Publications by authors named "Masakazu Fujimoto"

66 Publications

[Complete Remission of Metastatic Renal Cell Carcinoma with Invasion of the Duodenum and Pancreas after Treatment with Nivolumab Plus Ipilimumab Followed by Axitinib and Surgery : A Case Report].

Hinyokika Kiyo 2021 May;67(5):197-203

The Department of Urology, Kyoto University Hospital.

A man in his 60s was diagnosed with clear cell carcinoma of the right kidney with multiple lung metastases, tumor thrombus of the inferior vena cava (IVC), and invasion of the duodenum and pancreas. Ipilimumab plus nivolumab was administered as first-line therapy. After 3 treatment courses, computed tomography (CT) demonstrated a slight decrease in the size of the primary tumor and lung metastases. However, the patient became hemodynamically unstable due to persistent duodenal bleeding during treatment despite frequent blood transfusions. Axitinib was then initiated as second-line therapy. The duodenal bleeding ceased 10 days after starting axitinib and his anemia remissed. Subsequent CT showed further decrease in the size of the primary tumor and lung metastases. The patient underwent right nephrectomy after improvement of nutrition. IVC thrombectomy, and pancreaticoduodenectomy. The lung metastases disappeared on postoperative imaging and no additional treatment was provided. Twelve months after surgery, he was in good health and showed no signs of recurrence.
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http://dx.doi.org/10.14989/ActaUrolJap_67_5_197DOI Listing
May 2021

Evaluation of Weighted Diffusion Subtraction for Detection of Clinically Significant Prostate Cancer.

J Magn Reson Imaging 2021 Jun 4. Epub 2021 Jun 4.

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Diffusion-weighted imaging (DWI) is an important method for clinically significant prostate cancer (csPCa) diagnosis; however, the Prostate Imaging-Reporting and Data System (PI-RADS) requires the subjective assessment of "markedly hypointense or not" on apparent diffusion coefficient (ADC) map. We hypothesize that weighted diffusion subtraction (WDS) images, created by weighted subtraction of high and low b-value DWIs, might better show areas of ADC values below a set threshold, thus decreasing the subjectivity of the assessment.

Purpose: To evaluate the diagnostic ability of WDS for csPCa by comparing scores based on WDS images (DWI/WDS) with those based on PI-RADS DWI (DWI/ADC).

Study Type: Retrospective.

Subjects: Eighty-six PCa patients.

Field Strength/sequences: 3.0 T; DWI.

Assessment: Four readers assessed the probability of csPCa in lesions (overall, in the peripheral zone [PZ] and transitional zone [TZ]) using 5-point DWI/ADC and DWI/WDS scores. Prostatectomy specimens were the reference standard. ADC values and contrast between csPCa and normal prostate tissue on ADC maps and WDS images were calculated with reference to the pathological map.

Statistical Tests: Diagnostic ability was evaluated by Jackknife alternative free-response receiver-operating characteristic curve. Figure of merit (FOM), sensitivity, and positive predictive value (PPV) between the DWI/ADC and DWI/WDS scores were compared using paired t-test. Inter-reader agreement was analyzed using κ statistics, and the significance probability was calculated using the Z statistic. Wilcoxon signed-rank test was used to compare contrast between csPCa and normal prostate tissue on ADC maps and WDS images. A P value <0.05 was considered statistically significant.

Results: FOM and sensitivity of the DWI/WDS scores were significantly better than those of the DWI/ADC scores overall, in the PZ and TZ (FOM: overall, 0.715 vs. 0.783; PZ, 0.756 vs. 0.815; TZ, 0.653 vs. 0.738. Sensitivity: overall, 0.512 vs. 0.607; PZ, 0.485 vs. 0.573; TZ, 0.636 vs. 0.761). For PPV, a statistically significant difference was observed overall (0.727 vs. 0.777). The κ value of DWI/WDS score was significantly higher than that of DWI/ADC score overall and in the PZ (overall, 0.614 vs. 0.792; PZ, 0.609 vs. 0.797). Contrast was significantly higher overall in the PZ and TZ in WDS images (median, 1.26, 1.19, and 1.61) than in ADC maps (0.46, 0.47, and 0.41).

Data Conclusion: WDS images performed better than ADC maps in the diagnosis of csPCa and in inter-reader agreement of the diagnosis.

Level Of Evidence: 4 Technical Efficacy Stage: 2.
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http://dx.doi.org/10.1002/jmri.27771DOI Listing
June 2021

A multilocular thymic cyst associated with mediastinal seminoma: evidence for its medullary epithelial origin highlighted by POU2F3-positive thymic tuft cells and concomitant myoid cell proliferation.

Virchows Arch 2021 May 24. Epub 2021 May 24.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Multilocular thymic cyst (MTC) and germ cell tumors are common diseases that impact the mediastinum. Correctly diagnosing these diseases can be difficult because several other conditions can mimic them. We report a male patient with MTC associated with mediastinal seminoma. A needle biopsy of the mediastinal tumor revealed numerous epithelioid cell granulomas that mimicked sarcoidosis or mycobacterial infection. However, large atypical cells positive for Oct3/4 and KIT were noted between the granulomas; thus, we diagnosed the patient with mediastinal seminoma. The resected tumor, after chemotherapy, consisted of multiple cystic lesions, and a residual germ cell tumor was first considered. However, thymic medulla-specific elements, namely, POU2F3-positive thymic tuft cells and rhabdomyomatous myoid cells accompanying the epithelium, led to the correct diagnosis of MTC. Our case underscores the importance of recognizing the histological features associated with mediastinal seminoma and provides novel findings for MTC pathogenesis, namely, the presence of thymic tuft cells.
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http://dx.doi.org/10.1007/s00428-021-03125-2DOI Listing
May 2021

Benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma on the leg.

J Dermatol 2021 May 3. Epub 2021 May 3.

Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.1111/1346-8138.15943DOI Listing
May 2021

SMARCA4-deficient sinonasal carcinoma: A case report referring to the post-treatment histological changes.

Pathol Int 2021 Jun 21;71(6):435-437. Epub 2021 Apr 21.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

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http://dx.doi.org/10.1111/pin.13102DOI Listing
June 2021

EBV-positive Mucocutaneous Ulcer With Small Lymphocytic Infiltration Mimicking Nonspecific Ulceration.

Am J Surg Pathol 2021 05;45(5):694-700

Departments of Diagnostic Pathology.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorder may resemble nonspecific inflammation. We report 3 cases of immunosuppressed adult patients with small lymphocytic EBV ulcers in the skin and oral mucosa, characterized by a lack of atypical lymphocytic infiltration. All 3 cases were diagnosed in routine practice. For comparisons, cases of conventional Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) were reviewed which were extracted from our pathology archives (n=11). The present patients were 2 females and 1 male, aged above 70 years. The primary disease was rheumatoid arthritis (n=2) and dermatitis herpetiformis (n=1). The main source of immunosuppression was prednisolone (n=2) and methotrexate (n=1). The ulcers were located in the oral cavity, buttock, and/or external genitalia. Histology evaluation revealed nonspecific lymphocytic infiltration. Epstein-Barr virus-encoded small RNA (EBER)-positive cells were small and coexpressed CD20. The number of EBER-positive cells ranged from 52 to 132/HPF, which was within the range of that observed in the reviewed conventional EBVMCUs (range, 48 to 1328; median, 121). All 3 cases regressed spontaneously or by the reduction of immunosuppressants. Although the present cases lacked cytologic atypia, those clinical course and loads of EBER-positive cells (>50/HPF) suggested EBV involvement. Current cases of EBVMCU with small lymphocytic infiltration underscore the need for EBER in situ hybridization when an etiology of ulcer with predominant lymphocytes in an immunosuppressed patient is unclear.
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http://dx.doi.org/10.1097/PAS.0000000000001661DOI Listing
May 2021

Post-transplant Lymphoproliferative Disorders After Liver Transplantation: A Retrospective Cohort Study Including 1,954 Transplants.

Liver Transpl 2021 Mar 2. Epub 2021 Mar 2.

Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation/Pediatric Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening neoplasms after organ transplantation. Because of their rarity and multiple grades of malignancy, the incidence, outcomes, and clinicopathological features affecting patient survival after liver transplantation (LT) remain unclear. We reviewed 1,954 LTs in 1,849 recipients (1990-2020), including 886 pediatric (<18 years of age) and 963 adult recipients. The following clinicopathological factors were studied: age, sex, liver etiologies, malignancy grades, Epstein-Barr virus status, performance status (PS), Ann Arbor stage, international prognostic index, and histopathological diagnosis. Of 1,849 recipients, 79 PTLD lesions (4.3%) were identified in 70 patients (3.8%). After excluding 3 autopsy cases incidentally found, 67 (45 pediatric [5.1%] and 22 adult [2.3%]) patients were finally enrolled. Comorbid PTLDs significantly worsened recipient survival compared with non-complicated cases (P < 0.001). The 3-year, 5-year, and 10-year overall survival rates after PTLD diagnosis were 74%, 66%, and 58%, respectively. The incidence of PTLDs after LT (LT-PTLDs) was significantly higher (P < 0.001) with earlier onset (P = 0.002) in children, whereas patient survival was significantly worse in adults (P = 0.002). Univariate and multivariate analyses identified the following 3 prognostic factors: age at PTLD diagnosis ≥18 years (hazard ratio [HR], 11.2; 95% confidence interval [CI], 2.63-47.4; P = 0.001), PS ≥2 at diagnosis (HR, 6.77; 95% CI, 1.56-29.3; P = 0.01), and monomorphic type (HR, 6.78; 95% CI, 1.40-32.9; P = 0.02). A prognostic index, the "LT-PTLD score," that consists of these 3 factors effectively stratified patient survival and progression-free survival (P = 0.003 and <0.001, respectively). In conclusion, comorbid PTLDs significantly worsened patient survival after LT. Age ≥18 years and PS ≥2 at PTLD diagnosis, and monomorphic type are independent prognostic factors, and the LT-PTLD score that consists of these 3 factors may distinguish high-risk cases and guide adequate interventions.
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http://dx.doi.org/10.1002/lt.26034DOI Listing
March 2021

Systemic EBV-Positive Methotrexate-Related Lymphoproliferative Disorder Associated With Skin Lesion Resembling EBV-Positive Mucocutaneous Ulcer: A Report of Two Cases.

Am J Dermatopathol 2021 Feb 16. Epub 2021 Feb 16.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan Department of Dermatology, Hyogo Cancer Center, Akashi, Japan Departments of Hematology, and Dermatology, Takatsuki Red Cross Hospital, Takatsuki, Japan.

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http://dx.doi.org/10.1097/DAD.0000000000001930DOI Listing
February 2021

Multiple dermatomal granulomatous dermatitis concurring with herpes zoster.

J Dermatol 2021 Apr 13;48(4):e167-e168. Epub 2021 Feb 13.

Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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http://dx.doi.org/10.1111/1346-8138.15773DOI Listing
April 2021

Squamous Cell Carcinoma of the Scalp after Artificial Hair Implantation.

Plast Reconstr Surg Glob Open 2021 Jan 26;9(1):e3375. Epub 2021 Jan 26.

Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

A 48-year-old man with a protruding tumor on the parietal region had undergone treatment of alopecia using artificial synthetic fibers 2 or 3 times a year for 10 years from 30 to 39 years old. Three months before the first consultation at our hospital, he noticed a small tumor that had gradually shown bleeding and discharge, with expansion of the affected area. A diagnosis of squamous cell carcinoma (SCC) was made based on a biopsy, and we resected the tumor with a 1-cm surgical margin from the reddened area around the protruding tumor (14 × 11 cm), including the periosteum membrane. No tight adhesion was found between the periosteum and skull, so we excised the outer table of the skull of the central part (diameter: 8 cm) for a pathological analysis. A pathological study showed moderately differentiated SCC with a negative surgical margin. The whole tumor was surrounded by scar tissue with buried artificial hair implants. The second surgery was performed on the 15 postoperative day. An anterolateral thigh flap was divided into 2 flaps to fit the circle-shaped wound. This is the second report of SCC developing after artificial hair implantation in the frontal-parietal scalp. The whole protruding tumor was surrounded by scar tissue with buried artificial hair implants. Proving the direct causal relationship between inflammation of scar tissue and SCC generation is difficult; however, our pathological findings support the possibility of the harmful effects of artificial hair implants.
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http://dx.doi.org/10.1097/GOX.0000000000003375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862074PMC
January 2021

A case of Langerhans cell sarcoma on the scalp: Whole-exome sequencing reveals a role of ultraviolet in the pathogenesis.

Pathol Int 2020 Nov 16;70(11):881-887. Epub 2020 Aug 16.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Langerhans cell sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytological features and a Langerhans cell phenotype. The underlying genetic features are poorly understood, and only a few alterations, such as those of the MARK pathway-related genes, CDKN2A and TP53 have been reported. Here we present a 70-year-old male with LCS on the scalp and pulmonary metastasis. The multinodular tumor, 3.0 cm in diameter, consisted of diffusely proliferated pleomorphic cells with numerous mitoses (53/10 HPFs). Immunohistochemically, the tumor cells were positive for CD1a, Langerin and PD-L1, and the Ki-67 labeling index was 50%. These pathological features were consistent with LCS, and were also observed in the metastatic tumor. Whole-exome sequencing revealed that both the primary and metastatic tumors harbored a large number of mutations (>20 mutations/megabase), with deletion of CDKN2A and TP53 mutation, and highlighted that the mutational signature was predominantly characteristic of ultraviolet (UV) exposure (W = 0.828). Our results suggest, for the first time, that DNA damage by UV could accumulate in Langerhans cells and play a role in the pathogenesis of LCS. The high mutational burden and PD-L1 expression in the tumor would provide a rationale for the use of immune checkpoint inhibitors for treatment of unresectable LCS.
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http://dx.doi.org/10.1111/pin.13007DOI Listing
November 2020

Upper Gastrointestinal Langerhans Cell Histiocytosis: A Report of 2 Adult Cases and a Literature Review.

Int J Surg Pathol 2020 Oct 9:1066896920964566. Epub 2020 Oct 9.

Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.

Langerhans cell histiocytosis (LCH) with primary involvement of the upper gastrointestinal (GI) tract is rare. We report 2 adult cases of localized LCH in the upper-GI tract, including the second reported adult case of esophageal LCH and review 11 previously reported cases. Case 1 involved the esophagus of a 61-year-old man; histiocytosis was detected when endoscopy was performed for an examination of epigastric pain. Case 2 involved the stomach of a 56-year-old woman wherein the lesion was detected during a follow-up endoscopy after infection. Both biopsy specimens exhibited diffuse proliferation of mononuclear cells with nuclear convolution and a background of eosinophilic infiltrate. The cells were immunohistochemically positive for CD1a and langerin, and mutation was detected in Case 2. Follow-up endoscopy for both cases revealed that the lesions disappeared without any treatment. It is important to avoid misdiagnosing LCH of the upper-GI tract as a malignant neoplasm.
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http://dx.doi.org/10.1177/1066896920964566DOI Listing
October 2020

Primary hepatic lymphoma as other iatrogenic immunodeficiency-related lymphoproliferative disorders: a case report and review of the literature.

Mod Rheumatol Case Rep 2021 01 22;5(1):172-177. Epub 2020 Oct 22.

Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

We report a case of 68-year-old man with stable polymyositis complicated with primary hepatic lymphoma (PHL) as other iatrogenic immunodeficiency-related lymphoproliferative disorders (OIIA-LPD). Multiple liver masses were diagnosed as diffuse large B-cell lymphoma (DLBCL) by biopsy. The LPD was associated with Epstein-Barr virus (EBV) reactivation, because EBV-DNA was detected in peripheral blood, and EBV antigen was detected in the tumour. He presented with high fever, cytopenia and hyperferritinemia, suggesting hemophagocytosis. Only discontinuation of methotrexate and tacrolimus resulted in a dramatic regression of the liver masses and improvement of fever and cytopenia. We review six cases of OIIA-LPD localised in the liver. All cases were DLBCL; 4/6 cases (67%) were positive for EBV staining, and 2/6 cases (33%) were improved after the discontinuation of immunosuppressants. Screening for EBV in blood and liver tumour is important, when a patient in immunosuppressive status presented with liver masses.
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http://dx.doi.org/10.1080/24725625.2020.1826627DOI Listing
January 2021

Molecular Alterations in Vaginal Melanomas: Report of 4 Cases and Literature Review.

Am J Dermatopathol 2021 Jan;43(1):45-48

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Abstract: Melanomas of the female gynecological tract comprise approximately 18% of mucosal melanomas, a rare subtype of melanoma. Within the female genital tract, 70% of primary melanomas of the gynecological tract are from the vulva with the remainder occurring in the vagina and rarely, in the cervix. We investigate molecular alterations by next-generation sequencing-based molecular tests targeting 99 cancer genes and translocation/fusion assays in 4 and 3 vaginal melanomas, respectively. The ages of the 4 patients range from 65 to 90 years. Postmenopausal bleeding was the most common presenting symptom. Tumor size ranged from 0.5 to 6.6 cm. KIT L576P mutation was documented in case 1, whereas TP53 mutation was seen in cases 2 and 3 (L130F and Y163C). Case 2 also harbored NF2 E204Q and ATRX D1719H mutations. A number of gene copy alterations were noted in case 4, which included GNA11 loss, MYC gain, RET loss, SMO loss, SUFU loss, and TSC2 loss. No gene fusion was detected in any of the 3 tested cases. In conclusion, in addition to KIT, TP53, and ATRX mutations, which have been previously reported, our cases harbor NF2 mutation and multiple gene copy alterations that have not previously been documented in vaginal melanomas. These findings highlight the potential role of targeted therapy in this rare melanoma subtype.
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http://dx.doi.org/10.1097/DAD.0000000000001759DOI Listing
January 2021

Brentuximab vedotin for refractory anaplastic lymphoma kinase-negative anaplastic large cell lymphoma in leukemic phase with overexpression.

Hematol Rep 2020 May 15;12(1):8368. Epub 2020 May 15.

Department of Hematology/Oncology.

Anaplastic lymphoma kinase (ALK)- negative anaplastic large cell lymphoma (ALCL) is an aggressive CD30-positive non- Hodgkin lymphoma. ALK-ALCL rarely manifests with extensive bone marrow and peripheral blood involvement (known as "leukemic phase"). A 54-year-old woman was diagnosed with ALK-ALCL in leukemic phase, characterized by an extremely poor prognosis. Lymphoma cells in this case showed chromosomal translocation 1p36.1- encoded RUNX3 and overexpression of its protein. She was refractory to CHOP and salvage chemotherapy. Fortunately, she achieved complete remission with three cycles of Brentuximab vedotin (BV) and underwent umbilical cord blood transplantation. However, she died due to treatment-related mortality on day 129. The autopsy findings showed no lymphoma cells. Treatment strategy for ALK-ALCL is controversial, but the efficacy of BV in CD30-positive peripheral T-cell lymphoma not only as salvage regimens, but also in first line, has been reported in recent years. BV may be an effective option for ALK-ALCL in leukemic phase.
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http://dx.doi.org/10.4081/hr.2020.8368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256628PMC
May 2020

Up-Regulation of PARP1 Expression Significantly Correlated with Poor Survival in Mucosal Melanomas.

Cells 2020 05 5;9(5). Epub 2020 May 5.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Introduction: Mucosal melanoma is rare and associated with poorer prognosis in comparison to conventional melanoma subtypes. Little is known about the prognostic significance as well as possible associations between PARP1 and immunologic response in mucosal melanoma.

Methods: PARP1, PD-L1 and IDO1 immunostains were performed on 192 mucosal melanomas including 86 vulvar, 89 sinonasal, and 17 anorectal melanomas.

Results: By Kaplan-Meier analyses, high PARP1 expression correlated with worse overall and melanoma-specific survival (log-rank values = 0.026 and 0.047, respectively). Tumors with combined PARP1 and IDO1 high expression correlated with worse overall and melanoma-specific survival ( = 0.015, 0.0034 respectively). By multivariate analyses, high PARP1 expression remained a predictor of worse survival independent of stage. By Fisher's exact test, high PARP1 expression correlated with highly mitogenic tumors ( = 0.02). High tumoral PD-L1 and IDO1 expression were associated with ulcerated primary tumors ( = 0.019, 0.0019, respectively). By linear regression analyses, correlations between PARP1 expression versus IDO1 expression ( = 0.0001) and mitotic index ( = 0.0052) were observed.

Conclusion: Increased expression of PARP1 is an independent negative prognostic marker in mucosal melanomas. The association between PARP1 and IDO1 and their combined adverse prognostic role raise the potential of combined therapy in mucosal melanoma.
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http://dx.doi.org/10.3390/cells9051135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290913PMC
May 2020

Acquired agminated melanocytic nevus in the acral area is a potential mimicker of acral lentiginous melanoma: A three-case series report and published work review.

J Dermatol 2020 Jul 4;47(7):770-773. Epub 2020 May 4.

Department of Dermatology, Nara Medical University School of Medicine, Kashihara, Japan.

Agminated nevus refers to a clustered group of melanocytic nevi confined to a localized area of the body. It rarely involves acral skin, but recognition of acquired agminated nevus (AAN) in the acral area is clinically important because it may mimic acral lentiginous melanoma (ALM). However, acral AAN has only been described in a few case reports and its clinical characteristics remain unclear. We report three additional cases of acral AAN to further analyze the differential points between ALM. Clinical images, including those of dermoscopy, of three cases of acral AAN were reviewed. The lesions were located on the sole or lateral border of the foot. All acral AAN were flat and large in size (>20 mm in greatest dimension), and associated with asymmetry and irregular border. However, no parallel ridge pattern suggesting ALM was observed on dermoscopy. In two patients, the lesions on the sole were totally resected; microscopic evaluation of these two lesions confirmed junctional nests of banal melanocytes. AAN lesions on the sole with chronic mechanical pressure are slightly larger and more diffuse; thus, they may be more likely to be overdiagnosed as malignancy upon inspection than those in the non-acral area. Understanding the concept of the disease and careful dermoscopic evaluation leads to an accurate diagnosis.
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http://dx.doi.org/10.1111/1346-8138.15353DOI Listing
July 2020

Primary cutaneous peripheral T-cell lymphoma, not otherwise specified, associated with lymphomatoid papulosis after a 9-year follow up: A case report.

J Dermatol 2020 Jun 22;47(6):641-645. Epub 2020 Apr 22.

Departments of, Department of, Dermatology, Wakayama Medical University, Wakayama, Japan.

Lymphomatoid papulosis (LyP) is a self-limiting cutaneous T-cell lymphoproliferative disorder that may progress into malignant lymphoma. Most of the previously reported associated lymphomas are primary cutaneous anaplastic large-cell lymphoma and mycosis fungoides with a low mortality rate. We report a case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS), associated with LyP after long-term follow up. The patient was a 79-year old Japanese man followed up for 9 years. He suddenly developed a 3-cm ulcerated lesion on his forehead, which was diagnosed as an exacerbation of LyP. The lesion regressed after conservative treatment, but the patient soon developed multifocal pcPTCL-NOS. Thereafter, the patient developed pneumonia and cerebral infarction and died within a few months of the onset of malignant lymphoma. Aggressive cutaneous lymphoma may develop in LyP patients. The present case re-emphasizes the need for careful follow up of patients with persistent LyP.
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http://dx.doi.org/10.1111/1346-8138.15351DOI Listing
June 2020

HER2-amplified cervical gastric-type mucinous carcinoma with a primitive enterocyte phenotype.

Histopathology 2020 09 29;77(3):511-513. Epub 2020 Jun 29.

Department of Diagnostic Pathology, Kyoto University, Kyoto, Japan.

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http://dx.doi.org/10.1111/his.14119DOI Listing
September 2020

Comprehensive Clinicopathologic Analyses of Acquired Cystic Disease-associated Renal Cell Carcinoma With Focus on Adverse Prognostic Factors and Metastatic Lesions.

Am J Surg Pathol 2020 08;44(8):1031-1039

Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN.

Acquired cystic disease of kidney-associated renal cell carcinoma (ACD-RCC) is a distinct subtype of renal cell carcinoma with unique morphologic and clinicopathologic features. Generally, ACD-RCC is regarded as an indolent tumor; however, prognostic and outcomes data have been conflicted by the limited and relatively low number of cases with patient follow-up or adverse events. In this study, we focused on the histology of metastatic lesions and identifying prognostic factors associated with metastatic progression. From 32 cases in the cohort, 9 patients had metastasis [ACD-RCC (M+)] and 23 patients were without metastasis [ACD-RCC (M-)]. The median age of patients was 52 years; right side, n=10; left side, n=18; bilateral, n=4; median tumor size=2.6 cm; median hemodialysis duration=17 y; and the median duration of follow-up was 50 mo. Immunohistochemistry showed ACD-RCC to be racemase positive and CK7 negative to focally positive within tumor cells, with consistent positivity for renal histogenesis-associated markers (PAX8 and RCC antigen); S100A1 was a less reliable marker at metastatic sites. All metastatic ACD-RCC except 2 cases involved lymph nodes (para-aortic, renal hilar, subclavicular). Overall, 6/9 (67%) had visceral metastasis to sites including lung (n=3), liver (n=3), bone (n=5), stomach (n=1), and brain (n=1). In total, 5/9 (56%) metastatic tumors had distinctive cystic growth pattern at the metastatic site; intriguingly metastatic tumors had intrametastatic oxalate crystal deposition, a pathognomonic feature associated with primary tumors. Four of nine (44%) patients with ACD-RCC (M+) had fatal outcomes due to metastatic disease. Clinically significant adverse prognostic features associated with metastasis [median follow-up 47 mo, ACD-RCC (M+) vs. ACD-RCC (M-), 50 mo] included: duration of hemodialysis (≥20 vs. <20 y, P=0.0085) and tumor necrosis (P=0.049). Because of sufficient overlap between these parameters, the study was not able to identify parameters that would be reliable in further management strategies, in clinical settings. Our data indicate that ACD-RCC is a tumor which has distinct metastatic potential with nodal and visceral tropism and proclivity for cystic morphology at metastatic sites; this is the first report of the presence of oxalate crystals in metastatic tumors. Our data suggest that ACD-RCC patients with prolonged hemodialysis and tumoral coagulative necrosis require additional surveillance in view of the association of these parameters with metastatic progression.
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http://dx.doi.org/10.1097/PAS.0000000000001482DOI Listing
August 2020

Adipophilin expression in cutaneous malignant melanoma is associated with high proliferation and poor clinical prognosis.

Lab Invest 2020 05 19;100(5):727-737. Epub 2019 Dec 19.

Department of Diagnostic Pathology, Wakayama Medical University, Wakayama, Japan.

Adipophilin (ADP) is a primary protein component of lipid droplets (LDs). For more than half a century, certain types of cancer cells have been known to contain LDs in their cytoplasm. However, the pathological significance of ADP or LDs in cancer remains unclear. In the present study, we investigated the association between ADP and other pathological characteristics in cutaneous malignant melanomas to clarify the role of ADP in melanoma cells. We immunostained whole paraffin sections of primary cutaneous melanomas obtained from 90 cases for ADP, after which we analyzed the correlation between ADP immunohistochemistry (IHC) and patient survival data. We also studied the relationship between the ADP IHC score and in situ hybridization (ISH) score of ADP mRNA, and the Ki67-labeling index (Ki67-LI) by using tissue microarrays consisting of 74 primary cutaneous malignant melanomas, 19 metastasizing melanomas, and 29 melanocytic nevi. Finally, we analyzed the relationship between ADP expression and cell proliferation in cutaneous melanoma cell lines. We found that high ADP expression was associated with poor metastasis-free survival, disease-specific survival, and overall survival rates of patients with cutaneous melanomas (P < 0.05). By linear regression analysis, ADP IHC was correlated with increasing ADP mRNA ISH H-scores and Ki67-LI scores in melanocytic lesions (P < 0.01). ADP IHC and ADP ISH H-scores and Ki67-LI scores were greater in pT3-4 melanomas than in pT1-2 melanomas. In cell-based assays, cells with increased ADP expression showed higher proliferation rates compared with those of low-ADP cells. Thus, ADP expression in malignant melanoma was significantly associated with high cell proliferation and poor clinical prognosis. Our results thus indicate a significant association between ADP and melanoma progression, and we propose that ADP may be a novel marker of aggressive cutaneous melanoma with a lipogenic phenotype.
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http://dx.doi.org/10.1038/s41374-019-0358-yDOI Listing
May 2020

Ln-γ 2 chain of laminin-332 is a useful marker in differentiating between benign and malignant sclerosing adnexal neoplasms.

Histopathology 2020 Jan 13;76(2):318-324. Epub 2019 Nov 13.

Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka, Japan.

Aims: Laminin (Ln)-γ 2, one of the chains of Ln-332, is a marker of invasive tumours and is frequently expressed as a monomer in malignant tumours. Desmoplastic trichoepithelioma (DTE), some types of basal cell carcinoma (BCC) (infiltrating and morphoeic BCC) and microcystic adnexal carcinoma (MAC) belong to a group of tumours known as sclerosing adnexal neoplasms (SAN) that are frequently difficult to differentiate and often require immunohistochemistry for diagnosis. The aim of this study was to assess the usefulness of Ln-γ 2 expression in the differential diagnosis of DTE, infiltrating/morphoeic BCC, MAC and syringoma.

Methods And Results: In this study, we compared the expression of Ln-γ 2 in infiltrating/morphoeic BCC (n = 28), DTE (n = 26), MAC (n = 10) and syringoma (n = 20). Immunohistochemically, Ln-γ 2 positivity was noted in 96% (27 cases) of infiltrating/morphoeic BCC and 90% (nine cases) of MAC, while all DTE and syringoma cases were negative. Furthermore, Ln-γ 2 expression pattern in infiltrating/morphoeic BCC was different from that in MAC. Ln-γ 2 expression was found in the cytoplasm of tumour cells in infiltrating/morphoeic BCC tumour cells, while in MAC linear expression was noted both along tumour nests and in the cytoplasm.

Conclusion: Ln-γ 2 is a helpful adjunct in the differential diagnosis of SAN.
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http://dx.doi.org/10.1111/his.13974DOI Listing
January 2020

Mass-forming mucosa-associated lymphoid tissue lymphoma of the cecum treated by laparoscopy-assisted bowel resection.

Int Cancer Conf J 2019 Apr 3;8(2):66-70. Epub 2019 Jan 3.

1Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8510 Japan.

Colonic mucosa-associated lymphoid tissue (MALT) lymphoma is very rare, especially those which form a mass. Although the characteristics and treatment methods of gastric MALT lymphomas are well established, those of colonic MALT lymphomas have been insufficiently described. Here, we report a case of mass-forming cecal MALT lymphoma that was successfully treated by laparoscopy-assisted bowel resection. A 60-year-old woman with right lower abdominal pain and a palpable tumor was referred to our hospital. Colonoscopy showed a smooth elevated submucosal tumor-like lesion in the cecum. Histological and immunochemical findings were consistent with MALT lymphoma. Serum tumor marker levels were within normal range. Enhanced abdominal computed tomography showed a large tumor 55 mm in diameter in the cecum and edema of a few paracolic lymph nodes. The tumor was diagnosed as cecal MALT lymphoma classified as stage II1 by Lugano classification, and laparoscopy-assisted ileocecal resection was performed. The postoperative course was uneventful and the patient underwent eradication therapy for . A year after the operation she has had no recurrence. In patients with mass-forming colonic MALT lymphoma without dissemination, surgical resection may be a feasible treatment.
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http://dx.doi.org/10.1007/s13691-018-00355-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498264PMC
April 2019

Tumor Budding Is an Objective High-risk Factor Associated With Metastasis and Poor Clinical Prognosis in Cutaneous Squamous Cell Carcinoma Sized <4 cm.

Am J Surg Pathol 2019 07;43(7):975-983

Departments of Diagnostic Pathology.

Although most cases of early cutaneous squamous cell carcinoma (CSCC) are indolent, a small subset metastasize and can be fatal. However, high-risk features of CSCC are controversial, and it is difficult to predict the biological behavior. In this study, we have tested the prognostic significance of tumor budding in CSCCs <4 cm in diameter. Hematoxylin and eosin-stained sections of surgically resected CSCCs (24 metastasizing and 24 nonmetastasizing cases) <4 cm in size were reviewed retrospectively. Tumor bud, defined as an isolated cancer cell or a cluster comprising<5 cells, was counted at a hot spot (1.23 mm), and graded between 1 and 3; grade 1: 0 to 4 buds; grade 2: 5 to 9 buds; and grade 3: ≥10 buds. Cases with grades 2 or 3 were regarded as positive for tumor budding. We found that tumor budding was positive in 83.3% of metastasizing CSCC, and 37.5% of nonmetastasizing CSCC (P<0.01). Moreover, CSCCs with grade 3 tumor budding showed worse disease-specific survival (P<0.01). Regarding interobserver reproducibility, the median κ value for tumor budding was significantly higher than that for histologic differentiation (P<0.01). In conclusion, tumor budding may be a valuable histologic marker for risk stratification of early CSCC in routine practice. Patients with tumor budding positive CSCC may benefit from evaluation and close follow-up for regional node metastasis.
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http://dx.doi.org/10.1097/PAS.0000000000001284DOI Listing
July 2019

Identification of a novel CCDC22 mutation in a patient with severe Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia.

Int J Hematol 2019 Jun 31;109(6):744-750. Epub 2019 Jan 31.

Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan.

Aggressive natural killer cell leukemia (ANKL) is a rare neoplasm characterized by the systemic infiltration of Epstein-Barr virus (EBV)-associated NK cells, and rapidly progressive clinical course. We report the case of a 45-year-old man with intellectual disability who developed ANKL, and describe the identification of a novel genetic mutation of coiled-coil domain-containing 22 (CCDC22). He presented with persistent fever, severe pancytopenia, and hepatosplenomegary. Following bone marrow aspiration, numerous hemophagocytes were identified. High EBV viral load was detected in NK cells fractionation by qPCR. The initial diagnosis was EBV-related hemophagocytic lymphohistiocytosis (EBV-HLH). A combination of immunosuppressive drugs and chemotherapy was administered, but was unsuccessful in controlling the disease. Therefore, he was treated with HLA-matched related allogeneic hematopoietic stem cell transplantation. However, his condition deteriorated within 30 days, resulting in fatal outcome. Autopsy revealed many EBV-infected NK cells infiltrating major organs, consistent with ANKL. Furthermore, whole-exome sequencing identified a novel missense mutation of the CCDC22 gene (c.112G>A, p.V38M), responsible for X-linked intellectual disability (XLID). CCDC22 has been shown to play a role in NF-κB activation. Our case suggests that CCDC22 mutation might be implicated in pathogenesis of EBV-HLH and NK-cell neoplasms as well as XLID via possibly affecting NF-κB signaling.
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http://dx.doi.org/10.1007/s12185-019-02595-0DOI Listing
June 2019

High-Risk Human Papillomavirus E6/E7 mRNA Is Rarely Detected in Nonanogenital Cutaneous Squamous Cell Carcinoma: An RNA In Situ Hybridization-Based Tissue Microarray Study.

Am J Dermatopathol 2019 Mar;41(3):205-210

Departments of Diagnostic Pathology, and.

High-risk human papillomavirus (HR-HPV) is known to play an oncogenic role in squamous cell carcinoma (SCC) at certain anatomical sites, namely the uterine cervix, oropharynx, and anogenital skin. However, the association between HR-HPV and nonanogenital cutaneous SCC (CSCC) remains controversial. In this study, we addressed this controversy by performing HR-HPV E6/E7 mRNA in situ hybridization (ISH) on 243 CSCC samples. A cocktail of E6/E7 mRNA ISH probes, recognizing 18 HR-HPV genotypes, was applied to a tissue microarray of paraffin-embedded sections of 154 invasive and 89 in situ CSCC specimens. The anatomical sites of CSCC included the head and neck (n = 100), extremities (n = 100), trunk (n = 25), and anogenitalia (n = 18). We also investigated the correlation between the p16 expression and HR-HPV status by immunohistochemistry. The results of HR-HPV E6/E7 mRNA ISH showed that 5.8% (14/243) of all CSCC samples were positive for HR-HPV, including 66.7% (12/18) of the anogenital and only 0.9% (2/225) of the nonanogenital CSCC samples (P < 0.01). For the detection of diffuse p16 expression by immunohistochemistry, the sensitivity was 100% (14/14 HR-HPV-positive CSCC samples), and the specificity was 72.1% (165/229 HR-HPV-negative specimens). Thus, HR-HPV E6/E7 mRNA was rarely detected in nonanogenital CSCC, making it unlikely that the virus contributes to the pathogenesis of this malignancy. In addition, p16 immunoreactivity has a limited value as a surrogate marker for transcriptionally active HR-HPV in nonanogenital CSCC.
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http://dx.doi.org/10.1097/DAD.0000000000001289DOI Listing
March 2019

SF3B1, NRAS, KIT, and BRAF Mutation; CD117 and cMYC Expression; and Tumoral Pigmentation in Sinonasal Melanomas: An Analysis With Newly Found Molecular Alterations and Some Population-Based Molecular Differences.

Am J Surg Pathol 2019 02;43(2):168-177

Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Sinonasal melanomas encompass melanoma arising in the nasal cavity and paranasal sinuses. Despite recent advances in tumor genomics, correlation between mutational status and protein expression with prognosis and tumor pigmentation has not been carried out in sinonasal melanomas. Ninety-five sinonasal melanomas from 95 patients were included. As per univariate analyses, age was the only variable that significantly correlated with progression-free survival. SF3B1, NRAS, KIT, and BRAF mutations were documented in 7% (5/72), 22% (16/72), 22% (16/72), and 8% (6/72) of cases, respectively. Comutation was detected in 6 cases: NRAS and KIT in 2 cases; NRAS and BRAF in 2 cases; SF3B1, KIT, and BRAF in one case; and SF3B1, NRAS, and KIT in one case. Correlations approaching statistical significance were observed between BRAF mutation status and poorer overall survival and progression-free survival (log-rank P-values=0.054 and 0.061). Increased CD117 expression (33%, 29/88) and decreased nuclear cMYC expression (40%, 39/84) significantly correlated with cytoplasmic pigmentation. Several SF3B1, NRAS, and KIT mutations not previously documented in sinonasal melanomas were detected in our series, suggesting a potential role for targeted therapies. A similar frequency of SF3B1, NRAS, and KIT mutations was noted in Asian cases, whereas NRAS, KIT, and BRAF mutations were predominant in the United States and European cases; however, the number of included cases was small. The significant association between CD117 and cMYC expression with increased cytoplasmic pigmentation in our series suggests that the pigmented morphologic appearance of sinonasal melanomas could be attributed to the underlying oncogenic mutations and metabolic interaction.
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http://dx.doi.org/10.1097/PAS.0000000000001166DOI Listing
February 2019

Alpha-fetoprotein-producing rectal cancer successfully responded to preoperative chemoradiotherapy: case report.

Surg Case Rep 2018 Sep 6;4(1):111. Epub 2018 Sep 6.

Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8510, Japan.

Background: Alpha-fetoprotein (AFP) is produced by some tumors, such as hepatocellular carcinoma and yolk sac tumors, leading to an increase in serum AFP level. However, AFP in colorectal cancer is extremely rare. Treatment for AFP-producing cancer is often performed according to conventional methods, but oncological outcomes of both surgery and chemotherapy are poor. We report a case of a patient with AFP-producing rectal cancer which successfully responded to preoperative chemoradiotherapy.

Case Presentation: Rectal tumor was diagnosed in a 68-year-old man referred to our hospital. Colonoscopy showed a type 2 tumor in the lower rectum, and biopsy revealed an adenocarcinoma with enteroblastic differentiation. Serum tumor marker levels were 8.8 ng/ml in carcinoembryonic antigen (CEA) and 28.3 ng/ml in AFP. Clinical diagnosis was stage IIIB (T3N1M0), and preoperative chemoradiotherapy was performed to prevent local recurrence. Effective tumor reduction was observed, and serum tumor marker levels decreased to normal range. Low anterior resection with temporary diverting ileostomy was performed, and histology revealed residual adenocarcinoma. Pathological diagnosis was stage I (T2N0M0). The tumor was found to be an AFP-producing adenocarcinoma on further immunohistopathological examination. The postoperative course was uneventful, and the patient received adjuvant chemotherapy for 3 months.

Conclusions: The outcomes of preoperative chemoradiotherapy against AFP-producing rectal cancer are reported here for the first time. Based on our experience with this patient, it appears preoperative chemoradiotherapy for patients with AFP-producing advanced rectal cancer is feasible.
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http://dx.doi.org/10.1186/s40792-018-0520-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127073PMC
September 2018