Publications by authors named "Kazuhito Hatanaka"

44 Publications

Pulmonary infarction caused by sarcoidosis vascular involvement: A case report.

Pathol Int 2021 Jul 26;71(7):480-484. Epub 2021 Apr 26.

Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Sarcoidosis is a systemic granulomatous disease. In pulmonary sarcoidosis, granulomatous vascular involvement is a common feature that occurs in all types of vessels, including large elastic arteries to venules, but sarcoidosis complicated with pulmonary infarction has not been reported. We report a case of a 60 years old female, who was operated on a clinical diagnosis of lung cancer, and histological examination revealed a pulmonary infarction and sarcoidosis. In the pulmonary elastic arteries, granulomas infiltrated the adventitia and media, and caused elastic fiber collapse and destruction. Arterial occlusion by granulomas was observed in the edge of the infarcted area. It was considered that the arterial sarcoidosis granuloma involvement was the cause of pulmonary infarction. Sarcoidosis is a significant risk factor for cardiovascular events. However, pulmonary infarction is an extremely rare complication of sarcoidosis. Our case suggests that sarcoidosis may cause vascular events in the lungs.
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http://dx.doi.org/10.1111/pin.13104DOI Listing
July 2021

Hydrophilic Polymer in Thrombus Specimens Obtained During Thrombus Aspiration in the Setting of Percutaneous Interventions in Japan.

Int J Surg Pathol 2021 Apr 19;29(2):146-149. Epub 2020 Jun 19.

Tokai University, Isehara, Kanagawa, Japan.

Although hydrophilic polymer (HP) is used on vascular catheters to prevent medical device-related complications, HP emboli are well established as a potentially fatal iatrogenic phenomenon. HP embolus is thromboembolism by HP, which is mechanically disrupted from catheter during procedure. We reviewed 119 thrombus specimens obtained by percutaneous interventions from the coronary artery, vessels of inferior and superior limbs, cerebral artery, carotid artery, and renal vein. The frequency of HP was 28.6% (34/119 cases); 26.4% (24/91 cases), coronary artery; 50% (6/12 cases), artery of the lower limb; 28.6% (2/7 cases), vein of the lower limb; 0% (0/2), artery of the upper limb; 33.3% (1/3 cases), cerebral artery; 50% (1/2 cases), pulmonary artery; 0% (0/1 case), carotid artery; and 0% (0/1 case), renal vein. The range of numbers and diameter of HP was 1 to 127 per case and 10 to 934 µm, respectively. This is the first study concerning HP in thrombus specimens in Japan. We think that this study is significant because HP in thrombus specimens obtained from coronary artery in Japan seems to be of lower frequency than that of Europe. Although we suspect that the difference was caused by types of catheter, protocol, and procedure time of percutaneous interventions, we could not investigate correlation of HP in thrombus specimens with these factors. For future investigation, we should accumulate thrombus specimens obtained by routine procedure and device to clarify specific device-associated risk of disruption of HP.
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http://dx.doi.org/10.1177/1066896920934867DOI Listing
April 2021

Clinicopathological features of hydrophilic polymer emboli in Japanese autopsy cases.

APMIS 2018 Nov 15;126(11):838-841. Epub 2018 Oct 15.

Department of Pathology, Tokai University School of Medicine, Isehara, Japan.

Hydrophilic polymer is used on multiple endovascular devices to decrease friction between these devices and vessel walls. Although it can prevent medical device-related complications, hydrophilic polymer emboli (HPE) has recently been established as a potentially fatal iatrogenic phenomenon. HPE can cause tissue injury in numerous sites, including the brain, heart, lung, skin, and intestines. Most HPE reports have been from Europe and the USA. Therefore, we investigated the frequency, site distribution, and degree of tissue injury of HPE in 227 Japanese autopsy cases. HPE was noted in 3.1% (7/227 cases), and was only found in the lung or heart. There were no cases with tissue injury, such as vasculopathy, ischemia or infarction, associated with HPE. This is the first series study of HPE in Japanese autopsy cases. Unlike in reports from Europe and USA, HPE was only seen in the lung or heart and did not injure the surrounding tissue.
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http://dx.doi.org/10.1111/apm.12891DOI Listing
November 2018

Mixed adenoneuroendocrine carcinoma of the esophagogastric junction: a case report.

Surg Case Rep 2018 Jun 14;4(1):56. Epub 2018 Jun 14.

Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.

Background: Mixed adenoneuroendocrine carcinoma (MANEC) is a tumor of the gastrointestinal tract that contains both exocrine and endocrine components, with each component exceeding 30% of the total tumor area. Because MANECs are exceedingly rare, no therapeutic strategies have been established yet.

Case Presentation: An 81-year-old man was referred to our hospital with a 5-month history of dysphagia. Esophagogastroduodenoscopy revealed an ulcerated mass in the lower thoracic esophagus, extending up to the esophagogastric junction (33 to 40 cm from the incisors). The initial biopsy diagnosis was adenocarcinoma. Computed tomography revealed no evidence of lymph node or distant metastasis. The patient was treated by thoracoscopic esophagectomy with three-field lymph node dissection and gastric tube reconstruction via a posterior mediastinal approach, under the diagnosis of esophagogastric junctional cancer (T3N0M0, stage IIA). Histopathological examination revealed two distinct components, namely, a neuroendocrine carcinoma component and an adenocarcinoma component, and the patient was diagnosed as having mixed adenoneuroendocrine carcinoma (MANEC). He presented with liver metastasis 6 months after the surgery. Thereafter, the tumor became even more aggressive, and the patient died 8 months after the surgery.

Conclusions: We report a patient with MANEC of the esophagogastric junction. Close attention should be paid to such patients, as MANEC can be a highly aggressive tumor, showing rapid progression. In the treatment of MANEC, it is necessary to carefully consider the pathological features in each individual case.
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http://dx.doi.org/10.1186/s40792-018-0464-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999592PMC
June 2018

Pulmonary Adenocarcinoma Mimicking Desquamative Interstitial Pneumonia: Report of 2 Cases With Genetic Analysis.

Int J Surg Pathol 2018 Oct 2;26(7):655-659. Epub 2018 May 2.

1 Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

We report 2 cases of pulmonary adenocarcinoma mimicking desquamative interstitial pneumonia (DIP) with genetic analysis occurring in a 74-year-old woman and a 76-year-old woman. In both cases, the tumor was mainly composed of discohesive tumor cells, which filled and floated in the alveolar space in a DIP-like pattern. The tumor cells had abnormally large round to oval nuclei with fine chromatin and relatively abundant eosinophilic cytoplasm lacking pigmentation. Immunohistochemically, tumor cells in both cases were positive for CK7, TTF-1, napsin A, E-cadherin, β-catenin, and PD-L1 (one case had high expression and the other had low expression), and negative for CK5/6, CK20, p40, and ALK. However, the positive pattern of E-cadherin and β-catenin was incomplete on the circumference of the cell membrane in both cases and in one case, respectively. On genetic analysis, EGFR alteration (exon 21, L858R mutation) was observed in one case and ALK translocation was not observed in either. To the best of our knowledge, this is the first report of pulmonary adenocarcinoma mimicking DIP with genetic analysis.
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http://dx.doi.org/10.1177/1066896918773180DOI Listing
October 2018

CK7/CK20 Double-Negative Pulmonary Enteric Adenocarcinoma With Histopathological Evaluation of Transformation Zone Between Enteric Adenocarcinoma and Conventional Pulmonary Adenocarcinoma.

Int J Surg Pathol 2018 Aug 7;26(5):464-468. Epub 2018 Feb 7.

1 Tokai University School of Medicine, Isehara, Kanagawa, Japan.

We report a rare case of pulmonary enteric adenocarcinoma (PEA) exhibiting a immunohistochemical feature of CK7/CK20 double-negativity by evaluating the transformation zone between PEA and conventional pulmonary adenocarcinoma (CPA). A 75-year-old man was found to have a mass, 40 mm in diameter, in the right lower lobe on chest computed tomography, and underwent right lower lobectomy. Histologically, the tumor was composed of a PEA and CPA component. The dominant PEA component had medium to large complex glands with tall columnar cells with eosinophilic cytoplasm and brush-border. The CPA component comprised small to medium glands with cuboidal cells. Moreover, intermediate glands (INT), which had cuboidal to tall columnar cells, with morphological features between PEA and CPA, was also observed in the transformation area. Immunohistochemically, the PEA component was negative for CK7, CK20, and TTF-1, and positive for CDX2 and SATB2 (weak): the CPA component was negative for CK20, CDX2, and SATB2, and positive for CK7 and TTF-1: the INT were negative for SATB2, with intermingled positive signals for CK7, CK20, TTF-1, and CDX2. The final diagnosis was PEA based on the CPA component and not colorectal carcinoma. To distinguish CK7-negative PEA from metastatic colorectal carcinoma, careful examination for a CPA component is very useful along with clinical information. There are no reports that discuss about process of oncogenesis, de novo sequence or transformation from CPA of PEA. This is the first reported case of CK7/CK20 double-negative PEA, with analysis of the transformation zone between PEA and CPA components.
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http://dx.doi.org/10.1177/1066896918756737DOI Listing
August 2018

Napsin A levels in epithelial lining fluid as a diagnostic biomarker of primary lung adenocarcinoma.

BMC Pulm Med 2017 Dec 12;17(1):195. Epub 2017 Dec 12.

Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.

Background: It is crucial to develop novel diagnostic approaches for determining if peripheral lung nodules are malignant, as such nodules are frequently detected due to the increased use of chest computed tomography scans. To this end, we evaluated levels of napsin A in epithelial lining fluid (ELF), since napsin A has been reported to be an immunohistochemical biomarker for histological diagnosis of primary lung adenocarcinoma.

Methods: In consecutive patients with indeterminate peripheral lung nodules, ELF samples were obtained using a bronchoscopic microsampling (BMS) technique. The levels of napsin A and carcinoembryonic antigen (CEA) in ELF at the nodule site were compared with those at the contralateral site. A final diagnosis of primary lung adenocarcinoma was established by surgical resection.

Results: We performed BMS in 43 consecutive patients. Among patients with primary lung adenocarcinoma, the napsin A levels in ELF at the nodule site were markedly higher than those at the contralateral site, while there were no significant differences in CEA levels. Furthermore, in 18 patients who were undiagnosed by bronchoscopy and finally diagnosed by surgery, the napsin A levels in ELF at the nodule site were identically significantly higher than those at the contralateral site. In patients with non-adenocarcinoma, there were no differences in napsin A levels in ELF. The area under the receiver operator characteristic curve for identifying primary lung adenocarcinoma was 0.840 for napsin A and 0.542 for CEA.

Conclusion: Evaluation of napsin A levels in ELF may be useful for distinguishing primary lung adenocarcinoma.
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http://dx.doi.org/10.1186/s12890-017-0534-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727880PMC
December 2017

Aortic fibromuscular dysplasia complicated by dissection: a case report and review of literature.

Cardiovasc Pathol 2017 Nov - Dec;31:41-46. Epub 2017 Aug 9.

Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. Electronic address:

Fibromuscular dysplasia (FMD) is an idiopathic, segmental, nonatherosclerotic, non-inflammatory vascular disease, which is often complicated by the occurrence of dissection. Although it is known to occur in all arteries, aortic involvement is relatively rare. To date, 33 cases of aortic FMD have been reported in available English literature, among which only three cases have been complicated by the occurrence of dissection. We describe the case of a 40-year-old woman diagnosed with aortic FMD complicated by the occurrence of a type A aortic dissection. Non-invasive imaging revealed an ascending to descending thoracic aneurysm measuring 8 cm in diameter associated with dissection. Histopathologically, a segment of the wall of the aneurysm showed architectural disorganization of the aortic wall with loss of elastic fibers, collagen deposition, and irregular proliferation of smooth muscle cells in the intima and media-features suggesting FMD. No atheromatous plaque or medial cystic degeneration was observed in the aorta. Although aortic FMD is sometimes fatal, it is often very difficult to diagnose using imaging techniques. Therefore, performing a histopathological diagnosis is very important and should be emphasized.
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http://dx.doi.org/10.1016/j.carpath.2017.07.007DOI Listing
July 2018

Unusual morphology of a pulmonary blastoma having an epithelial component with focally significant nuclear pleomorphism.

Pathol Int 2017 07 23;67(7):370-372. Epub 2017 May 23.

Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.

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http://dx.doi.org/10.1111/pin.12541DOI Listing
July 2017

The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes.

J Hum Genet 2017 Jul 9;62(7):671-678. Epub 2017 Mar 9.

Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan.

Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous. In this study, we newly constructed a microRNA (miRNA) expression signature of SCLC by analysis of autopsy specimens. Based on the resultant signature, four miRNAs (miR-27a-5p, miR-485-3p, miR-34-5p and miR-574-3p) were found to be candidate anti-tumor miRNAs. To investigate their functional importance, we first validated the downregulation of miR-27a-5p and miR-34b-3p in SCLC clinical specimens. Next, we demonstrated that ectopic expression of both miR-27a-5p and miR-34b-3p significantly inhibited cancer cell aggressiveness. Our in silico analyses showed that four genes (topoisomerase 2 alpha (TOP2A), maternal embryonic leucine zipper kinase (MELK), centromere protein F (CENPF) and SRY-box 1 (SOX1) were identified as miR-27a-5p- and miR-34b-3p-regulated genes. Based on immunohistochemical analysis, TOP2A, MELK and CENPF were involved in SCLC pathogenesis. These genes might contribute to high proliferation and early metastatic spread of SCLC cells. Elucidation of differentially expressed miRNA-mediated cancer pathways based on SCLC signature may provide new insights into the mechanisms of SCLC pathogenesis.
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http://dx.doi.org/10.1038/jhg.2017.27DOI Listing
July 2017

Diagnostic efficacy of liquid-based cytology for solid pancreatic lesion samples obtained with endoscopic ultrasound-guided fine-needle aspiration: Propensity score-matched analysis.

Dig Endosc 2017 Jul 21;29(5):608-616. Epub 2017 Mar 21.

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background And Aim: There is a paucity of data on the diagnostic efficacy of liquid-based cytology (LBC) for pancreatic samples obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Using propensity score matching, we retrospectively analyzed the additional diagnostic value of LBC compared to a conventional Papanicolaou smear (CPS) for samples of solid pancreatic lesions obtained by EUS-FNA.

Methods: This cohort study included 126 matched patients who underwent initial EUS-FNA for solid pancreatic lesions between January 2009 and August 2014. CPS was used for cytology of EUS-FNA samples obtained until May 2012 (63 patients). Subsequently, LBC was used for cytological analysis (63 patients). Diagnostic yields of CPS and LBC for malignancy were compared. Risk factors for cytological misdiagnosis with LBC were investigated.

Results: Overall rate of malignancy was 86% after matching. LBC had higher diagnostic sensitivity and accuracy than CPS (96.6% vs 84.0%, P = 0.03; and 96.8% vs 87.3%, P = 0.05). LBC was significantly more sensitive for diagnosing pancreatic head lesions (96.4% vs 78.1%, P = 0.04). The sensitivity for pancreatic ductal adenocarcinoma (PDAC) with LBC was higher (98.1% vs 83.0%, P = 0.009). Multivariate analysis revealed that malignant tumors other than PDAC (P = 0.004) and lesion size ≤20 mm (P = 0.046) were risk factors for LBC misdiagnosis in all participants.

Conclusions: For solid pancreatic lesions, LBC of EUS-FNA samples contributes to the diagnosis of malignancy. Malignant tumors other than PDAC and small tumors are difficult to diagnose using EUS-FNA and LBC.
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http://dx.doi.org/10.1111/den.12827DOI Listing
July 2017

Epithelioid schwannoma of the skin displaying unique histopathological features: a teaching case giving rise to diagnostic difficulties on a morphological examination of a resected specimen, with a brief literature review.

Diagn Pathol 2017 Jan 19;12(1):11. Epub 2017 Jan 19.

Department of Pathology, Field of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.

Background: Epithelioid schwannoma as a rare variant poses a challenge to all pathologists, as this uncommon entity is extremely difficult to conclusively diagnose by morphological analyses on a resected sample alone owing to its unique histopathological features. However, few papers have described the detailed clinicopathological characteristics of epithelioid schwannoma.

Case Presentation: A 65-year-old female presented with a history of a flat and slightly elevated firm and tan plaque accompanied by occasional tenderness, measuring 10 × 8 mm, in the right joint of her hand 1 year before resection. A gross examination of a locally resected specimen revealed an encapsulated nodular lesion, yellow-whitish in color, partly filled with blood. A microscopic examination showed that the tumor predominantly consisted of a solid proliferation of epithelioid cells having mildly enlarged and round to partially spindled nuclei and abundant vacuolated or clear cytoplasm with very few mitotic figures and modest nuclear size variation, associated with focal hyalinized, cystic and hemorrhagic degeneration. This well-demarcated tumor was surrounded by dense, hyalinized and layered fibrocollagenous stroma. Immunohistochemically, these tumor cells were diffusely positive for S-100 protein and had a very low MIB-1 labeling index, and type IV collagen was strongly reactive with reduplicated basal lamina of them. We ultimately made a diagnosis of cutaneous epithelioid schwannoma.

Conclusion: We should be aware that, since pathologists might misinterpret epithelioid schwannoma as other soft tissue tumors, including its malignant counterpart, a wide panel of immunohistochemical antibodies can be powerful supplementary tools for identifying a very rare entity of conventional schwannoma.
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http://dx.doi.org/10.1186/s13000-017-0604-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5248503PMC
January 2017

Filamin C promotes lymphatic invasion and lymphatic metastasis and increases cell motility by regulating Rho GTPase in esophageal squamous cell carcinoma.

Oncotarget 2017 Jan;8(4):6353-6363

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

To establish treatments to improve the prognosis of cancer patients, it is necessary to find new targets to control metastasis. We found that expression of FilaminC (FLNC), a member of the actin binding and cross-linking filamin protein family is correlated with lymphatic invasion and lymphatic metastasis in esophageal squamous cell carcinoma (ESCC) by increasing cell motility through activation of Rho GTPase.Immunohistochemistry analysis showed that FLNC expression in ESCC is associated with lymphatic invasion, metastasis, and prognosis. FLNC knockdown in esophageal cancer cell lines decreased cell migration in wound healing and transwell migration assays, and invasion in transwell migration assays. Furthermore, FLNC knockdown reduced the amount of activated Rac-1 (GTP-Rac1) and activated Cdc42 (GTP-Cdc42). Our results suggest that FLNC expression is a useful biomarker of ESCC metastatic tendency and that inhibiting FLNC function may be useful to control the metastasis of ESCC.
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http://dx.doi.org/10.18632/oncotarget.14087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351637PMC
January 2017

Immunohistochemical expression of mucin antigens in gallbladder adenocarcinoma: MUC1-positive and MUC2-negative expression Is associated with vessel invasion and shortened survival.

Histol Histopathol 2017 Jun 27;32(6):585-596. Epub 2016 Sep 27.

Department of Pathology, Field of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Mucins play pivotal roles in influencing cancer biology, for example affecting carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to investigate the significance of expression profiles of two mucins in particular, MUC1 and MUC2, their correlations with various clinicopathological features, and prognosis in gallbladder adenocarcinoma (GBAC). We performed immunohistochemistry from patients with surgically resected GBAC, using antibodies against mucin core proteins MUC1/DF3 and MUC2/Ccp58 in 81 paraffin-embedded tumor samples. MUC1 or MUC2 expression was considered to be high when ≥ 20% or 10% of the GBAC cells showed positive staining, respectively. High MUC1 expression was revealed to have a significant relationship to the presence of pathologically lymphatic and vascular invasion, and regional lymph node metastasis. By contrast, high MUC2 expression showed a significant correlation with pathologically perineural invasion, T stage ≥ 3, and post-operative recurrence. Moreover, MUC1 showed significantly positive co-expression and potentially complementary correlations with MUC2. Multivariate analyses demonstrated that the high MUC1 expression group had significantly shorter disease-specific survival times. However, the combination of both high MUC1 and MUC2 expression did not predict worse outcome in GBACs. Therefore, although each mucin has a somewhat important role in the pathogenesis of GBAC progression, MUC1 can independently predict vessel invasion and poor prognosis in patients with GBAC. The detection of MUC1 might well offer a useful parameter for providing clinical management and treatment against postsurgical GBACs.
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http://dx.doi.org/10.14670/HH-11-824DOI Listing
June 2017

Complete regression of primary cutaneous malignant melanoma associated with distant lymph node metastasis: a teaching case mimicking blue nevus.

BMC Res Notes 2016 Jul 26;9:366. Epub 2016 Jul 26.

Department of Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background: Malignant melanoma (MM) tends to be spontaneously regressed, however, complete regression of primary cutaneous MM is an extremely rare phenomenon. Our aim is to be aware that pathologists and/or dermatologists can readily misinterpret it as the other benign or malignant lesions.

Case Presentation: A gradually growing and verrucous hypopigmented macule had been noticed in the right sole of a 65-year-old Japanese male since 2 years before, and it turned to be a solitary bluish to black patch with surrounding depigmentation and was recently decreased in size. In parallel, the patient had a rapidly growing black-pigmented mass lesion at the right inguen. The cutaneous specimen from the sole showed an aggregation of many melanophages predominantly in the middle to deep layer of dermis, associated with surrounding fibrosis, reactive vascular proliferation and CD8-positive T-lymphocytic infiltrate, covered by attenuated epidermis with absence of rete ridge. However, no remnant MM cells were completely seen in the step-serial sections. We first interpreted it as blue nevus. By contrast, the inguinal mass revealed a diffuse proliferation of highly atypical mono- to multi-nucleated large cells having abundant eosinophilic cytoplasm in the enlarged lymph node tissue. Immunohistochemical findings demonstrated that these atypical cells were specifically positive for HMB45 and Melan A. Therefore, we finally made a diagnosis of complete regression of primary cutaneous MM associated with distant lymph node metastasis of MM.

Conclusion: Careful, not only general/cutaneous but histopathological, examinations should be necessary and adjunctive aids for reaching the correct diagnosis of complete regression of cutaneous MM.
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http://dx.doi.org/10.1186/s13104-016-2174-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960676PMC
July 2016

PCP4/PEP19 promotes migration, invasion and adhesion in human breast cancer MCF-7 and T47D cells.

Oncotarget 2016 Aug;7(31):49065-49074

Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Purkinje cell protein (PCP) 4/peptide (PEP) 19 is expressed in Purkinje cells where it has a calmodulin-binding, anti-apoptotic function. We recently demonstrated that PCP4/PEP19 is expressed and inhibit apoptosis in human breast cancer cell lines. In the present study we investigated the role of PCP4/PEP19 in cell morphology, adhesion, migration, and invasion in MCF-7 and T47D human breast cancer cell lines. Knockdown of PCP4/PEP19 reduced the formation of filopodia-like cytoplasmic structures and vinculin expression, and enhanced E-cadherin expression. Activities of migration, invasion, and cell adhesion were also decreased after the knockdown of PCP4/PEP19 in MCF-7 and T47D cells. These results suggested that PCP4/PEP19 promotes cancer cell adhesion, migration, and invasion and that PCP4/PEP19 may be a potential target for therapeutic agents in breast cancer treatment which act by inhibiting epithelial-mesenchymal transition and enhancing apoptotic cell death.
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http://dx.doi.org/10.18632/oncotarget.7529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226490PMC
August 2016

Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas.

Oncotarget 2016 Jul;7(27):42553-42565

Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.

Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.
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http://dx.doi.org/10.18632/oncotarget.9924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173155PMC
July 2016

The First Case of Pulmonary Alveolar Proteinosis With Small Cell Lung Carcinoma.

Int J Surg Pathol 2016 Apr 30;24(2):135-8. Epub 2015 Oct 30.

Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant lipids and proteins. It is usually autoimmune and secondary to hematologic malignancy or infection. To date, only 5 case reports of PAP associated with lung cancers, including 2 cases of squamous cell carcinoma and 3 cases of adenocarcinoma, have been published. To the best of our knowledge, no case of PAP with small cell lung carcinoma has been reported thus far. We herein report the first case of PAP associated with small cell lung carcinoma.
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http://dx.doi.org/10.1177/1066896915614893DOI Listing
April 2016

Serum B cell-activating factor (BAFF) level in connective tissue disease associated interstitial lung disease.

BMC Pulm Med 2015 Sep 30;15:110. Epub 2015 Sep 30.

Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.

Background: Interstitial lung diseases (ILDs) are common in patients with connective tissue diseases (CTDs). Although the diagnosis of an underlying CTD in ILD (CTD-ILD) affects both prognosis and treatment, it is sometimes difficult to distinguish CTD-ILD from chronic fibrosing interstitial pneumonia (CFIP). B cell-activating factor belonging to the tumour necrosis factor family (BAFF) plays a crucial role in B cell development, survival, and antibody production.

Methods: We examined serum levels of BAFF, surfactant protein D (SP-D), and Krebs von den Lungen-6 (KL-6) in 33 patients with CTD-ILD, 16 patients with undifferentiated CTD-ILD, 19 patients with CFIP, and 26 healthy volunteers. And we analysed the relationship between serum BAFF levels and pulmonary function, as well as the expression of BAFF in the lung tissue of patients with CTD-ILD.

Results: Serum levels of BAFF were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. However, there were no significant differences in serum levels of SP-D and KL-6. Furthermore, serum BAFF levels in CTD-ILD patients were inversely correlated with pulmonary function. BAFF was strongly expressed in the lungs of CTD-ILD patients, but weakly in normal lungs.

Discussion: This is the first study to demonstrate that serum BAFF levels were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. Furthermore, serum BAFF levels were correlated with pulmonary function. We consider that serum BAFF levels in patients with CTD-ILD reflect the presence of ILDs disease activity and severity.

Conclusion: These finding suggest that BAFF may be a useful marker for distinguishing CTD-ILD from CFIP.
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http://dx.doi.org/10.1186/s12890-015-0105-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589966PMC
September 2015

Unilateral Absence of the Right Pulmonary Artery Accompanied by Right Lung Cancer.

Ann Thorac Surg 2015 Sep;100(3):1113

Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai.

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http://dx.doi.org/10.1016/j.athoracsur.2015.05.106DOI Listing
September 2015

Anti-apoptotic effects of PCP4/PEP19 in human breast cancer cell lines: a novel oncotarget.

Oncotarget 2014 Aug;5(15):6076-86

Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

The PCP4/PEP19 is a calmodulin-binding anti-apoptotic peptide in neural cells but its potential role in human cancer has largely been unknown. We investigated the expression of PCP4/PEP19 in human breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 cells, and found that estrogen receptor (ER)-positive MCF-7 and ER-negative SK-BR-3 cells expressed PCP4/PEP19. In the MCF-7 cells, cell proliferation was estrogen-dependent, and PCP4/PEP19 expression was induced by estrogen. In both cell lines, PCP4/PEP19 knockdown induced apoptosis and slightly decreased Akt phosphorylation. Knockdown of calcium/calmodulin-dependent protein kinase kinase 1 (CaMKK1), resulting in decreased phospho-Akt(Thr308), enhanced apoptosis in SK-BR-3 but not in MCF-7 cells. CaMKK2 knockdown moderately decreased phospho-Akt(Thr308) and increased apoptosis in MCF-7 cells but not in SK-BR-3 cells. These data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. PCP4/PEP19 can therefore potentially serve as independent oncotarget for therapy of PCP4/PEP19-positive breast cancers irrespective of ER expression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171614PMC
http://dx.doi.org/10.18632/oncotarget.2161DOI Listing
August 2014

Evaluation of napsin A, TTF-1, p63, p40, and CK5/6 immunohistochemical stains in pulmonary neuroendocrine tumors.

Am J Clin Pathol 2014 Sep;142(3):320-4

Department of Pathology, University of Michigan, Ann Arbor; and.

Objective: A panel of immunohistochemical (IHC) stains frequently used to subclassify non-small cell lung cancers (NSCLCs) includes napsin A, TTF-1, CK5/6, p40, and p63. The expression profiles of these stains in neuroendocrine tumors have not been systematically evaluated.

Method: Sixty-eight resected pulmonary neuroendocrine tumors, including 52 typical carcinoids (TCs), eight atypical carcinoids (ACs), seven small cell carcinomas (SCLCs) and one large cell neuroendocrine carcinoma (LCNEC), were stained for napsin A, TTF-1, p63, p40, and CK5/6. Tumors were scored as positive (>1% tumor cells reactive) or negative, and percentage of reactive tumor cells was recorded.

Results: Napsin A, p63, p40, and CK5/6 were consistently negative in neuroendocrine tumors. TTF-1 was positive in 17 of 52 TCs, 4 of 8 ACs, 5 of 7 SCLCs, and 0 of 1 LCNECs.

Conclusion: Pulmonary neuroendocrine tumors have a distinct but nonspecific profile on IHC panel commonly applied to subclassify NSCLCs. They are napsin A-/p40-/p63-/CK5/6-/TTF-1±. Recognizing this profile may have value in separating neuroendocrine tumors from NSCLCs.
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http://dx.doi.org/10.1309/AJCPGA0IUA8BHQEZDOI Listing
September 2014

Pulmonary rhabdomyomatous dysplasia of the newborn in neurofibromatosis type 1.

Pathol Res Pract 2014 May 9;210(5):318-20. Epub 2013 Nov 9.

Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Japan. Electronic address:

Proliferation of non-neoplastic striated muscle cells in the lung is rare and has been frequently observed in cases of cardiovascular and pulmonary congenital malformations. We present an extremely rare case of pulmonary rhabdomyomatous dysplasia (RD) in neurofibromatosis type 1 (NF-1). A male neonate was born at 35 weeks' gestation after normal pregnancy. Postnatally, besides patent ductus arteriosus and posterior mediastinal mass, abnormal cystic lesions in the left upper and lower lung were detected. No bronchial atresia and stenosis were identified. Partial lobectomy specimens showed hypoplastic lung parenchyma with cystic lesions resembling terminal bronchioles and distinctive proliferation of non-neoplastic striated muscle fibers in the interstitium. The posterior mediastinal mass consisted of neurofibroma. Considering that café au lait spots and freckling occurred at 2 months of age, a diagnosis of NF-1 was made. The patient died of aspiration pneumonia at the age of 30 months. To the best of our knowledge, this is the first case of pulmonary RD in NF-1.
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http://dx.doi.org/10.1016/j.prp.2013.10.008DOI Listing
May 2014

The hyaline vascular type of Castleman's disease of the ovary: a case report.

Int J Surg Pathol 2014 Oct 7;22(7):652-5. Epub 2014 Jan 7.

Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

Castleman's disease in the pelvic cavity is rare. We present a 72-year-old woman with hyaline vascular type of Castleman's disease of the right ovary. Right ovarian enlargement was detected in the medical examination. Computed tomography revealed a solid mass, measured 2.5 cm in size, in the right ovary. A bilateral salpingo-oophorectomy was performed. Morphologically, lymphoid follicles with regressed germinal centers (GCs) were surrounded by a broad mantle zone composed of concentric rings of small lymphocytes, and the hyalinized blood vessels with plump endothelial cells penetrated radially into GCs. Proliferation of follicular dendritic cells, which were positive for CD21 and epidermal growth factor receptor, were detected in GCs and mantle zone. No other lesions were found. To the best of our knowledge, this is the first case of hyaline vascular type of Castleman's disease of ovarian primary.
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http://dx.doi.org/10.1177/1066896913517936DOI Listing
October 2014

Paratesticular dedifferentiated liposarcoma with leiomyosarcomatous differentiation: a case report with a review of literature.

Diagn Pathol 2013 Aug 23;8:142. Epub 2013 Aug 23.

Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.

Unlabelled: Paratesticular liposarcoma is a rare neoplasm, described in single case studies or components of larger studies, as histologically well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DL). However, leiomyosarcomatous differentiation is an extremely rare occurrence in WDL and DL. We report a case of leiomyosarcomatous differentiation in a 77-year-old man. The patient presented with a painless right scrotal mass. Magnetic resonance imaging showed a large mass along the right spermatic cord. The resected mass, measuring 17.5 × 12 × 5 cm, was composed of a high-grade pleomorphic undifferentiated sarcomatous component with necrosis. Atypical smooth muscle differentiation was also detected. Additional tumor sampling revealed the presence of a WDL component. Immunohistochemical analysis of the pleomorphic sarcomatous component showed positive staining for MDM2 and CDK4, and negative staining for alpha smooth muscle actin (αSMA) and desmin. The smooth muscle component was positive for αSMA and desmin, and negative for MDM2 and CDK4. Extension from primary retroperitoneal sarcoma was not proved. We diagnosed of DL with leiomyosarcomatous differentiation.

Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1484291498104021.
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http://dx.doi.org/10.1186/1746-1596-8-142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846147PMC
August 2013

Bronchiolitis obliterans associated with Stevens-Johnson Syndrome: histopathological bronchial reconstruction of the whole lung and immunohistochemical study.

Diagn Pathol 2013 Aug 6;8:134. Epub 2013 Aug 6.

Department of Respiratory Medicine, Toho University Omori Medical Center, Omorinishi 6-11-1, Ota-ku, Tokyo 143-8541, Japan.

Unlabelled: This study presents an extremely rare case of constrictive bronchiolitis obliterans (BO) associated with Stevens-Johnson Syndrome (SJS) provides the morphological and immunohistochemical features using histopathological bronchial reconstruction technique. A 27-year-old female developed progressive dyspnea after SJS induced by taking amoxicillin at the age of 10. Finally, she died of exacerbation of type II respiratory failure after 17 years from clinically diagnosed as having BO. Macroscopic bronchial reconstruction of the whole lungs at autopsy showed the beginning of bronchial obliterations was in the 4th to 5th branches, numbering from each segmental bronchus. Once they were obliterated, the distal and proximal bronchi were dilated. Microscopic bronchial reconstruction demonstrated the localization of obliteration was mainly from small bronchi to membranous bronchioli with intermittent airway luminal narrowing or obliteration. Moreover, CD3-, CD20-, and CD68-positive cells were found in the BO lesions. CD34- and D2-40-positive cells were mainly distributed in the peribronchiolar lesions and bronchiolar lumens, respectively. SMA- and TGF-β-positive cells were seen in the fibrous tissue of BO lesions.

The Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1071703140102601.
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http://dx.doi.org/10.1186/1746-1596-8-134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751748PMC
August 2013

Recurrent solitary fibrous tumor of the pleura with malignant transformation and non-islet cell tumor-induced hypoglycemia due to paraneoplastic overexpression and secretion of high-molecular-weight insulin-like growth factor II.

Intern Med 2012 1;51(23):3267-72. Epub 2012 Dec 1.

Division of Nephrology and Metabolism, Kanto Rosai Hospital, Japan.

A 41-year-old man was diagnosed with a solitary fibrous tumor (SFT) of the pleura in the posterior mediastinum. Despite two surgeries for excision, the SFT recurred and progressed with direct invasion of the chest wall and bone metastases. He was hospitalized because of cerebral infarction and presented with recurrent severe hypoglycemia fourteen years later. High-molecular-weight (HMW) insulin-like growth factor II (IGF-II) was identified in the serum and tumor using Western blotting and immunohistochemistry. These findings suggested that the cause of the recurrent severe hypoglycemia was SFT production of HMW IGF-II, a mediator of non-islet cell tumor-induced hypoglycemia (NICTH).
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http://dx.doi.org/10.2169/internalmedicine.51.7906DOI Listing
September 2014

A case of complete hydatidiform mole in a perimenopausal woman with diagnostic usefulness of p57(kip2) immunohistochemistry and HER2 fluorescent in situ hybridization.

Pathol Res Pract 2012 Feb 22;208(2):118-20. Epub 2011 Dec 22.

Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Gestational trophoblastic disease in perimenopausal women is very rare. A 53-year-old perimenopausal woman complained about amenorrhea lasting over a period of 4months. Ultrasound showed enlargement of the uterus with a complex echogeneous area in the uterine cavity. Serum human chorionic gonadotropin was 67,611mIU/ml. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The uterus contained hemorrhagic and fragile tumor with grape-like vesicles in the enlarged endometrial cavity. Microscopic examination revealed hydropically degenerated villi with circumferential hyperplasia of atypical trophoblast and cistern formation. p57(kip2) immnostaining was negative in villous cytotrophoblasts and stromal cells. Moreover, fluorescent in situ hybridization for HER2 was scored as diploid. These findings are consistent with complete hydatidiform mole. The diagnosis of hydatidiform mole must be considered in perimenopausal women, and the combination of p57(kip2) immunostaining and HER2 fluorescent in situ hybridization seems to be a very useful testing strategy for difficult situations regarding the differential diagnosis of completed and partial hydatidiform mole.
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http://dx.doi.org/10.1016/j.prp.2011.11.005DOI Listing
February 2012

A Case of Primary Bone Marrow B-Cell Non Hodgkin's Lymphoma with Severe Thrombocytopenia: Case Report and A Review of the Literature.

Indian J Hematol Blood Transfus 2010 Sep 6;26(3):106-8. Epub 2010 Oct 6.

A 78-year-old man presented with persistent gingival bleeding. He had low platelet count of 1.0 × 10(9)/L without any lymphadenopathy. Bone marrow specimen showed diffusely distributed small-sized lymphocytes. Combined with immunophenotypic analysis, a diagnosis of primary bone marrow B-cell non-Hodgkin's lymphoma was made. Thrombocytopenia was considered to be caused by autoimmune destruction of platelets.
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http://dx.doi.org/10.1007/s12288-010-0040-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002093PMC
September 2010
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