of SN mapping on SPECT/CT, the findings of other modalities and clinicopathological factors in predicting the SN status. RESULTS: Patients with SNs located in the Level I area were evaluated. Of the 355 lesions (94.8 %) assessed, six cases (1.6 %) were not detected using any imaging method. According to the final histological diagnosis, 298 lesions (78.2 %) were node negative and 83 lesions (21.7 %) were node positive. The univariate analysis showed that SN status was significantly correlated with the number of SNs detected on SPECT/CT in the Level I area (P = 0.0048), total number of SNs detected on SPECT/CT (P = 0.011), findings of planar lymphoscintigraphy (P = 0.011) and findings of a handheld gamma probe during surgery (P = 0.012). According to the multivariate analysis, the detection of multiple SNs on SPECT/CT imaging helped to predict SN metastasis. CONCLUSIONS: The number of SNs located in the Level I area detected using the SPECT/CT system may be a predictive factor for SN metastasis.

Molecular Characteristics of Basaloid Squamous Cell Carcinoma of the Esophagus: Analysis of KRAS, BRAF, and PIK3CA Mutations and LINE-1 Methylation.

BACKGROUND: Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare carcinoma with distinct characteristics, and was recently recognized as a variant of squamous cell carcinoma (SCC). We previously revealed genetic and epigenetic alterations associated with esophageal SCCs in relation to clinical outcome, including mutations in KRAS, BRAF, and PIK3CA, p53 expression, and long interspersed nucleotide element-1 (LINE-1) methylation, a surrogate marker for global DNA methylation level. In this study, we explored these features in BSCC. METHODS: A database of 502 esophageal cancers was used to evaluate the clinical and molecular characteristics of BSCC. KRAS, BRAF, and PIK3CA mutations and LINE-1 methylation were analyzed by pyrosequencing. RESULTS: Of 502 tumors, 22 (4.4 %) were pathologically diagnosed as BSCC, and 440 (87 %) as SCC. No prognostic differences between BSCC and SCC cases were identified (p = 0.41). KRAS or BRAF mutations were not observed in BSCCs. While 23 % of SCC tumors harbored a PIK3CA mutation, all BSCC cases were wild-type for PIK3CA (p = 0.002), and there were no differences in p53 expression between BSCCs and SCCs (p = 0.57), as assessed by immunohistochemistry. Furthermore, BSCC tissues exhibited significantly lower levels of LINE-1 methylation than SCC tissues (p < 0.0001). CONCLUSIONS: These findings imply that esophageal BSCC and SCC retain different cellular phenotypes with distinct genetic and epigenetic alterations; thus, tailored therapeutic strategies should be developed against each cancer type.

Intra-abdominal mucinous adenocarcinoma of urachal origin: report of a case.

Intra-abdominal mucinous cystic tumors can be difficult to diagnose preoperatively. We report a case of histologically diagnosed primary urachal adenocarcinoma: a rare type of bladder tumor. This case report is interesting for clinicians. The patient was an 86-year-old man who presented with acute abdominal pain. Computed tomography (CT) showed a large cystic mass with calcification, near the apex of the urinary bladder. Laparotomy revealed a large intra-abdominal cystic mass adherent to the anterior abdominal wall and superior to the urinary bladder. We performed laparoscopic-assisted resection and partial cystectomy. The cystic mass measured approximately 15 × 14 × 11 cm and contained mucinous material. Histological examination revealed that it extended to the muscle of the bladder wall and that its epithelium was composed of atypical cells with increased papillary morphology. The mucinous material was glycoprotein with degenerative fatty tissue, and calcification was recognized partly in the specimen. Thus, we comprehensively diagnosed a mucinous cystic adenocarcinoma of urachal origin.

[Regression of primary rectal MALT lymphoma after Helicobacter pylori eradication].

A 74-year-old-man was referred to our hospital to undergo examination and therapy for a rectal polypoid lesion. MALT lymphoma of the rectum (stage IE) was diagnosed by performing a biopsy of the tumor during colonoscopy. The patient received eradication therapy against Helicobacter pylori (H. pylori) because of chronic gastritis due to H. pylori, and a complete remission was documented after this therapy. However, MALT lymphoma recurred 18 months later. Our observations in this case suggest that eradication therapy against H. pylori may be useful not only for gastric MALT lymphoma but also for colorectal MALT lymphoma.

Comparison of prognostic values between combined immunohistochemical score of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67 and the corresponding gene expression score in breast cancer.

In the clinical diagnosis of breast cancer, immunohistochemistry panels with estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki-67 are routinely used, and they have been proposed for the classification of breast tumors into distinct subtypes. Gene expression analysis with formalin-fixed paraffin-embedded material have also become widely available recently, but the prognostic values of corresponding gene panels compared with these four immunohistochemical panels had never tested. We independently evaluated the 5-year relapse risk-estimation scores using semiquantitative data of four immunohistochemical panels (Ku-IHC4 score) and compared these with the results of four-gene expression profiling of formalin-fixed paraffin-embedded specimens (Ku-FFPE4 score) in a consecutive series of 235 primary invasive breast cancer patients. Ku-IHC4 score was revealed to be an independent predictor of recurrence other than Ku-FFPE4 score in a multivariate model analyzed by classical clinical parameters (Ku-IHC4 score vs Ku-FFPE4 score; χ(2): 14.2 vs 2.5, P: 0.0002 vs 0.11). When patients were trichotomized into high-, intermediate- and low-risk groups using the thresholds determined from the approximately calculated 5-year relapse rate, Kaplan-Meier analyses showed a significant difference among the three groups in Ku-IHC4 score (log-rank, P<0.0001), but not in Ku-FFPE4 score. The high-risk group according to Ku-FFPE4 score showed contradictory low recurrence rates (Ku-IHC4 score vs Ku-FFPE4 score, 53.1 vs 24.8%), which might be caused by risk-dependently extended error ranges. We show that the Ku-IHC4 score, consisted with semiquantitative measures of immunohistochemistry, provides better prognostic information than the corresponding quantitative RNA measurements. Prognostication tools such as the Ku-IHC4 score may be potentially useful in screening which patients had better be assessed by further testing using other genes rather than ER, PgR, HER2 and Ki-67 to determine critical aspects of therapeutic decision making.

Differential expression of basement membrane type IV collagen α2 and α6 chains as a prognostic factor in patients with extrahepatic bile duct carcinoma.

BACKGROUND: The destruction of the basement membrane (BM) is the first step in cancer invasion and metastasis. Type IV collagen is a major component of the BM, and is composed of six genetically distinct α(IV) chains; α1(IV) to α6(IV). The loss of α5(IV) and α6(IV) chains from the epithelial BM at the early stage of cancer invasion has been reported in several types of cancers. However, the expression of α5(IV) and α6(IV) chains in extrahepatic bile duct carcinoma (EBDC) remains unclear. METHODS: We examined the expression of α(IV) chains by immunohistochemistry using 71 resected EBDC specimens. Prognostic significance of α(IV) chains was examined by Cox regression and Kaplan-Meier analyses. RESULTS: In the invasive cancer, the expression of α6(IV) chain in the BM was lost partially or completely preceded by the loss of α2(IV) chain. The loss of α6(IV) chain in the BM of the invasive cancer was related to the tumor classification, TNM stages, and the expression of α2(IV) chain. The patients with α2(IV)-negative and α6(IV)-negative chains had significantly poorer prognosis than those with α2(IV)-positive and α6(IV)-positive/negative chains (P = 0.04). CONCLUSIONS: The loss of α2(IV) and α6(IV) chains might be a useful prognostic factor in patients with EBDC.

Hidradenocarcinoma showing prominent mucinous and squamous differentiation and associated pagetoid cells.

Herein, we report a 63-year-old man presenting with hidradenocarcinoma showing prominent mucinous and squamous differentiation on his back. The tumor was dermal-based, solid and cystic. Tumor cells with squamous differentiation and with keratin pearl formation were identified predominantly in the superficial dermis, and mucinous cells were identified principally in the cystic lesion in the deep dermis. Interestingly, the additional feature of pagetoid cells was identified in the overlying epidermis. Both the mucinous cells in hidradenocarcinoma and pagetoid cells had intracytoplasmic mucin; however, they had different histopathologic findings and immunophenotypes. Mucinous cells in hidradenocarcinoma had small nuclei and abundant intracytoplasmic mucin presenting goblet cells with low rate of positive immunostaining for p53 and Ki67. In contrast, pagetoid cells had larger nuclei with less intracytoplasmic mucin. Both p53- and Ki67-positive cells were increased in pagetoid cells. Additionally, mucinous cells in hidradenocarcinoma were MUC1(+)/MUC2(-)/MUC5AC(+)/MUC6(+), but pagetoid cells were MUC1(+; focal)/MUC2(-)/MUC5AC(-)/MUC6(+; focal). The derivation of pagetoid cells is unclear; however, the localized small region of pagetoid cells over the hidradenocarcinoma in the present case may suggest a common histogenesis of these two malignant neoplasms.

Evaluation of tumor stiffness by elastography is predictive for pathologic complete response to neoadjuvant chemotherapy in patients with breast cancer.

BACKGROUND: Breast elastography (EG), which can objectively evaluate tumor stiffness, has been useful for differentiation of benign and malignant breast lesions. However, the value of EG for prediction of response to systemic therapy is poorly understood. METHODS: The baseline evaluations of EG in 55 patients who received neoadjuvant chemotherapy were reviewed. We investigated the correlation between tumor stiffness and response to neoadjuvant chemotherapy. Tumor stiffness was evaluated by the Tsukuba elasticity scoring system. RESULTS: The mean EG scores were significant lower for the clinical and pathologic complete response (pCR) groups than for the others. When we categorized patients into two groups according to tumor stiffness, 26 patients were assigned to the low EG group (soft, scores from 1 to 3) and 29 patients were assigned to the high EG group (hard, score 4 and 5). The low EG group had significantly higher clinical complete response and pCR rates than the high EG group (clinical complete response, low EG group 38 % vs. high EG group 10 %, P = 0.024; pCR, low EG group 50 % vs. high EG group 14 %, P = 0.003, respectively). Furthermore, multivariate analysis indicated that estrogen receptor, human epidermal growth factor receptor 2, and low EG (odds ratio 13.04, 95 % confidence interval 1.19-458.28, P = 0.035) were independent predictive factors of pCR. CONCLUSIONS: Tumor stiffness evaluated by EG bears predictive potential for response to neoadjuvant chemotherapy. Stiffness evaluated by EG may be recognized as a clinically significant tumor characteristic, comparable to other data obtained by functional imaging techniques.

Carcinogenesis of intraductal papillary mucinous neoplasm of the pancreas: loss of microRNA-101 promotes overexpression of histone methyltransferase EZH2.

BACKGROUND: The mechanisms of IPMN carcinogenesis are as yet unclear. This study aimed to determine whether expression of EZH2 promotes neoplastic progression of IPMN and PDCA, and to elucidate regulation of EZH2 expression by miR-101. METHODS: EZH2 mRNA and protein expression were investigated in 8 human pancreatic cancer cell lines by PCR and western blotting. Pre-miR-101 and anti-miR-101 were transfected into pancreatic cancer cells to elucidate EZH2 regulation by miR-101. To evaluate whether EZH2 modulates malignant progression of IPMN, EZH2 expression in IPMN was examined by immunohistochemistry. Next, we collected malignant and benign cells from FFPE samples of IPMNs using laser capture microdissection and extracted the RNA. miR-101 expression in IPMN was assessed using real-time PCR. RESULTS: All pancreatic cancer cell lines expressed EZH2 mRNA and protein. The induction of miR-101 by transfection of pre-miR-101 in MIA PaCa-2 was closely related to a reduction in EZH2 protein production compared with control, whereas there was little difference in the expression of EZH2 mRNA. Anti-miR-101 transfected pancreatic cancer cells showed an increase in EZH2 protein, while the level of EZH2 mRNA was not elevated. Immunohistochemistry revealed that the expression of EZH2 was significantly higher in malignant than benign IPMN. Expression of miR-101 was significantly lower in malignant IPMN than benign IPMN. CONCLUSIONS: MiR-101 targets EZH2 at the posttranscriptional level, and loss of miR-101 could be a trigger for the adenomacarcinoma sequence of IPMN by upregulation of EZH2. This study suggests miR-101-EZH2 blockade as a potential therapeutic target in IPMN carcinogenesis.

Fatty acid synthase is a predictive marker for aggressiveness in meningiomas.

Meningiomas are the most frequent intracranial tumors. Although most are benign WHO grade I tumors, grade II and III tumors are aggressive and survival is poor. Treatment options for grade II and III meningiomas are limited, and molecular targets are few. The re-programming of metabolic pathways including glycolysis, lipogenesis, and nucleotide synthesis is a hallmark of the physiological changes in cancer cells. Because fatty acid synthase (FAS), the enzyme responsible for the de-novo synthesis of fatty acids, has emerged as a potential therapeutic target for several cancers, we investigated its involvement in meningiomas. We subjected 92 paraffin-embedded samples from 57 patients with grade I, 18 with grade II and III, and six with radiation-induced tumors to immunohistochemical study of FAS. Whereas its expression was increased in grade II and III meningiomas (62.9 %) compared with grade I tumors (29.8 %) (chi-squared test: p < 0.001), FAS was expressed in grade I tumors with a high MIB-1 index and infiltration into surrounded tissues. All radiation-induced meningiomas expressed FAS and its expression was positively correlated with the MIB-1 index (p < 0.005). Our findings suggest that increased FAS expression reflects the aggressiveness of meningiomas and that it may be a novel therapeutic target for treatment of unresectable or malignant tumors.

Lymphatic vessel invasion detected by the D2-40 monoclonal antibody is an independent prognostic factor in node-negative esophageal squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: D2-40 staining has been reported to be useful for both identifying lymphatic vessel invasion (LVI) and counting lymphatic vessel density (LVD) in various cancers. The aim of this study was to clarify the prognostic significance of D2-40 staining in patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 159 consecutive patients with ESCC who underwent an esophagectomy with lymph node dissection were eligible. LVI was diagnosed by both hematoxylin-eosin (LVI-HE) and D2-40 staining (LVI-D2-40) in the largest central sections of the entire tumors, while both the intratumoral and peritumoral LVD were counted by D2-40 staining. The correlation between the prognosis and clinicopathological factors was investigated. RESULTS: An univariate analysis revealed that tumor invasion beyond the muscularis propria, lymph node metastasis (LNM), LVI-HE, LVI-D2-40, high intratumoral LVD, and blood vessel invasion correlated with worse patients' prognosis (P < 0.05). A multivariate analysis revealed LNM to be the only independent prognostic factor in all cases (P = 0.0083). On the other hand, when the prognostic factors of 83 patients without LNM were investigated, LVI-D2-40 was revealed to be the only independent prognostic factor (P = 0.048). CONCLUSIONS: LVI detected by D2-40 staining was an independent prognostic factor in patients with node-negative ESCC.

[A case of cancer of the pancreatic tail with disseminated carcinomatosis of the bone marrow].

Disseminated carcinomatosis of the bone marrow derived from solid cancer has a very poor prognosis, with disseminated intravascular coagulation(DIC). A 72-year-old man was admitted to our hospital after detection of a tumor in the pancreatic tail by CT imaging. Several images revealed that he suffered from cancer of the tail of the pancreas with multiple liver and bone metastases. Endoscopic ultra-sonography-guided fine needle aspiration detected adenocarcinoma cells from the tumor of the pancreatic tail. We also performed bone marrow aspiration, which confirmed adenocarcinoma cells in the bone marrow. We started to administer 1,000 mg/m2 of gemcitabine weekly. Laboratory data revealed that thrombocytopenia had occurred, and it developed into DIC after the first the administration of gemcitabine. In spite of the DIC state with thrombocytopenia, we were able to provide anticancer treatment using combination gemcitabine and S-1. He recovered from his DIC state, and the primary tumor was shrunk with a decrease of tumor markers after 2 courses of combination chemotherapy. Chemotherapy might be required for disseminated carcinomatosis of the bone marrow in order to promote tumor shrinkage and to prolonged expected survival, even if DIC was developed.

Pigmented hepatocellular adenoma: report of a case.

Hepatocellular adenoma is a rare, benign neoplasm that is related to the use of contraceptives or androgenic-anabolic steroids. A 51-year-old man with no history of steroid use was found to have a liver tumor. Plain computed tomography showed a high-density tumor that was enhanced in the arterial phase, and the enhancement was prolonged in the delayed phase. Magnetic resonance imaging showed that the tumor was hyperintense on in- and opposed-phase T1-weighted gradient recalled echo images and hyperintense on T1-weighted spin echo images. A partial hepatic resection was performed. A histological examination revealed normal hepatocyte-like tumor cells, composed of abundant dark brown granules of Dubin-Johnson-like pigment, which stained positively for Masson-Fontana stain. The tumor was diagnosed to be a very rare hepatocellular adenoma with the deposition of Dubin-Johnson-like pigment.

Phosphorylated mTOR expression is associated with poor prognosis for patients with esophageal squamous cell carcinoma.

BACKGROUND: The mammalian target of rapamycin (mTOR) plays central roles in the regulation of cell growth and proliferation by monitoring nutrient availability, cellular energy level, oxygen level, and mitogenic signals. The aberrant activation of mTOR in relation to clinical outcome has been reported in several types of cancers. mTOR is increasingly important as a potential target for anticancer therapy. Nonetheless, a prognostic feature of mTOR activation in esophageal squamous cell carcinoma (ESCC) remains uncertain. MATERIALS AND METHODS: First, in order to validate phospho-specific mTOR antibody (Ser2448), phosphorylated mTOR (p-mTOR) expression levels in five ESCC cell lines under cultural conditions with or without everolimus (mTOR inhibitor, also known as RAD001) were evaluated by in vitro immunohistochemistry and immunoblotting. Second, we examined p-mTOR expression by immunohistochemistry using 143 resected ESCC specimens. Prognostic significance of p-mTOR expression was examined by Cox regression and Kaplan-Meier analyses. RESULTS: Among 143 patients, 71 (49.7%) were classified into p-mTOR-positive and 72 (50.3%) were classified into p-mTOR-negative. Compared with p-mTOR-negative patients, p-mTOR-positive patients experienced high overall mortality [hazard ratio (HR) 2.44; 95% confidence interval (CI), 1.24-4.83; P = 0.008], which persisted in multivariate analysis (multivariate HR 2.92; 95% CI, 1.48-5.78; P = 0.002). A similar finding was observed for esophageal cancer-specific mortality. p-mTOR expression was not related with any clinical or pathologic variables including age, sex, tumor location, histological grading, operative procedure, T classification (tumor invasion), or lymph-node metastasis. CONCLUSIONS: p-mTOR overexpression was independently associated with poor prognosis in ESCC, supporting the potential for mTOR as a therapeutic target for ESCC.

Macrophages in Langerhans cell histiocytosis are differentiated toward M2 phenotype: their possible involvement in pathological processes.

Although numerous macrophages are found in the lesions of Langerhans cell histiocytosis (LCH), their activation phenotypes and their roles in the disease process have not been clarified. Paraffin-embedded LCH samples were examined on immunohistochemistry and it was found that CD163 can be used to distinguish infiltrated macrophages from neoplastic Langerhans cells (LC). The number of CD163-positve macrophages was positively correlated with the number of multinucleated giant cells (MGC), indicating that most MGC are derived from infiltrated macrophages. A significant number of CD163-positive macrophages were positive for interleukin (IL)-10 and phospho-signal transducer and activator of transcription-3 (pSTAT3), an IL-10-induced signal transduction molecule. This indicates that these macrophages are polarized to anti-inflammatory macrophages of M2 phenotype. Tumor-derived macrophage-colony-stimulating factor (M-CSF) was considered to responsible for inducing M2 differentiation of infiltrated macrophages. The number of CD163-positive macrophages in different cases of LCH varied, and interestingly the density of CD163-positive macrophages was inversely correlated with the Ki-67-positivity of LC. Although the underlying mechanism is not fully elucidated, macrophage-derived IL-10 was considered to be involved in the suppression of tumor cell proliferation via activation of STAT3.

A case of ectopic adrenocorticotropic hormone-producing pancreatic neuroendocrine tumor with multiple liver metastases.

Ectopic adrenocorticotropic hormone (ACTH) production by the pancreatic neuroendocrine tumor (p-NET) is relatively rare, and patients with this tumor show poor prognosis. In this study, we present the case of a 64-year-old woman who presented with ectopic ACTH syndrome due to p-NET with multiple liver metastases. Computed tomography revealed that she had multiple masses in the liver and a solid mass in the head of the pancreas. Endocrinological examinations revealed markedly elevated plasma ACTH (735.0 pg/mL) and cortisol (34.7 microg/dL) levels associated with hypokalemia (2.7 mEq/L), diabetes and typical Cushingoid features. Histological examinations by needle biopsy of liver tumors in S5 and S8 indicated metastatic ACTH-producing NET, which was also confirmed by venous sampling. The metastatic live tumor was somatostatin receptor (SSTR)-2a- and SSTR-5-positive as revealed by immunohistochemical staining, and reverse transcription polymerase chain reaction revealed divergent expression patterns of SSTRs, pro-opiomelanocortin, and gastrin mRNA. To avoid complications of hypercortisolemia, metyrapone was first administered to reduce the cortisol levels. After near-normalization of cortisol levels, transarterial chemoembolization and somatostatin analogue treatment were performed. The combination of these treatments effectively decreased ACTH and cortisol levels and also ameliorated hyperglycemia. We have achieved controlled hormone secretion and prevented tumor growth in this patient for more than 20 months, suggesting that highly individualized treatment for NET should be undertaken because of its divergent and heterogeneous characteristics.