Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.

Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.

Gastric adenocarcinoma of fundic gland type arising from heterotopic gastric glands during a 19-year follow-up period.

A 73-year-old man with prior history of duodenal ulcer has been undergoing periodic upper gastrointestinal endoscopy since 1999. In 2017, a 25-mm submucosal tumor-like protrusion was detected in the lesser curvature of the upper stomach; histological examination of the lesion revealed gastric adenocarcinoma of fundic gland type. En bloc resection was achieved using endoscopic submucosal dissection. The patient was histopathologically diagnosed with gastric adenocarcinoma of fundic gland type arising from heterotopic gastric glands. Immunohistochemical staining was positive for MUC5AC, MUC6, pepsinogen I, and proton pump but negative for MUC2 and CD10. Moreover, the patient's Ki-67 labeling index score was extremely low. The presence of MUC5AC indicated that the tumor differentiated to the foveolar epithelium and fundic glands. Gastric adenocarcinoma of fundic gland type that differentiates to several directions has a higher malignant potential than the disease that differentiates to chief cells. A retrospective review of the patient's previous endoscopic examination revealed that the submucosal tumor-like protrusion existed since 2000; tumor size increased from 8 mm in 2000 to 25 mm in 2017. The present case is rare in that the carcinoma arose from heterotopic gastric glands. Moreover, the 19-year follow-up revealed that the tumor differentiated to the foveolar epithelium, considered as having high-grade malignancy.

De novo proliferative glomerulonephritis with monoclonal IgG deposits of the IgG1κ subtype in a kidney allograft.

Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) has recently been described in cases with glomerular disease. Only 16 cases of recurrent or de novo PGNMID have been reported in the transplanted kidney. Here we report a case of de novo PGNMID in a renal allograft diagnosed in the early stage by protocol biopsy. A 41-year-old male with end-stage kidney disease caused by focal glomerular sclerosis received a living-related kidney transplant. The post-transplantation course was stable, except for an early episode of acute T cell-mediated rejection. Mesangial C1q deposition was found on the 3-year protocol biopsy. On the 4-year protocol biopsy, mild mesangioproliferative changes and deposition of IgG, C1q, C3, IgG1, and κ light chain were evident, confirming the diagnosis of PGNMID of the IgG1κ subtype. Furthermore, mild proteinuria was detected at that time. Because a subsequent haematological examination revealed high copy number Epstein-Barr virus (EBV) DNA and free κ light chain in blood, the post-transplant lymphoproliferative disorder (PTLD) was suspected. Mycophenolate mofetil (MMF) was discontinued and rituximab was administered for the treatment of PTLD; subsequently, the improvement in proteinuria and serum creatinine was found 2 months after rituximab administration.

Microvascular inflammation in early protocol biopsies of renal allografts in cases of chronic active antibody-mediated rejection.

AIM: Chronic active antibody-mediated rejection (chronic ABMR) is one important cause of late-stage renal allograft loss. However, few reports have used protocol biopsy to observe changes over time in cases that develop chronic ABMR. The aim of this study was to use protocol biopsy to clarify the histological features of cases that develop chronic ABMR. METHODS: We recruited 379 ABO compatible patients who underwent protocol biopsy at our hospital from 2010 to 2014. Seventeen of these patients were diagnosed with chronic ABMR (chronic ABMR group), and 12 patients were class 2 donor-specific antibody (DSA) positive and were not diagnosed with chronic ABMR (class 2 DSA-positive group). With the addition of a control group consisting of 30 DSA negative patients, these three groups were compared for Banff factors in protocol biopsies taken 3 months, 6 months, 1 year, 3 years, and 5 years after the transplant. RESULTS: Three months post transplant, the chronic ABMR group had a significantly higher number of patients exhibiting g + ptc > 0 than that in the control group (P = 0.01). At 1, 3, and 5 years post transplant, significantly more subjects in the chronic ABMR and class 2 DSA-positive groups compared with the control group exhibited g + ptc > 0 (P < 0.03). Five years post transplant, the chronic ABMR group exhibited a significantly higher mean c4d score than that in the control group (P = 0.02). The only significant difference observed between the chronic ABMR group and the class 2 DSA-positive group was in cg scores at 5 years post transplant, which were significantly higher in the chronic ABMR group (P = 0.03). CONCLUSIONS: These results suggest that cases exhibiting microvascular inflammation in the early post-transplant period may develop chronic ABMR, and it would be highly beneficial to perform focused electron microscope surveillance of these cases.

Tonsillectomy ameliorates histological damage of recurrent immunoglobulin A nephropathy after kidney transplantation.

AIM: Recurrence of immunoglobulin A (IgA) nephropathy (IgAN) after renal transplantation is important as a cause of graft failure under improving rejection control. However, no specific therapy for recurrent IgAN is currently available. In this study, we evaluated the histological efficacy of tonsillectomy for allograft IgAN. METHODS: Fifteen kidney recipients (male 9, female 6, mean age 40.9 ± 9.3 years), who received a diagnosis of IgA nephropathy by allograft biopsy, were enrolled in this study. Tonsillectomy was performed 44.1 ± 27.1 months after the kidney transplantation. All patients underwent a repeat graft biopsy at 23.8 ± 15.8 months after tonsillectomy. RESULTS: Six patients had microhematuria before tonsillectomy. At 12 months after treatment, the microhematuria disappeared in five of these patients and one patient had mild hematuria. Three patients had severe proteinuria (more than 1.0 g/gCr) before tonsillectomy and improved after treatment. On histological analysis, four patients had acute lesions including cellular or fibrocellular crescents. The acute lesions disappeared after these treatments in all patients. Eleven patients had chronic lesions including global sclerosis, segmental sclerosis and fibrous crescents. The chronic lesion was ameliorated in six patients, unchanged in three and deteriorated in two patients. CONCLUSIONS: Tonsillectomy improves not only clinical findings but also ameliorates histological damage caused by recurrent IgAN after kidney transplantation. Tonsillectomy is a novel and effective treatment for recurrent IgAN.