Publications by authors named "Yoichiro Okubo"

61 Publications

Thyroid-Associated Ophthalmopathy after Radioactive Iodine Therapy for Metastatic Follicular Thyroid Carcinoma.

Case Rep Endocrinol 2021 11;2021:3024639. Epub 2021 Jun 11.

Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, 2-3-2 Nakao Asahi-ku, Yokohama, Kanagawa 241-8515, Japan.

Thyroid-associated ophthalmopathy (TAO) is an inflammation of the extraocular muscles and periorbital connective tissue caused by autoantibodies against common antigens to both the thyroid and orbit. The release of antigens and induction of hypothyroidism caused by radioactive iodine (RAI) therapy may exacerbate TAO. Here, we present the case of a 67-year-old-woman treated with RAI therapy for metastatic follicular thyroid carcinoma who presented with TAO during the course of sorafenib administration. Tg and TgAb levels were gradually decreased with sorafenib and lenvatinib treatment, and TAO was improved without any ophthalmologic treatment.
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http://dx.doi.org/10.1155/2021/3024639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213507PMC
June 2021

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

J Anus Rectum Colon 2021 28;5(2):167-172. Epub 2021 Apr 28.

Department of Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.

Objectives: Molecular profiling of marker mutations has become an essential aspect in the treatment planning for colorectal cancer (CRC). Anaplastic lymphoma kinase () 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.
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http://dx.doi.org/10.23922/jarc.2020-068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084530PMC
April 2021

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

Transl Lung Cancer Res 2021 Mar;10(3):1292-1304

Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.

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 (7/16 cases), (6/16 cases), (4/16 cases), (3/16 cases), (3/16 cases), (2/16 cases), and (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 and . 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 mutations. The microsatellite instability, tumor mutation burden, and PD-L1 expression status suggest a poor response to immune checkpoint therapy.
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http://dx.doi.org/10.21037/tlcr-20-1158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044470PMC
March 2021

Intraoperative extracorporeal irradiation for giant sarcoma-infiltrated calvarium: a case report.

Br J Neurosurg 2021 Feb 28:1-5. Epub 2021 Feb 28.

Department of Neurosurgery, Kanagawa Cancer Center, Yokohama, Japan.

Large bone defects that occur after resection of calvarial tumours are commonly remedied using titanium meshes or bone prostheses. However, these methods have several problems. While intraoperative extracorporeal radiotherapy for bone flaps could avoid these problems, there have been only a few reports wherein meningiomas were treated with 120 Gy irradiation. Moreover, no reports are available on calvarial metastasis of sarcoma, and the therapeutic radiation dose remains uncertain. Here, we report a case of giant calvarial metastasis of myxoid liposarcoma treated with intraoperative extracorporeal radiotherapy at a dose of 50 Gy. The treatment resulted in successful tumour control followed by favourable bone reconstruction.
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http://dx.doi.org/10.1080/02688697.2021.1888875DOI Listing
February 2021

Histopathological study of carcinoma showing thymus-like differentiation (CASTLE).

Malays J Pathol 2020 08;42(2):259-265

Kanagawa Cancer Center, Department of Pathology, 2-3-2, Nakao, Asahi-Ku, Yokohama, Kanagawa, 241-8515, Japan.

Introduction: Carcinoma showing thymus-like differentiation (CASTLE) is a rare tumour that mainly arises from the thyroid gland, or occasionally, from the head and neck. Although the 10-year survival rate of patients with CASTLE is approximately 80%, local recurrence and distant metastasis are observed in some cases. A recent systematic review for CASTLE indicated that the prognostic factors are treatment-dependent, and postoperative radiotherapy significantly improves patient survival.

Case Report: Herein, we describe and compare three cases of CASTLE, including a case with distant metastasis despite administering postoperative chemotherapy. Thus, the mechanisms underlying metastasis of CASTLE are unclear. This case study helps to elucidate the histopathological risk factors of metastasis in CASTLE.

Discussion: We found that prominent lymphovascular invasion and higher proliferative activities might be risk factors of metastasis in CASTLE. In addition, we have summarised the cytological, morphological, and immunohistochemical features of CASTLE for an accurate diagnosis.
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August 2020

Membrane type 1 matrix metalloproteinase regulates anaplastic thyroid carcinoma cell growth and invasion into the collagen matrix.

Biochem Biophys Res Commun 2020 09 4;529(4):1195-1200. Epub 2020 Aug 4.

Organoid Biology Unit, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Electronic address:

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive cancer types; however, the molecular mechanism contributing to the aggressive characteristics remain unclear. Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an important role in cancer invasion and has been associated with a poor prognosis in various malignant neoplasms. In this study, we investigated the relationship between MT1-MMP expression and the proliferation and invasion of ATC cells, along with the association with clinicopathologic factors in patients with ATC. Suppression of MT1-MMP reduced the proliferation and invasion of ATC cells, and suppressed ERK activity, indicating a role in cancer cell proliferation in collagen matrix culture conditions. The expression of MT1-MMP was detected in 29 of 34 (85.3%) surgical specimens from ATC patients. In addition, the expression of MT1-MMP in the tumor lesion was higher than that of normal and stromal tissues. Collectively, these results suggest that elevated MT1-MMP expression plays a role in the pathogenesis of ATC, which may promote its aggressive characteristics such as proliferation and invasion, highlighting a potential new therapeutic target.
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http://dx.doi.org/10.1016/j.bbrc.2020.06.043DOI Listing
September 2020

A Case of Unresectable Papillary Thyroid Carcinoma Treated with Lenvatinib as Neoadjuvant Chemotherapy.

Case Rep Endocrinol 2020 11;2020:6438352. Epub 2020 May 11.

Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan.

A 75-year-old woman visited a nearby clinic with complaints of right clavicle discomfort, and she underwent diagnostic thoracoscopic lung biopsy, being diagnosed with lung metastasis and a right-upper mediastinal mass. The superior mediastinum mass was extrapulmonary and covered by the pleura, and it was not biopsied. Papillary thyroid carcinoma was diagnosed following biopsy of the lung metastasis. Only a small tumor, with a maximum diameter of 70 mm from the right neck to the superior mediastinum, in the thyroid gland invades the internal jugular vein and subclavian vein, forming a tumor embolus in the right brachiocephalic vein and reaching the vicinity of the superior vena cava. For life-saving purposes, we obtained approval from the Cancer Board of Kanagawa Cancer Center and used lenvatinib according to unresectable undifferentiated cancer IRB approval number 28-41. The tumor had shrunk after 4 months, and surgery was performed. The postoperative course has been good, and the patient is being followed up. The patient is alive three months after surgery, and lung metastases have disappeared on CT images. This case is reported as a successful case of neoadjuvant chemotherapy and interval debulking surgery.
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http://dx.doi.org/10.1155/2020/6438352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238324PMC
May 2020

Clinicopathological and molecular features of hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinomas.

J Clin Pathol 2020 Dec 6;73(12):819-825. Epub 2020 May 6.

Urology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.

Aims: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies.

Methods: Ten Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for was carried out. Somatic mutations in and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours.

Results: All patients had germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing ; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence.

Conclusions: HLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.
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http://dx.doi.org/10.1136/jclinpath-2020-206548DOI Listing
December 2020

Occult Thyroid Carcinoma without Malignant Thyroid Gland Findings during Preoperative Examination: Report of Three Cases.

Case Rep Endocrinol 2020 10;2020:4249067. Epub 2020 Apr 10.

Department of Surgery, Yokohama City University School of Medicine, Yokohama, Japan.

Occult thyroid carcinoma preceded by clinical manifestations and findings from extrathyroidal tumors is rare. The lack of malignant findings in the thyroid during the preoperative examination makes diagnosis difficult. We encountered a 71-year-old man with a primary ectopic thyroid carcinoma causing superior vena cava syndrome. Although no malignant findings were found in the thyroid gland, biopsy of bone metastases led to the diagnosis of thyroid cancer. HE staining of bone metastases revealed nuclear features of papillary carcinoma, and immunostaining was positive for thyroglobulin and PAX-8. The second case involved an 84-year-old man with a mediastinal tumor and suspected thyroid cancer because of high thyroglobulin levels in blood. The pathological tumor finding was papillary thyroid cancer. The last case was that of a 56-year-old woman lacking preoperative thyroid examination malignant findings, but with cervical lymph node metastasis. The thyroglobulin level of the lymph node puncture fluid was useful for preoperative diagnosis. We performed total thyroidectomy plus bilateral modified neck dissection. Pathology revealed a 1 mm papillary carcinoma in the left lobe. All of these cases were difficult to diagnose. However, we combined the results of various tests such as radiographic imaging, blood tests, and immunohistological tests to diagnose our patients.
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http://dx.doi.org/10.1155/2020/4249067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171659PMC
April 2020

[A Case of Long-Term Survival after Multidisciplinary Treatment for Gastrointestinal Neuroendocrine Carcinoma].

Gan To Kagaku Ryoho 2019 Dec;46(13):2270-2272

Dept. of Gastrointestinal Surgery, Kanagawa Cancer Center.

A 55-year-old man was admitted to our hospital for examination and treatment of a transverse colon tumor detected at a nearby hospital. After CT, FDG-PET, and laparotomy biopsy, he was diagnosed with neuroendocrine cancer(Ki-67 index 40%)without distant metastasis. He underwent transverse colectomy. The pathological diagnosis was transverse colon neuroendocrine cancer(Ki-67 index 24.7%). Six courses of carboplatin and etoposide therapy as adjuvant chemotherapy were administered. Seven months after surgery, he developed lung metastasis that was surgically removed by partial lung resection. Eighteen months after the initial surgery, liver metastasis developed in S5 and S8. A right hepatic lobectomy was performed and there has been no recurrence after hepatectomy. The patient remains alive at 3 years and 4 months after initial treatment.
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December 2019

Gangliocytic paraganglioma: An overview and future perspective.

Authors:
Yoichiro Okubo

World J Clin Oncol 2019 Sep;10(9):300-302

Department of Pathology, Kanagawa Cancer Center, Yokohama, Kanagawa 241-8515, Japan.

Gangliocytic paraganglioma (GP) is rare neuroendocrine tumor (NET) with a good prognosis that commonly arising from duodenum. Although the tumor is characterized by its unique triphasic cells (epithelioid, spindle, and ganglion-like cells), the proportions of these three tumor cells vary widely from case to case, and occasionally, morphological and immunohistochemical similarities are found between GP and NET G1 (carcinoid tumors). Further, GP accounts for a substantial number of duodenal NETs. Therefore, GP continues to be misdiagnosed, most often as NET G1. However, GP has a better prognosis than NET G1, and it is important to differentiate GP from NET G1. In this article, I wish to provide up-to-date clinicopathological information to help oncologists gain better insight into the diagnosis and clinical management of this tumor.
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http://dx.doi.org/10.5306/wjco.v10.i9.300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766464PMC
September 2019

Two cases of thyroid gland invasion by upper mediastinal carcinoma

Endocrinol Diabetes Metab Case Rep 2019 Jun 30;2019(1). Epub 2019 Jun 30.

Department of Surgery, Yokohama City University School of Medicine, Yokohama, Japan

Summary: The objective this study is to report two cases of thyroid gland invasion by upper mediastinal carcinoma. Mediastinal tumors are uncommon and represent 3% of the tumors seen within the chest. In reports on mediastinal masses, the incidence of malignant lesions ranged from 25 to 49%. The thyroid gland can be directly invaded by surrounding organ cancers. We report these cases contrasting them to the case of a thyroid cancer with mediastinal lesions. Case 1 was a 73-year-old woman who was diagnosed with papillary thyroid carcinoma, and she underwent surgery and postoperative radioactive iodine. Case 2 was a 74-year-old man who was diagnosed with non-small-cell lung carcinoma, favor squamous cell carcinoma, and he underwent chemoradiotherapy. Case 3 was a 77-year-old man who was diagnosed a thymic carcinoma based on pathological findings and referred the patient to thoracic surgeons for surgical management. The images of the three cases were similar, and the differential diagnoses were difficult and required pathological examination. Primary thyroid carcinoma and invading carcinoma originating from the adjacent organs need to be distinguished because their prognoses and treatment strategies are different. It is important to properly diagnose them by images and pathological findings.

The thyroid gland in the anterior neck can be directly invaded by surrounding organ cancers. Primary thyroid carcinoma and invading carcinoma originating from the adjacent organs need to be distinguished because their prognoses and treatment strategies are different. It is important to properly diagnose by images and pathological findings.
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http://dx.doi.org/10.1530/EDM-19-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589857PMC
June 2019

GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer.

Int J Cancer 2020 03 22;146(5):1369-1382. Epub 2019 Jul 22.

Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Japan.

The prognosis of patients with progressive prostate cancers that are hormone refractory and/or have bone metastasis is poor. Multiple therapeutic targets to improve prostate cancer patient survival have been investigated, including orphan GPCRs. In our study, we identified G Protein-Coupled Receptor Class C Group 5 Member A (GPRC5A) as a candidate therapeutic molecule using integrative gene expression analyses of registered data sets for prostate cancer cell lines. Kaplan-Meier analysis of TCGA data sets revealed that patients who have high GPRC5A expression had significantly shorter overall survival. PC3 prostate cancer cells with CRISPR/Cas9-mediated GPRC5A knockout exhibited significantly reduced cell proliferation both in vitro and in vivo. RNA-seq revealed that GPRC5A KO PC3 cells had dysregulated expression of cell cycle-related genes, leading to cell cycle arrest at the G2/M phase. Furthermore, the registered gene expression profile data set showed that the expression level of GPRC5A in original lesions of prostate cancer patients with bone metastasis was higher than that without bone metastasis. In fact, GPRC5A KO PC3 cells failed to establish bone metastasis in xenograft mice models. In addition, our clinical study revealed that GPRC5A expression levels in prostate cancer patient samples were significantly correlated with bone metastasis as well as the patient's Gleason score (GS). Combined assessment with the immunoreactivity of GPRC5A and GS displayed higher specificity for predicting the occurrence of bone metastasis. Together, our findings indicate that GPRC5A can be a possible therapeutic target and prognostic marker molecule for progressive prostate cancer.
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http://dx.doi.org/10.1002/ijc.32554DOI Listing
March 2020

[A Case of Mediastinal Lymph Node Recurrence after Endoscopic Submucosal Dissection of Esophageal Cancer].

Gan To Kagaku Ryoho 2018 Dec;45(13):2297-2299

Dept. of Gastrointestinal Surgery, Kanagawa Cancer Center.

We report a case of mediastinal lymph node recurrence of esophageal cancer after endoscopic submucosal dissection (ESD). We first administered chemotherapy and then performed esophagectomy. A 78-year-old man underwent ESD for early esophageal cancer at a different hospital in January 2015. H e was diagnosed pathologically with scc, pSM1, pHM1, pVM0, ly0, v0. Additional treatment was not administered because of his age. In June 2017, chest enhanced CT showed swollen mediastinal lymph nodes. This was diagnosed as a recurrence of esophageal cancer, and he presented at our hospital. We first performed chemotherapy for that lesion, because the swollen lymph node was large and may have invaded the surrounding organs. We then performed esophagectomy.
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December 2018

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

Front Oncol 2018 27;8:291. Epub 2018 Jul 27.

Department of Pathology, Kanagawa Cancer Center, Kanagawa, Japan.

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. 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. 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. 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.
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http://dx.doi.org/10.3389/fonc.2018.00291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072869PMC
July 2018

Hereditary leiomyomatosis and renal cell cancer without cutaneous manifestations in two Japanese siblings.

Int J Urol 2018 09 29;25(9):832-835. Epub 2018 Jul 29.

Department of Urology, Kanagawa Cancer Center, Yokohama, Japan.

Hereditary leiomyomatosis and renal cell cancer is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis, and an aggressive type 2 papillary renal cell carcinoma. The disease is caused by a germline mutation in the fumarate hydratase gene. We report a familial hereditary leiomyomatosis and renal cell cancer in two siblings. A 34-year-old woman underwent nephrectomy for treatment of a renal cell carcinoma. The patient's sister had been diagnosed with renal cell carcinoma at 28 years-of-age and died of the disease. Neither sister had apparent skin tumors. Histopathology of the renal cell carcinomas of the siblings showed tubulocystic and papillary architectures with high nuclear grades. Immunostaining showed no fumarate hydratase expression in either tumor. Genomic DNA sequencing of the patient showed a germline mutation in the fumarate hydratase gene (c.675delT). Although there is no epidemiological information on Asian hereditary leiomyomatosis and renal cell cancer, physicians should be aware that typical cutaneous leiomyomatosis might not always be present in patients with hereditary leiomyomatosis and renal cell cancer.
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http://dx.doi.org/10.1111/iju.13760DOI Listing
September 2018

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

Mod Pathol 2018 09 21;31(9):1404-1417. Epub 2018 May 21.

Department of Pathology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.

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.
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http://dx.doi.org/10.1038/s41379-018-0057-zDOI Listing
September 2018

[A Case of Unresectable Advanced Gastric Cancer Treated by Seven Courses of Chemotherapy with Docetaxel, Cisplatin, and S-1Followed by Conversion Surgery Achieved Five Year Relapse Free Survival].

Gan To Kagaku Ryoho 2018 Apr;45(4):755-757

Dept. of Gastrointestinal Surgery, Kanagawa Cancer Center.

The patient is a 51-year-old man.Upper gastrointestinal endoscopy revealed gigantic type 3 gastric cancer.Enhanced abdominal CT demonstrated a gigantic mass of 15×7 cm in the stomach, and a large number of peritoneal dissemination with moderate amount of ascites.The patient was diagnosed with cT4aN3bM1(peritoneal dissemination), Stage IV gastric cancer(JPN ver8)and was treated by chemotherapy with docetaxel(40mg/m / 2 day 1)plus cisplatin(60mg/m2 day 1)plus S-1(80mg/m2 day 1-14).After 7 courses of chemotherapy, peritoneal dissemination was disappeared.The patient received total gastrectomy and D2 lymphadenectomy as a conversion surgery.The pathological findings revealed a T0N0M0, stage 0; the tumor was determined to be Grade 3 owing to the chemotherapeutic effect.Without postoperative adjuvant therapy, the patient is alive without recurrence at the 5 years follow-up after operation.
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April 2018

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

BMC Cancer 2017 Nov 16;17(1):769. Epub 2017 Nov 16.

Department of Pathology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-Ku, Yokohama, Kanagawa, 241-8515, Japan.

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.
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http://dx.doi.org/10.1186/s12885-017-3769-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693490PMC
November 2017

Gangliocytic Paraganglioma Is Often Misdiagnosed as Neuroendocrine Tumor G1.

Authors:
Yoichiro Okubo

Arch Pathol Lab Med 2017 10;141(10):1309

Department of Pathology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-Ku, Yokohama, Kanagawa, Japan.

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http://dx.doi.org/10.5858/arpa.2017-0102-LEDOI Listing
October 2017

Gangliocytic Paraganglioma: a Diagnostic Pitfall of Rare Neuroendocrine Tumor.

Authors:
Yoichiro Okubo

Endocr Pathol 2017 06;28(2):186

Department of Pathology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-Ku, Yokohama, Kanagawa, 241-8515, Japan.

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http://dx.doi.org/10.1007/s12022-017-9481-8DOI Listing
June 2017

Neuroendocrine Differentiation in Breast Cancer: Clinicopathological Significance of Bcl-2 Positive Solid Papillary Carcinoma.

Case Rep Med 2016 25;2016:9501410. Epub 2016 Dec 25.

Department of Pathology, Chiba Cytopathological Center, 5-27-8 Nishifuna, Funabashi, Chiba 273-0031, Japan.

Solid papillary carcinoma (SPC) is considered a rare malignant breast tumor. Maluf and Koerner first reported this disease entity as a special type of ductal carcinoma in situ with several characteristic histopathological features, including low-grade cellular atypia, intracellular or extracellular mucin deposition, and solid papillary growth pattern, as well as neuroendocrine differentiation. The present paper describes a case of SPC with bcl-2 expression, which is known as a marker for malignancy of neuroendocrine tumors. Interestingly, despite bcl-2 expression being a poor prognostic indicator of neuroendocrine tumors, the patient with this tumor has achieved long-term survival (approximately 6 years) at the time of writing this report. Because previous investigators reported that bcl-2 expression might play a role in the inhibition of the development of breast cancer, we suggest that bcl-2 expression might reflect a good prognosis in patients with SPC, rather than being a poor prognostic indicator, as it is in several types of neuroendocrine tumor. However, to confirm this hypothesis, further investigation is required.
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http://dx.doi.org/10.1155/2016/9501410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220427PMC
December 2016

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

Gastroenterol Res Pract 2016 21;2016:5257312. Epub 2016 Dec 21.

Department of Pathology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-Ku, Yokohama, Kanagawa 241-8515, Japan.

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.
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http://dx.doi.org/10.1155/2016/5257312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209618PMC
December 2016

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

Diagn Pathol 2016 Nov 8;11(1):128. Epub 2016 Nov 8.

Department of Pathology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-Ku, Yokohama, Kanagawa, 241-8515, Japan.

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/mm to 73.9/mm and LMVD values from 0/mm to 22.9/mm. 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.
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http://dx.doi.org/10.1186/s13000-016-0580-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100185PMC
November 2016

Evasion of Innate Immune Responses by the Highly Virulent Cryptococcus gattii by Altering Capsule Glucuronoxylomannan Structure.

Front Cell Infect Microbiol 2015 6;5:101. Epub 2016 Jan 6.

Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases Tokyo, Japan.

Cryptococcus neoformans causes life-threatening diseases mainly in immunosuppressed hosts such as AIDS patients; C. gattii causes disseminated infections even in healthy hosts. To identify the possible molecular mechanisms underlying this difference in virulence, we investigated the survival and histopathology of lung tissue in wild-type and CD4-depleted mice infected with C. neoformans H99 and C. gattii JP02 (the highly virulent strain isolated in Japan); we then compared dendritic cell (DC) cytokine release responses to different cell fractions from these two strains. JP02-infected mice exhibited shorter survival and fewer inflammatory cells in the lung than H99-infected control mice. Depletion of CD4-related cellular immunity reduced survival of H99-infected mice but had no effect on the survival or inflammatory cell infiltration in JP02-infected mice, suggesting that JP02 evades immune detection. To identify the molecule(s) conferring this difference, we measured cytokine production from murine DCs co-cultured with H99 and JP02 in vitro. The levels of inflammatory cytokines from DCs treated with intact JP02 cells, the extracted capsule, secreted extracellular polysaccharides, and purified glucuronoxylomannan (GXM) were markedly lower than those induced by intact H99 cells and corresponding H99 fractions. Structural analysis of GXM indicated that JP02 altered one of two O-acetyl groups detected in the H99 GXM. Deacetylated GXM lost the ability to induce inflammatory cytokine release from DCs, implicating these O-acetyl groups in immune recognition. We conclude that the highly virulent C. gattii processes a structural alteration in GXM that allows this pathogen to evade the immune response and therefore elimination.
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http://dx.doi.org/10.3389/fcimb.2015.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701946PMC
June 2016

Investigation of ossification in the posterior longitudinal ligament using micro-focus X-ray CT scanning and histological examination.

Diagn Pathol 2015 Nov 21;10:205. Epub 2015 Nov 21.

Department of Orthopedic Surgery, Toho University Omori Medical Center, 6-11-1, Omori-Nishi, Ota-Ku, Tokyo, 143-8541, Japan.

Background: Ossification in the posterior longitudinal ligament (PLL) correlates with changes of enthesis during the early stages of development, but this issue remains controversial, as little is known regarding the details of this process. The aim of the present study was to elucidate part of the ossification mechanism. Thus, in the present study, we observed and evaluated minute ossifications in the PLL that did not exhibit symptoms of ossification of the posterior longitudinal ligament (OPLL).

Methods: The subjects in the present study were derived from serial autopsy cases from January 2009 to December 2013 at Toho University Omori Medical Center, Japan. Minute ossifications in the PLL from autopsy subjects without any history of OPLL were screened as high-density areas using micro-focus X-ray CT, and the foci were histologically examined. Subsequently, we conducted both micro-focus X-ray CT image analysis and histological examination, and evaluated the correlation between these findings and putative predictive factors reported in previous studies.

Results: A total of 103 individuals among the 267 subjects involved in the present study were analyzed within the study period. There were no cases involving OPLL identification prior to death, and no subjects presented with neurological symptoms of myelopathy. The incidence of cases involving high-density areas greater than 0.1 mm(2) in the PLL was 46.6 %, half of which revealed mature bone structures inside this area. Thus, the high-density areas comprised three types: a continuous posterior-annular fibrosus type (23 cases), an isolated posterior-annular fibrosus type (11 cases), and a posterior-vertebral type (29 cases). However, a positive correlation was observed between the proportion of high-density areas, age (Pearson r = 0.265, p < 0.01), and HbA1c (Pearson r = 0.294, p < 0.01). Histological examination confirmed that these high-density areas involved calcification with or without mature bone formation.

Conclusions: We evaluated minute foci of calcification with and without ossification in the PLL from 103 cadavers, generating the following observations: 1. Minute calcification foci greater than 0.1 mm(2) were observed in the PLL of 48 cases (46.6 %), half of which revealed mature bone structures inside this area (23.3 %). 2. The proportion of minute calcification foci observed in the present study was correlated with age and glucose tolerance, suggesting changes in the OPLL in the early stage. 3. Three different mechanisms of ossification were suggested: The two structures developed behind the disc might reflect the elongation of enthesis or rupture of annular fibrosus, while the remaining structure developed behind the vertebral body might reflect a dystrophic calcification-based bony metaplasia sequence.
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http://dx.doi.org/10.1186/s13000-015-0440-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654799PMC
November 2015

Simultaneous resection of bilateral anomalous systemic supply to the basal segments of the lungs: a case report.

J Cardiothorac Surg 2015 Oct 31;10:140. Epub 2015 Oct 31.

Division of Chest Surgery, Toho University School of Medicine, Tokyo, Japan.

Background: Anomalous systemic arterial supply to the normal basal lung segments is a sequestration spectrum variant (Pryce type 1) that is distinguished from pulmonary sequestration by normal bronchopulmonary and parenchymal tissues.

Case Presentation: A 33-year-old Japanese man was referred to our hospital because of an abnormal pulmonary shadow. Computed tomography showed two aberrant arteries arising from the descending aorta and running into the lower lung lobes on each side, without any bronchial anomaly. He was diagnosed with bilateral anomalous systemic supply to the basal segments. A left thoracotomy was performed and the aberrant arteries were ligated and dissected at their origin followed by left basal segmentectomy. Simultaneous right S10 segmentectomy was performed under video-assisted thoracic surgery.

Conclusion: Although bilateral anomalous systemic arterial supply to the basal segments is extremely rare, knowledge of this anomaly should allow for a definitive diagnosis and appropriate therapy.
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http://dx.doi.org/10.1186/s13019-015-0366-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628301PMC
October 2015

Histological study of chronic pulmonary aspergillosis.

Diagn Pathol 2015 Sep 3;10:153. Epub 2015 Sep 3.

Department of Surgical Pathology, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.

Background: Chronic pulmonary aspergillosis (CPA) has been accepted the criteria for the diagnosis of pulmonary Aspergillus infection. Whereas, either pathophysiology or signs of CPA remains still controversial.

Methods: In this study, we histopathologically investigated 25 specimens of CPA, surgically resected.

Results: 21 (84 %) of that comprised male. There were 21 cases with mild impairment of the immune system and/or a scar mostly due to old tuberculosis. There is a tendency for a negative correlation between peripheral blood white cell numbers and value level of beta-(1,3)-D-glucan. Four cases showed a granular fluorescent signal in granulation tissue surrounding the cavity without the fungal aspects itself.

Conclusions: In conclusion, acute inflammatory exudate along the terminal respiratory tract is most significant pathophysiolocial complication of the CPA, caused to organizing pneumonia, which derives fatal respiratory failure. In addition, the viability of fungus does not concern extension of exudative inflammation at the site of erosion along terminal airway.
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http://dx.doi.org/10.1186/s13000-015-0388-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558778PMC
September 2015

A case of postoperative hepatic granuloma presumptively caused by surgical staples/clipping materials.

Diagn Pathol 2015 Jul 9;10:90. Epub 2015 Jul 9.

Department of Surgical Pathology, Toho University School of Medicine, 6-11-1 Omori-Nishi, 143-8541, Ota-Ku, Tokyo, Japan.

A 66-year-old man with postsigmoidectomy status for colon cancer received laparoscopic partial hepatectomy due to a hepatic mass with employing titanium clips were for a vascular clamp. Histological examination showed liver metastasis from sigmoid colon cancer. Twenty-nine months after the partial hepatectomy, a mass developed on the stump at the hepatic resection. Laparoscopic left lateral segmentectomy was conducted under suspicion of cancer recurrence and an automatic titanium stapling device was used. The macroscopically cut surface of the liver showed a grey-white solid nodule measuring 23 x 20 mm and involving metal clips. The nodule was consistent with granuloma microscopically. Twenty-three months after the segmentectomy, a mass reappeared on the hepatic radial margin and an open left lateral hepatic lobectomy was performed because of its growth tendency. Histopathological examination revealed granuloma similar to the previous instance. Since these nodules formed a granulomatous lesion surrounding metal staples/clips and evidence of caseous necrosis was lacking, granuloma due to surgical staples/clips was suspected. Sporadic case reports of postoperative pulmonary granuloma at the staple line have been published previously, but there are no articles detailing a case involving hepatic granuloma. We present our case as the first report of postoperative staple-line hepatic granuloma.
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http://dx.doi.org/10.1186/s13000-015-0291-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495706PMC
July 2015

Gangliocytic paraganglioma: a multi-institutional retrospective study in Japan.

BMC Cancer 2015 Apr 12;15:269. Epub 2015 Apr 12.

Department of Surgical Pathology, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan.

Background: Gangliocytic paraganglioma (GP) is an extremely rare benign tumor that commonly arises from the second part of the duodenum. Since GP exhibit neither prominent mitotic activity nor Ki-67 immunoreactivity, this tumor is often misdiagnosed as neuroendocrine tumor (NET) G1 (carcinoid tumor). However, patients with GP may have a better prognosis than patients with NET G1. This fact emphasizes the importance of differentiating GP from NET G1, but few studies have reported the epidemiology and histopathology of GP because of its rarity. To differentiate GP from NET G1 with ease, we conducted a multi-institutional retrospective study analyzing the morphometric and immunohistochemical features of this tumor.

Methods: Since only a limited number of patients with GP could be identified in our institute, we conducted a multi-institutional retrospective study of GP in Japan, which was approved by the Ethics Committee of our medical institute. The obtained tissue sections underwent detailed morphometric and immunohistochemical analyses. Additionally, to differentiate GP from NET G1 with ease, immunohistochemical findings were compared.

Results: In our examination of 12 cases of duodenal GP, we found that epithelioid cells of GP exhibited positive reactivity for progesterone receptor and pancreatic polypeptide, whereas tumor cells of NET G1 were completely negative reactivity for both. Additionally, although GP is considered to be an extremely rare NET, we found that four (40.0%) of the ten patients at our institute with duodenal NET G1 actually had GP.

Conclusions: Although GP is regarded as a rare NET, our results suggest that it accounts for a substantial percentage of duodenal NETs. Additionally, confirmation of immunoreactivity for progesterone receptor and pancreatic polypeptide can assist in differentiating GP from NET G1.
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http://dx.doi.org/10.1186/s12885-015-1308-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399421PMC
April 2015
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