Publications by authors named "Teppei Morikawa"

204 Publications

Autoimmune pulmonary alveolar proteinosis with features similar to nonspecific interstitial pneumonia.

Respir Med Case Rep 2022 3;36:101591. Epub 2022 Feb 3.

Division of Respirology, NTT Medical Center Tokyo, Tokyo, Japan.

A 58-year-old woman with cough and dyspnea who was suspected of having idiopathic interstitial pneumonia had been treated with corticosteroids and cyclosporine, but the symptoms had worsened. There were no findings to suspect pulmonary alveolar proteinosis (PAP) in the bronchoalveolar lavage fluid, 17 months after the start of treatment. The transbronchial lung biopsy specimens showed eosinophilic bodies that strongly stained with periodic acid-Schiff staining. Anti-granulocyte macrophage colony-stimulating factor (anti-GM-CSF) antibodies were detected in her serum. We diagnosed the patient with autoimmune PAP. Thus, we present a rare case of PAP presenting atypical radiological images and bronchoalveolar lavage fluid findings.
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http://dx.doi.org/10.1016/j.rmcr.2022.101591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076885PMC
February 2022

Impact of Neoadjuvant Chemotherapy on SATB2 Expression in Colorectal Carcinomas: SATB2 Positivity is Preserved in Most Cases, but Down-Expressed in Effective Cases of Chemotherapy.

Int J Surg Pathol 2022 Mar 27:10668969221088881. Epub 2022 Mar 27.

Department of Diagnostic Pathology, 13635NTT Medical Center Tokyo, 5-9-22 Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.

Special AT-rich sequence-binding protein 2 (SATB2) is a novel, diagnostically useful, and highly sensitive immunohistochemical marker for both primary and metastatic colorectal or appendiceal tumors. In the present study, we aimed to assess the impact of neoadjuvant chemotherapy on SATB2 expression in primary colorectal carcinomas and their corresponding liver metastases. Forty-four patients with colorectal carcinomas who received neoadjuvant chemotherapy were included. SATB2 expression in specimens of biopsy, resected primary colorectal carcinomas, and resected metastatic foci were examined by immunohistochemistry and compared to caudal-type homeobox transcription factor 2 (CDX2). Using a modified H-score, expressions were scored semiquantitatively for both staining intensity and tumor cell proportion with nuclear staining. SATB2 was positive in 43/44 cases (98%) in biopsy specimens, 42/44 cases (96%) in resected colorectal carcinomas with neoadjuvant chemotherapy, and 9/9 cases (100%) with liver metastases. However, these expressions were variably decreased, and the H-score was lower in resected colorectal carcinomas (158 ± 69) than in biopsy specimens (174 ± 60) (p < 0.01). The proportion of SATB2-positive area of colorectal carcinoma was 93% in metastatic foci, while the CDX2-positive area was 78%. When categorized by histopathological tumor regression, the most effective tumors of chemotherapy showed the lowest H-score in resected colorectal carcinomas among the three groups (p < 0.01). SATB2 is a useful marker for both primary colorectal carcinoma and corresponding liver metastases, even with neoadjuvant chemotherapy. However, caution should be exercised when performing needle biopsy for metastatic foci with neoadjuvant therapy because expressions could be decreased, especially in chemotherapy-effective cases, and show immunohistochemically negative results.
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http://dx.doi.org/10.1177/10668969221088881DOI Listing
March 2022

Insulin-like growth factor II-producing colonic carcinoma presenting with non-islet cell tumor hypoglycemia: An autopsy report revealing neuroendocrine differentiation in the metastatic foci and literature review.

Pathol Int 2022 Mar 28;72(3):193-199. Epub 2022 Jan 28.

Department of Diagnostic Pathology, NTT Medical Center Tokyo, Tokyo, Japan.

Non-islet cell tumor hypoglycemia (NICTH) is a very rare symptom of severe hypoglycemia associated with extrapancreatic tumors. It is considered to be caused by insulin-like growth factor (IGF)-II. There have been no autopsy cases of colorectal carcinoma with NICTH confirmed with both serum high molecular weight and tumoral IGF-II. We report the case of a 46-year-old woman with advanced sigmoid colon cancer and liver metastases. She underwent open sigmoidectomy, and histologically, the lesion was a differentiated-type tubular adenocarcinoma. Postoperative chemotherapy was initiated. However, she experienced repeated hypoglycemia attacks 10 months after the operation, while the liver metastases increased. We examined the cause of hypoglycemia, and finally diagnosed her with NICTH associated with high molecular weight IGF-II production, which was proven by Western immunoblot of the serum. She died 12 months after surgery and was examined by autopsy. Liver metastases showed a transition from adenocarcinoma to carcinoma with neuroendocrine differentiation. Immunohistochemistry showed that both metastatic carcinoma of the liver and primary colonic adenocarcinoma were positive for IGF-II. Neuroendocrine differentiation in liver metastases proven by an autopsy may have contributed to tumor growth, which may have exacerbated the symptoms.
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http://dx.doi.org/10.1111/pin.13205DOI Listing
March 2022

Neuroendocrine Neoplasms of the Breast: The Latest WHO Classification and Review of the Literature.

Cancers (Basel) 2021 Dec 31;14(1). Epub 2021 Dec 31.

Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan.

Breast tumors with neuroendocrine (NE) differentiation comprise an uncommon and heterogeneous group of tumors, including invasive breast cancer of no special type (IBC-NST) with NE features, neuroendocrine tumors (NETs), and neuroendocrine carcinoma (NEC). The most recent World Health Organization (WHO) classification in 2019 defined neuroendocrine neoplasms (NENs) of the breast (Br-NENs) as tumors in which >90% of cells show histological evidence of NE differentiation, including NETs (low-grade tumors) and NEC (high-grade). Due to the low prevalence of these tumors and successive changes in their diagnostic criteria over the years, only limited evidence of these tumors exists, derived mainly from case reports and retrospective case series. Breast tumors with NE differentiation are usually treated like the more commonly occurring IBC-NSTs. Immunohistochemistry (IHC) of breast tumors with NE differentiation usually shows a hormone receptor (HR)-positive and human epidermal growth factor type 2 (HER2)-negative profile, so that hormonal therapy with cyclin-dependent kinase (CDK)4/6 inhibitors or other targeted agents would be reasonable treatment options. Herein, we present a review of the literature on breast tumors with NE differentiation as defined in the latest WHO 2019 classification, and discuss the clinical management of these tumors.
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http://dx.doi.org/10.3390/cancers14010196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750232PMC
December 2021

Differential diagnosis of thymic epithelial neoplasms on computed tomography using the diameter of the thymic vein.

Medicine (Baltimore) 2021 Nov;100(46):e27942

Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

Abstract: Although differentiating benign and malignant thymic epithelial lesions is important to avoid unnecessary treatment and predict prognosis, it is challenging because of overlaps in the chest computed tomography (CT) findings. In this study, we investigated whether the diameter of the thymic vein and other CT findings could differentiate between benign (thymoma and thymic cysts) and malignant (thymic carcinoma, [TCa]) lesions.We conducted a retrospective study across two tertiary referral hospitals in Japan between November 2009 and June 2018. We included 12 patients with TCa, 34 patients with thymomas, and 17 patients with thymic cysts. We analyzed the receiver operating characteristic (ROC) curve to determine the best cut-off values and performed univariate and multivariate analyses of CT findings to distinguish TCa from other benign lesions. Post-hoc analysis was performed for the maximum short axis of the thymic vein using the Mann-Whitney U test, and the number of the maximum short axis of the thymic vein ≥ the cutoff was determined using the Fisher exact test with a family-wise error-correction using Bonferroni's method.ROC analysis showed that a maximum short axis of the thymic vein ≥2 mm was considerably more frequent in TCa than in the other lesions (P < .001 for both), with 83% sensitivity and 86% specificity. Univariate and multivariate analyses revealed the association with TCa of the number of the maximum short axis of the thymic vein ≥2 mm (P = .005, multivariate generalized linear model analysis), ill-defined margin (P = .001), and mediastinal lymphadenopathy (P < .001). Thymic vein diameter was in descendimg order of TCa > thymoma > thymic cysts with statistically significant differences between the groups (Ps < .05).Thymic vein diameter was significantly longer in TCa than in thymoma and thymic cysts. Measurement of the maximum short axis of the thymic vein could be a powerful diagnostic tool to differentiate TCa from thymoma and thymic cysts.
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http://dx.doi.org/10.1097/MD.0000000000027942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601265PMC
November 2021

Immune-related dermatitis during combined treatment with pembrolizumab and axitinib in a patient with metastatic renal cell\x92carcinoma with stasis dermatitis.

IJU Case Rep 2021 Nov 5;4(6):386-390. Epub 2021 Aug 5.

Urology NTT Medical Center Tokyo Tokyo Japan.

Introduction: The combination of pembrolizumab and axitinib has recently been approved as a first-line treatment for previously untreated metastatic renal cell carcinoma. However, immune-related adverse events are not well known.

Case Presentation: A 65-year-old male was diagnosed with renal cell carcinoma with metastases to the brain and lungs. The patient had a medical history of stasis dermatitis. During the combined treatment of pembrolizumab and axitinib, blisters appeared on the lower extremities. Skin biopsy revealed septal panniculitis, pustules, and perivascular lymphocytic and neutrophilic infiltration of the skin, and the patient was diagnosed with immune-related dermatitis. The dermatitis improved with oral prednisolone treatment.

Conclusion: A case of immune-related dermatitis during combinatorial treatment with pembrolizumab and axitinib for renal cell carcinoma has been reported. Preexisting stasis dermatitis may have affected the onset and deterioration of immune-related dermatitis.
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http://dx.doi.org/10.1002/iju5.12356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560444PMC
November 2021

The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men.

Clin Transl Gastroenterol 2021 08 1;12(8):e00338. Epub 2021 Aug 1.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Introduction: We recently described the sulfur microbial diet, a pattern of intake associated with increased gut sulfur-metabolizing bacteria and incidence of distal colorectal cancer (CRC). We assessed whether this risk differed by CRC molecular subtypes or presence of intratumoral microbes involved in CRC pathogenesis (Fusobacterium nucleatum and Bifidobacterium spp.).

Methods: We performed Cox proportional hazards modeling to examine the association between the sulfur microbial diet and incidence of overall and distal CRC by molecular and microbial subtype in the Health Professionals Follow-Up Study (1986-2012).

Results: We documented 1,264 incident CRC cases among 48,246 men, approximately 40% of whom had available tissue data. After accounting for multiple hypothesis testing, the relationship between the sulfur microbial diet and CRC incidence did not differ by subtype. However, there was a suggestion of an association by prostaglandin synthase 2 (PTGS2) status with a multivariable adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.31 (95% confidence interval: 0.99-1.74, Ptrend = 0.07, Pheterogeneity = 0.04) for PTGS2-high CRC. The association of the sulfur microbial diet with distal CRC seemed to differ by the presence of intratumoral Bifidobacterium spp. with an adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.65 (95% confidence interval: 1.14-2.39, Ptrend = 0.01, Pheterogeneity = 0.03) for Bifidobacterium-negative distal CRC. We observed no apparent heterogeneity by other tested molecular markers.

Discussion: Greater long-term adherence to the sulfur microbial diet could be associated with PTGS2-high and Bifidobacterium-negative distal CRC in men. Additional studies are needed to further characterize the role of gut microbial sulfur metabolism and CRC.
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http://dx.doi.org/10.14309/ctg.0000000000000338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323793PMC
August 2021

Acute tubulointerstitial nephritis in a patient with early bronchial tuberculosis.

J Formos Med Assoc 2022 Feb 21;121(2):557-562. Epub 2021 Jul 21.

Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.

Patients with chronic kidney disease (CKD) are commonly at high risk of tuberculosis (TB). Conversely, TB rarely causes tubulointerstitial nephritis. A 75-year-old Japanese man who was undergoing periodic follow-ups for CKD stage G3aA3 with membranous nephropathy was diagnosed with acute kidney injury (AKI) (estimated glomerular filtration rate [eGFR]: 15 mL/min/1.73 m) without prerenal AKI. He reported developing recent-onset cough 3 weeks prior to presenting to us. Renal biopsy revealed acute tubulointerstitial nephritis along with known membranous nephropathy. CD4 helper T cells comprised most lymphocytes in the tubulointerstitium. Results of the interferon-gamma release assay, sputum smear test, polymerase chain reaction (PCR), and culture test were positive for TB. Chest computed tomography revealed thickening of the left bronchial wall; therefore, a diagnosis of early bronchial TB was made; his urine culture and PCR were negative for TB. At four months after TB treatment with no immunosuppressive therapy, his eGFR improved to 50 mL/min/1.73 m, and based on this progress, the AKI was diagnosed as tuberculosis-associated tubulointerstitial nephritis (TATIN). Although TATIN typically occurs with chronic or miliary tuberculosis, it is very rare in early bronchial TB. Identification of TATIN is important in kidney diseases of unknown etiology, and treatment with anti-TB drugs is necessary.
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http://dx.doi.org/10.1016/j.jfma.2021.07.010DOI Listing
February 2022

Granulomatous prostatitis with high suspicion of prostatic adenocarcinoma on radiological imaging.

IJU Case Rep 2021 Jul 6;4(4):247-249. Epub 2021 May 6.

Departments of Department of Urology NTT Medical Center Hospital Shinagawa-ku Japan.

Introduction: Granulomatous prostatitis is a benign inflammatory condition of the prostate that may mimic prostatic adenocarcinoma on magnetic resonance imaging findings. Even in the era of multiparametric magnetic resonance imaging, the differential diagnosis of granulomatous prostatitis from malignancy remains difficult.

Case Presentation: A 69-year-old man with abnormal magnetic resonance imaging and positron emission tomography/magnetic resonance imaging findings, and a prostate-specific antigen value of 2.48 ng/mL underwent prostate needle biopsy. He had a history of urinary tract infection 3 months prior to presentation. Multiparametric magnetic resonance imaging showed low-intensity signals on T2-weighted images, slightly high-intensity signals on diffusion-weighted images, and low values on apparent diffusion coefficients. The prostate imaging-reporting and data system version 2 score was 3. Histological examination revealed granulomatous prostatitis.

Conclusion: For patients with preceding urinary tract infections, granulomatous prostatitis should be considered as a differential diagnosis, even when magnetic resonance imaging and positron emission tomography suggest prostatic adenocarcinoma.
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http://dx.doi.org/10.1002/iju5.12300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255296PMC
July 2021

A new classification for the diagnosis of superficial non-ampullary duodenal epithelial tumors using endocytoscopy: A prospective study.

J Gastroenterol Hepatol 2021 Nov 28;36(11):3170-3176. Epub 2021 Jun 28.

Department of Gastroenterology, NTT Medical Center Tokyo, Tokyo, Japan.

Background And Aim: Although the frequency of endoscopic diagnosis of superficial non-ampullary duodenal epithelial tumors (SNADETs) has been increasing in recent years, no criteria for the endoscopic diagnosis of these tumors have been established yet. The aim of this study was to assess the usefulness of endocytoscopy for diagnosis SNADETs and to establish new criteria.

Methods: This prospective study was conducted at the NTT Medical Center Tokyo from May 2019 to July 2020, and a total of 100 consecutive SNADETs were enrolled. All the endocytoscopic images of the lesions and surrounding normal mucosa were classified into three groups according to the degree of structural atypia and the nuclear morphology and size. The endocytoscopic diagnoses using endocytoscopic classification was compared with the final histopathological diagnoses.

Results: Data of 93 patients with 98 lesions were included in the analysis. The preoperative diagnosis by endocytoscopy coincided with the final histopathological diagnosis in 85 (86.7%) of 98 SNADETs. In addition, the sensitivity and specificity for VCL 4/5 were 87.7% and 85.4%, respectively. In contrast, the accuracy, sensitivity, and specificity of preoperative diagnosis by biopsy were 64.3%, 50.9%, and 82.9%, respectively. Preoperative diagnosis by endocytoscopy showed significantly superior accuracy and sensitivity as compared with preoperative biopsy diagnosis (P < 0.001, respectively).

Conclusions: This new classification (endocytoscopic classification) allows prediction of the tumor histopathology in real time, during endocytoscopy without biopsy, and is expected to be of help in determining the appropriate therapeutic strategies for individual cases of SNADETs. (Clinical trial registration number: UMIN000038643.).
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http://dx.doi.org/10.1111/jgh.15585DOI Listing
November 2021

Assessment of surgical outcomes of off-clamp open partial nephrectomy without renorrhaphy for ≥T1b renal tumours.

Int J Clin Oncol 2021 Oct 16;26(10):1955-1960. Epub 2021 Jun 16.

Department of Urology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa-ku, Tokyo, 141-8625, Japan.

Purpose: To assess the surgical outcomes of off-clamp open partial nephrectomy without renorrhaphy. In the era of robot-assisted surgeries, open partial nephrectomy remains a surgical option for  ≥ T1b renal tumours. Although the necessity of renal pedicle clamping and renorrhaphy in open partial nephrectomy for larger tumours remains to be discussed, reports on this issue are rare.

Methods: Twenty-seven open partial nephrectomies for  ≥ T1b renal tumours were performed without renal pedicle clamping or renorrhaphy. A soft coagulation system was used to control bleeding from the resection bed. Surgical results, complications, and predictors of perioperative estimated glomerular filtration rate (eGFR) preservation at 1 month and 3 months after surgery were analysed.

Results: The median estimated volume of blood loss was 420 mL. The rates of perioperative eGFR preservation were 88.9 and 87.3% at 1 and 3 months after surgery, respectively. Tumour size was an independent predictor of perioperative eGFR preservation at 1 month after surgery, whereas age and exophytic/endophytic properties of the tumour were independent predictors of perioperative eGFR preservation at 3 months after surgery.

Conclusion: Open partial nephrectomy without renal pedicle clamping or renorrhaphy could be safely performed for  ≥ T1b renal tumours, even when tumours were entirely endophytic and located close to the renal pedicle. Mild perioperative eGFR reduction was observed. Although surgical indications should be carefully considered in these cases, off-clamp open partial nephrectomy without renorrhaphy is a feasible procedure for patients with  ≥ T1b renal tumours.
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http://dx.doi.org/10.1007/s10147-021-01966-0DOI Listing
October 2021

Molecular classification and diagnostics of upper urinary tract urothelial carcinoma.

Cancer Cell 2021 06;39(6):793-809.e8

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.
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http://dx.doi.org/10.1016/j.ccell.2021.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9110171PMC
June 2021

Clinical significance of CD8 and FoxP3 tumor-infiltrating lymphocytes and MFG-E8 expression in lower rectal cancer with preoperative chemoradiotherapy.

Mol Clin Oncol 2021 May 5;14(5):87. Epub 2021 Mar 5.

Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Preoperative chemoradiotherapy (CRT) for rectal cancer contributes to tumor down-staging and decreases locoregional recurrence. However, each patient shows a significantly different response to CRT. Therefore, the identification of predictive factors to CRT response would be beneficial to avoid unnecessary treatment. Cancer immunity in patients has been suggested to play an important role in the eradication of the tumor by CRT. In the present study, the utility of CD8 and forkhead box P3 (FoxP3) tumor-infiltrating lymphocytes (TILs) and the expression of a novel immuno-regulatory factor, lactadherin (MFG-E8), in predicting CRT effectiveness in patients with rectal cancer was examined. A total of 61 patients with rectal cancer, who underwent curative resection following CRT were included in the study. The numbers of CD8 and FoxP3 TILs in a biopsy taken before CRT and MFG-E8 expression level in the specimens obtained at the time of the surgery after CRT were examined using immunohistochemical staining, and their association with clinicopathological characteristics, including patient survival, was determined. The tumors with more CD8 TILs in the biopsy samples before CRT showed a significantly more favorable CRT response. The patients with tumors and a higher number of CD8 TILs before CRT also exhibited significantly longer disease-free and overall survival times. Higher MFG-E8 expression level in post-CRT specimens was significantly associated with favorable CRT response; however, no significant association was found with any other clinicopathological characteristics, including survival time. The number of CD8 TILs before CRT was a valuable predictor for CRT response and was associated with favorable prognosis in patients with lower rectal cancer and who were treated with CRT. High MFG-E8 expression level after CRT was also associated with a favorable CRT response.
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http://dx.doi.org/10.3892/mco.2021.2249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976375PMC
May 2021

Cystic Lesion of Dissected Pararectal Lymph Node in a Female Patient With Rectal Carcinoma: A Rare Pattern of Nodal Metastasis Mimicking a Serous Inclusion Cyst.

Int J Surg Pathol 2021 Oct 18;29(7):804-807. Epub 2021 Mar 18.

NTT Medical Center Tokyo, Tokyo, Japan.

Nodal metastatic foci of colorectal carcinoma are usually solid nodules. Serous inclusions are occasionally found in lymph nodes, particularly in female patients, and they occasionally form cysts. An 86-year-old woman was treated with laparoscopic low anterior resection and D3 lymph node dissection for advanced rectal carcinoma. A cyst with serous fluid and no necrotic debris was found within one of the dissected pararectal lymph nodes. Histologically, the cyst was lined by low columnar-to-cuboid epithelium with mild nuclear atypia, mimicking a serous inclusion cyst. Immunohistochemically, the epithelial cells were positive for caudal type homeobox 2 and negative for Wilms' tumor suppressor gene1. Immunohistochemistry for p53 showed a diffuse strong positivity, indicating a mutant as seen in primary rectal carcinoma. Thus, the nodal cystic lesion was confirmed to be a metastatic lesion. It is important to carefully assess a nodal cystic lesion to confirm whether it is benign or malignant.
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http://dx.doi.org/10.1177/10668969211003959DOI Listing
October 2021

Histopathological heterogeneity in an atypical type A thymoma variant with pulmonary metastases.

Pathol Int 2021 06 3;71(6):438-440. Epub 2021 Mar 3.

Department of Pathology, NTT Medical Center Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1111/pin.13089DOI Listing
June 2021

ABO Blood Group and Risk of Pancreatic Carcinogenesis in Intraductal Papillary Mucinous Neoplasms.

Cancer Epidemiol Biomarkers Prev 2021 05 2;30(5):1020-1028. Epub 2021 Mar 2.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: ABO blood group has been associated with risks of various malignancies, including pancreatic cancer. No study has evaluated the association of ABO blood group with incidence of pancreatic carcinogenesis during follow-up of patients with intraductal papillary mucinous neoplasms (IPMN).

Methods: Among 3,164 patients diagnosed with pancreatic cysts at the University of Tokyo (Tokyo, Japan) from 1994 through 2019, we identified 1,815 patients with IPMN with available data on ABO blood group. We studied the association of ABO blood group with incidence of pancreatic carcinoma, overall and by carcinoma types [IPMN-derived carcinoma or concomitant pancreatic ductal adenocarcinoma (PDAC)]. Utilizing competing-risks proportional hazards models, we estimated subdistribution hazard ratios (SHR) for incidence of pancreatic carcinoma with adjustment for potential confounders, including cyst characteristics.

Results: During 11,518 person-years of follow-up, we identified 97 patients diagnosed with pancreatic carcinoma (53 with IPMN-derived carcinoma and 44 with concomitant PDAC). Compared with patients with blood group O, patients with blood groups A, B, and AB had multivariable SHRs (95% confidence intervals) for pancreatic carcinoma of 2.25 (1.25-4.07; = 0.007), 2.09 (1.08-4.05; = 0.028), and 1.17 (0.43-3.19; = 0.76), respectively. We observed no differential association of ABO blood group with pancreatic carcinoma incidence by carcinoma types.

Conclusions: In this large long-term study, patients with IPMN with blood group A or B appeared to be at higher risk of pancreatic carcinoma compared with those with blood group O.

Impact: ABO blood group can be a biomarker for pancreatic cancer risk among patients with IPMNs.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1581DOI Listing
May 2021

Squamous differentiation is a potential biomarker predicting tumor progression in patients treated with pembrolizumab for urothelial carcinoma.

Pathol Res Pract 2021 Mar 8;219:153364. Epub 2021 Feb 8.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. Electronic address:

Immune checkpoint inhibitor (ICI) is widely used and highly effective for some cancer patients but may result in disease progression in others. Hyperprogressive disease in particular is characterized by an acceleration of tumor growth during ICI therapy and has been reported in patients including those with urothelial carcinoma. Biomarkers predicting treatment efficacy are crucial to avoid tumor progression and unnecessary adverse effects. This study aims to clarify the predictors of disease progression for ICI treatment in patients with urothelial carcinoma. We analyzed the response pattern of 23 urothelial carcinomas treated with pembrolizumab and its association with pathological features and potential immunohistochemical markers including EGFR, MDM2, p53, p16, and programmed cell death ligand-1 (PD-L1) expression and CD8- and CD204-positive cell infiltration. During ICI therapy, 13 (57 %) patients showed progressive disease including 6 (26 %) with hyperprogressive disease. Notably, squamous differentiation combined with MAC387 expression was observed exclusively in cases with progressive disease (6 of 13, 46 %); it was not present in cases with stable disease or partial/complete response (0 of 10, p = 0.0019). All tumors with squamous differentiation showed positive staining for EGFR. Additionally, the loss of p16 expression occurred more frequently in cases with progressive disease (8 of 13, 62 %) than in other cases (3 of 10, 30 %), but this finding did not reach statistical significance. Squamous differentiation was also significantly associated with shorter overall survival. Based on our observations, squamous differentiation may be a novel biomarker for predicting disease progression in patients with urothelial carcinoma who receive pembrolizumab.
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http://dx.doi.org/10.1016/j.prp.2021.153364DOI Listing
March 2021

Prognostic significance of tertiary Gleason pattern in the contemporary era of Gleason grade grouping: A narrative review.

Int J Urol 2021 06 12;28(6):614-621. Epub 2021 Feb 12.

Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.

Since the Gleason score was developed in 1966 as a histological classification for prostate cancer, it has been widely used in clinical practice and has evolved over time. The concept of a "tertiary Gleason pattern" (also known as a minor Gleason pattern) was first proposed in 2000, and has been used in clinical practice since the 2005 International Society of Urological Pathology conference. The prognostic significance of a tertiary Gleason pattern has been widely validated in various settings of prostate cancer, whereas its definition has yet to be fully established. Currently, a provisional definition of tertiary Gleason pattern is "<5% Gleason pattern 4 or 5 in radical prostatectomy specimens." In contrast, "Gleason grade grouping" was proposed in 2013 and came into use in clinical practice in 2016 according to the 2014 International Society of Urological Pathology conference. Although the prognostic significance of Gleason grade grouping has already been widely confirmed, it does not incorporate the concept of tertiary Gleason pattern. Recently, the 2019 International Society of Urological Pathology conference discussed how to handle tertiary Gleason pattern in the current Gleason scoring system, but no consensus was reached on the issue. This review summarizes the evidence on the prognostic significance of tertiary Gleason pattern and discusses how to deal with it in the context of the contemporary Gleason grade grouping. It also refers to reporting of the percentage of Gleason patterns 4 and 5, as well as quantitative Gleason score models incorporating tertiary Gleason pattern.
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http://dx.doi.org/10.1111/iju.14524DOI Listing
June 2021

CD10-Negative Primary Breast Follicular Lymphoma: A Rare Case of Primary Breast Lymphoma With an Atypical Immunophenotype Mimicking Marginal Zone Lymphoma.

Int J Surg Pathol 2021 Jun 30;29(4):400-403. Epub 2020 Nov 30.

NTT Medical Center Tokyo, Tokyo, Japan.

In this article, we report the case of a 78-year-old woman who consulted our hospital for a right breast mass detected on mammography during her cancer screening. Biopsy specimens showed atypical lymphocytic infiltration with a follicle-like growth pattern, suggesting a follicular lymphoma (FL). Immunohistochemically, the atypical lymphoid cells were diffusely and strongly positive for CD20, BCL2, and BCL6, but negative for CD10. IGH- translocation was confirmed by fluorescence in situ hybridization analysis, leading to the diagnosis of primary breast FL. The most important differential diagnosis of this case was marginal zone lymphoma (MZL), which usually shows a CD10/BCL2 immunophenotype and is one of the common histological types in primary breast lymphomas. FLs with an atypical immunophenotype exist in a certain percentage of patients. Therefore, FL is considered to be a heterogeneous entity. It is important to distinguish FL from MZL in primary breast lymphomas because FLs may have a worse prognosis than MZLs.
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http://dx.doi.org/10.1177/1066896920977690DOI Listing
June 2021

Anaplastic Lymphoma Kinase-Positive Lung Cancer with Mucoepidermoid Carcinoma Differentiation: A Case Report.

Case Rep Oncol 2020 May-Aug;13(2):1037-1041. Epub 2020 Sep 1.

Division of Respiratory Medicine, NTT Medical Center Tokyo, Tokyo, Japan.

Mucoepidermoid carcinoma (MEC) of the lung is an extremely rare tumor, and a standard chemotherapy has not been established. Furthermore, little work has been conducted on the genetic characteristics of MEC. We herein report the case of a 42-year-old nonsmoking male patient who was referred to our hospital due to cough. Chest computed tomography demonstrated infiltration and atelectasis in the right lower lobe. He was eventually diagnosed with non-small cell lung cancer (NSCLC) with MEC differentiation corresponding to clinical stage IVA (cT4N2M1a[PLE]). Genetic testing for EGFR mutations was negative, but positive for anaplastic lymphoma kinase (ALK) fusion gene. After 2 weeks of first-line treatment with alectinib, the tumor decreased in size and his symptoms improved. Advanced MEC is a rare tumor, and reports on the treatment of ALK-positive NSCLC with MEC differentiation are rare.
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http://dx.doi.org/10.1159/000510042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548870PMC
September 2020

B7-H3 expression in upper tract urothelial carcinoma associates with adverse clinicopathological features and poor survival.

Pathol Res Pract 2020 Dec 21;216(12):153219. Epub 2020 Sep 21.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

B7-H3, a member of the B7 superfamily, is an immune checkpoint molecule. An association between B7-H3 expression and poor survival has been reported in many types of cancer. However, its prognostic value in patients with upper tract urothelial carcinoma (UTUC) has not yet been reported. The aim of this study was to examine the clinical significance of tumor B7-H3 expression in UTUC. B7-H3 positivity was observed in 36 of 271 cases (13 %) by immunohistochemistry and was significantly associated with several adverse clinicopathological features such as tumor grade, tumor stage, and lymph node metastasis. In addition, B7-H3 positivity was significantly associated with shorter metastasis-free survival and cancer-specific survival. We also found that B7-H3/programmed cell death ligand-1 (PD-L1) co-positivity was significantly associated with worse prognosis. These results suggest the utility of B7-H3 positivity and B7-H3/PD-L1 co-positivity as novel prognostic biomarkers in UTUC, and the potential usefulness of B7-H3 targeted therapy for patients with UTUC, the effect of which may be enhanced by combination with programmed cell death-1 /PD-L1 blockade.
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http://dx.doi.org/10.1016/j.prp.2020.153219DOI Listing
December 2020

Latent prostate cancer among Japanese males: a bibliometric study of autopsy reports from 1980-2016.

Jpn J Clin Oncol 2021 Jan;51(1):156-159

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo.

Prostate cancer is one of the most common malignancies, but a substantial portion remains latent throughout the patients' lifetime. Analysis of temporal change in the latent prostate cancer pool would be beneficial for clinical decision-making, but longitudinal autopsy studies are rare. We conducted a hand-search of the Annual of Pathological Autopsy Cases in Japan from 1980 to 2016 for cases of latent prostate cancer. Of 570 997 males aged 30 or older, latent prostate cancer was detected in 12 562 patients (2.2%). Proportion of detected cases correlated strongly with 'aging rate', the percentage of population aged 65 or older (squared Pearson's correlation coefficient r2 = 0.972, P value <0.0001). Temporal increase in proportion was also seen in each age group as well. This continuous growth reinforces evidence from past Japanese reports on latent prostate cancer. The rapidly rising ageing rate of Japan may forecast further increase in the latent prostate cancer pool moving forward.
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http://dx.doi.org/10.1093/jjco/hyaa161DOI Listing
January 2021

Clinicopathologic Characteristics of Esophageal Ectopic Sebaceous Glands: Chronological Changes and Immunohistochemical Analysis.

Int J Surg Pathol 2021 Jun 26;29(4):378-384. Epub 2020 Aug 26.

NTT Medical Center Tokyo, Tokyo, Japan.

Esophageal ectopic sebaceous glands are very rare lesions. A series of 5 cases in a single report has been the maximum number described in the English literature to date. We conducted a clinicopathologic study of 8 cases of esophageal ectopic sebaceous glands. The median patient age at the time of diagnosis was 60 years (range, 50-71 years), and 7 of the 8 patients were male. A focal lesion was observed in 7 cases, whereas 1 case exhibited multiple lesions throughout the esophagus. Four patients had previously undergone upper gastrointestinal endoscopy; in 3 patients, the focal lesion had not been detected. After diagnosis, 3 cases showed spontaneous regression at least once. Immunohistochemically, sebocytes of all 8 cases were negative for the estrogen receptor (ER) and the progesterone receptor (PgR), whereas sebocytes of 5 cases were positive for the androgen receptor (AR). Basal/parabasal cells were positive for AR, ER, and PgR in 5, 7, and 4 cases, respectively. GATA3 was expressed in the sebocytes and basal/parabasal cells of 6 out of 7 available cases, whereas all of 7 available cases were negative for mammaglobin and GCDFP15. Our report provides the basic clinicopathologic characteristics of esophageal ectopic sebaceous glands by the largest case series reported in English literature to date. Furthermore, the chronological changes, particularly spontaneous regression, and immunohistochemical expression of hormone receptors and GATA3 are compatible with lesions resulting from congenital misplacement under hormonal regulation. Therefore, they seem to be congenital misplacements detectable as a result of hormonal stimulated growth.
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http://dx.doi.org/10.1177/1066896920951844DOI Listing
June 2021

Relationship between time-varying status of reflux esophagitis and Helicobacter pylori and progression to long-segment Barrett's esophagus: time-dependent Cox proportional-hazards analysis.

BMC Gastroenterol 2020 Aug 15;20(1):270. Epub 2020 Aug 15.

Department of Gastroenterology, NTT Medical Center, Tokyo, Tokyo, Japan.

Background: Reflux esophagitis (RE) and absence of Helicobacter pylori (non-H. pylori) are considered to be associated with the progression to long-segment Barrett's esophagus (LSBE). However, it is difficult to assess this association because RE and H. pylori status can change during follow-up. Additionally, the association between H. pylori eradication and LSBE remains unclear.

Methods: A total of 11,493 asymptomatic Japanese subjects who underwent medical check-ups and were endoscopically diagnosed with short-segment Barrett's esophagus (SSBE) between May 2006 and December 2015 were enrolled. The hazards of progression to LSBE were compared between time-varying RE and H. pylori infection/eradication by time-dependent multivariable Cox proportional hazards models.

Results: A total of 7637 subjects who underwent additional medical check-ups after being diagnosed with endoscopic SSBE were analyzed. Subjects with RE and without current/past H. pylori infection were strongly associated with a higher rate of progression to LSBE (adjusted hazard ratio [HR]: 7.17, 95% confidence interval [CI]: 2.48-20.73, p < 0.001 for RE and non-H. pylori vs. non-RE and H. pylori groups). Subjects with H. pylori had a lower rate of progression to LSBE (adjusted HR: 0.48, 95% CI: 0.22-1.07, p = 0.07 for H. pylori vs. non-H. pylori). Hazards of progression to LSBE were still lower in the H. pylori eradication group than that of the non-H. pylori group (adjusted HR: 0.51, 95% CI: 0.18-1.46, p = 0.21).

Conclusions: RE and non-H. pylori were associated with the progression to LSBE, considering the changes in exposures. H. pylori infection was associated with the prevention of the development of LSBE irrespective of RE. The environment preventive of the development of LSBE persists for at least a few years after H. pylori eradication.
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http://dx.doi.org/10.1186/s12876-020-01418-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429870PMC
August 2020

Uterine cervical squamous cell carcinoma with reactive multinucleated giant cells expressing cluster of differentiation 204: A case report and literature review.

J Obstet Gynaecol Res 2020 Oct 10;46(10):2174-2178. Epub 2020 Aug 10.

Department of Diagnostic Pathology, NTT Medical Center Tokyo, Tokyo, Japan.

Uterine cervical squamous cell carcinoma (SCC) with reactive multinucleated giant cells (MGC) is extremely rare. Here we present the case of a 49-year-old woman treated with radical hysterectomy, bilateral adnexectomy and lymph node dissection. Histologically, the cervical tumor was diagnosed as nonkeratinizing SCC of pT1b1N0M0, with negative surgical margin. Many MGC including osteoclast-like giant cells with immunohistochemical expression of cluster of differentiation 204, a marker for the M2 macrophage, were present around the tumor nests. The patient received postoperative radiation therapy and achieved 22 months of disease-free survival after the surgery. M2 macrophages promote aggressiveness of the carcinoma and it is suggested that SCC of the cervix with reactive MGC might have poor prognosis; however, our case paradoxically showed a favorable course. From literature review of six cases, including our case, the effect of MGC-reaction may vary with respect to other factors, such as age, cancer stage or histological type.
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http://dx.doi.org/10.1111/jog.14404DOI Listing
October 2020

Simple scoring system for the diagnosis of superficial non-ampullary duodenal epithelial tumors.

Dig Endosc 2021 Mar 28;33(3):399-407. Epub 2020 Aug 28.

Divisions of, Division of, Gastrointestinal Endoscopy, NTT Medical Center Tokyo, Tokyo, Japan.

Background And Aims: Differentiating superficial non-ampullary duodenal epithelial tumors (SNADETs) that harbor malignant potential is important. We developed a simple scoring system and investigated whether it enables the differentiation of low-grade adenoma and high-grade adenoma/adenocarcinoma.

Patients And Methods: We retrospectively enrolled 197 consecutive patients with 207 SNADETs who underwent endoscopic resection at NTT Medical Center Tokyo between March 2016 and May 2019. Endoscopic findings were compared between Vienna Classification (VCL) C3 and C4/5 lesions. A multivariate logistic regression analysis was performed to develop a scoring system to identify VCL C4/5 lesions. The efficacy of our scoring system was elucidated among five novice and five expert endoscopists.

Results: Of 207 SNADETs, 66 and 141 lesions were pathologically diagnosed as VCL C3 and C4/5. A multivariate logistic regression analysis identified a tumor diameter of 10-19 mm (OR, 3.81; 95% CI, 1.02-14.2; P = 0.04), a tumor diameter ≥20 mm (OR, 95.2; 95% CI, 10.4-871.0; P < 0.001), a red color (OR, 14.5; 95% CI, 3.55-59.6; P < 0.001), the presence of irregular surface pattern (OR, 12.4; 95% CI, 3.00-51.4; P < 0.001), and the presence of irregular vessel pattern (OR, 13.7; 95% CI, 4.03-46.6; P < 0.001) as independent significant predictors of VCL C4/5. Considering these results, we developed a scoring system. Using an appropriate cutoff value, the diagnostic accuracy, sensitivity and specificity were calculated as 92%, 95% and 93%. The average diagnostic accuracy did not differ between novice and expert endoscopists (86% vs 87%, P = 0.76).

Conclusions: Our scoring system was useful for differentiating VCL C3 and C4/5 lesions. UMIN Clinical Trials (No. 000039063).
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http://dx.doi.org/10.1111/den.13762DOI Listing
March 2021

Cisplatin plus pemetrexed therapy and subsequent immune checkpoint inhibitor administration for malignant peritoneal mesothelioma without pleural lesions: Case report.

Medicine (Baltimore) 2020 May;99(22):e19956

Division of Respirology.

Rationale: Malignant peritoneal mesothelioma is a rare tumor with a poor prognosis and has no recommended therapy after first-line pemetrexed and platinum-based chemotherapy. Moreover, effects of immune checkpoint inhibitors on peritoneal mesothelioma remains to be elucidated. We herein report the case of a 75-year-old man with peritoneal mesothelioma treated with cisplatin plus pemetrexed and subsequent nivolumab.

Patient Concerns: A 75-year-old man was referred to our hospital due to lower abdominal pain.

Diagnosis: Positron emission tomography-computed tomography (CT) showed the accumulation of fluorodeoxyglucose in an intraperitoneal mass. A histological examination of a laparoscopic biopsy specimen revealed malignant peritoneal mesothelioma.

Interventions: After 4 cycles of cisplatin plus pemetrexed and 13 subsequent cycles of pemetrexed maintenance therapy showed beneficial responses until CT revealed liver metastasis. Nivolumab was then administered as the second-line therapy.

Outcomes: After 3 cycles of biweekly nivolumab administration, he developed severe abdominal distention. CT revealed an intraperitoneal mass growing much more rapidly than ever, indicating hyperprogressive disease after nivolumab treatment. He ultimately died 51 days after the initial nivolumab administration.

Lessons: To our knowledge, this is the first report of hyperprogressive disease in a case of peritoneal mesothelioma after nivolumab treatment. While immune checkpoint inhibitors may be promising therapeutic strategies for treating malignant peritoneal mesothelioma, careful monitoring must be practiced with their application.
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http://dx.doi.org/10.1097/MD.0000000000019956DOI Listing
May 2020

Progressively increasing density of the solid center of a ground-glass nodule in a solitary pulmonary capillary hemangioma: A case report.

Pathol Int 2020 Aug 5;70(8):568-573. Epub 2020 May 5.

Department of Diagnostic Pathology, NTT Medical Center Tokyo, Tokyo, Japan.

Solitary pulmonary capillary hemangiomas (SPCHs) are recently recognized, rare benign lesions that form solitary nodules owing to capillary proliferation. These lesions are usually detected incidentally as small ground-glass nodules (GGNs) on computed tomography (CT), and progressively enlarge over time. The radiological distinction from peripheral lung cancers is particularly challenging. However, to date, there have been no reports on progressive changes in the central density of SPCH on CT. An asymptomatic 49-year-old man was referred to our hospital for an abnormal shadow that was detected on chest CT during medical check-up. He was subsequently followed-up with chest CT. The nodule increased in size, and the central area became progressively denser. He underwent surgery 5 years and 10 months after the first visit owing to suspicion of lung cancer. Despite the collapse of the surgical specimen by artifacts, histopathological examination revealed a diagnosis of SPCH; collagenous fibers were found in the walls of the intralesional capillaries. The patient is presently alive without any recurrence, 6 months after the operation. In this case, the SPCH demonstrated a GGN with progressively increasing density of the central solid area on the CT. This remarkable feature made the preoperative distinction from lung cancer particularly difficult.
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http://dx.doi.org/10.1111/pin.12945DOI Listing
August 2020

Quantification of the individual risk of each Gleason pattern, including tertiary Gleason pattern 5, after radical prostatectomy: development of the modified Gleason grade grouping (mGGG) model.

BMC Cancer 2020 May 1;20(1):371. Epub 2020 May 1.

Department of Urology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.

Background: While the new Gleason grade grouping (GGG), which started in 2016, has been widely validated in prostate cancer, it does not incorporate the concept of tertiary Gleason pattern 5. Furthermore, no study has "quantified" the individual risk of each Gleason pattern, including tertiary Gleason pattern 5, after radical prostatectomy.

Methods: We reviewed 1022 men with adjuvant-treatment-naïve prostate cancer who underwent radical prostatectomy between 2005 and 2017. The primary endpoint was biochemical recurrence-free survival, defined as two consecutive prostate-specific antigen measurements ≥0.2 ng/ml after surgery. The individual quantitative risk score (IQRS) of each amount (primary/secondary/tertiary) of each Gleason pattern (3/4/5) was calculated using the Cox regression model. On the basis of the IQRS, the modified Gleason grade grouping (mGGG) model was developed. As a robustness analysis of the mGGG model, salvage treatment-free survival was also assessed.

Results: During a median follow-up of 45 months, 229 of 1022 (22.4%) patients developed biochemical recurrence. The IQRS of each Gleason pattern was as follows: primary 5, 1.81 points (hazard ratio [HR] 6.13); secondary 5, 1.37 points (HR 3.92); tertiary 5, 0.87 points (HR 2.39); primary 4, 1.07 points (HR 2.91); secondary 4, 0.79 points (HR 2.21); and any Gleason pattern 3, 0 points (HR 1). Based on the IQRS, the mGGG model was developed, which classified patients into the following five groups: I (3 + 3 or less); II (3 + 4); III (4 + 3); IV (3 + 4 + t5, 4 + 3 + t5, 3 + 5, 5 + 3, and 4 + 4); V (4 + 4 + t5, 4 + 5, 5 + 4, and 5 + 5). The c-index for biochemical recurrence-free survival was significantly improved from 0.655 of the original GGG model to 0.672 of the mGGG model (P < 0.05). In the robustness analysis, the c-index for salvage treatment-free survival was also significantly improved from 0.619 of the original GGG model to 0.638 of the mGGG model (P < 0.05).

Conclusions: The quantitative risk of tertiary (< 5%) Gleason pattern 5 is slightly higher than that of secondary (5-50%) Gleason pattern 4. Our newly developed mGGG model more accurately predicts outcomes after radical prostatectomy than the original GGG model.
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http://dx.doi.org/10.1186/s12885-020-06880-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195773PMC
May 2020
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