Pathological survey of precursor lesions in cholangiocarcinoma.

BACKGROUND: To clarify the pathological significance of two precursors (high-grade biliary intraepithelial neoplasm [BilIN] and intraductal papillary neoplasm of bile duct [IPNB]) in cholangiocarcinomas (CCAs). METHODS: Ninety-one cases of CCA (47 distal CCAs [dCCAs], 31 perihilar CCAs [pCCAs] and 13 intrahepatic CCAs of large duct type [LD-iCCAs]) were examined for their association with precursors. Neoplastic intraepithelial lesions without underlying infiltrating carcinoma in the surrounding mucosa of CCAs were considered to reflect high-grade BilIN. High-grade BilIN and IPNB were subdivided into gastric, biliary, intestinal and oncocytic subtypes, while CCAs were subdivided into gastrobiliary, intestinal and oncocytic subtypes. The postoperative overall survival (OS) was examined. RESULTS: Fifty-four and 8 of 91 CCAs were associated with high-grade BilIN and IPNB, respectively, while these precursors were unidentifiable in the remaining CCAs. A majority of CCAs were of the gastrobiliary subtype, while the intestinal subtype was occasionally detected, and the oncocytic subtype was rare. CCAs with high-grade BilIN showed a similar postoperative OS to CCAs without precursors, while CCAs with IPNB showed a favorable postoperative OS compared to CCAs without precursors. CONCLUSIONS: CCAs were frequently associated with precursors; high-grade BilIN may be a major precursor and IPNB a minor one. CCAs with IPNB showed a favorable postoperative OS compared to CCAs with high-grade BilIN.

Intraepithelial involvement of non-neoplastic glands in papillary preinvasive neoplasms of the biliary tract: a potential diagnostic pitfall.

Intracholecystic papillary neoplasms of the gallbladder (ICPN) and intraductal papillary neoplasms of the bile duct (IPNB) show intramural neoplastic growths in addition to intraluminal papillary or polypoid neoplastic growth. Such intramural growths include intraepithelial involvement of non-neoplastic glands by preinvasive neoplastic epithelia (glandular involvement) as well as stromal invasive carcinoma. A total of 29 ICPN cases and 84 IPNB cases were pathologically examined for their glandular involvement. Glandular involvement was characterized by intramural neoplastic glands (1) showing cytological and phenotypical similarities to intraluminal preinvasive papillary neoplasms and (2) showing reminiscent configurations of non-neoplastic glands, such as (i) a mixture of preinvasive neoplastic epithelia and non-neoplastic epithelia within the same glands, (ii) neoplastic glands close to or within clustered non-neoplastic glands, or (iii) continuous growth of intraluminal preinvasive neoplastic glands into the walls. Such glandular involvement was found in 16 of 29 ICPN and 48 of 84 IPNB, and 15 of the former and 28 of the latter were not associated with invasive carcinoma. Non-invasive ICPN and IPNB with glandular involvement showed a favorable postoperative overall survival (OS). Glandular involvement by preinvasive neoplastic epithelia was frequently found in ICPN and IPNB. Such lesions may be diagnostic pitfalls in ICPN and IPNB referring to invasion. Glandular involvement without invasive carcinoma was not associated with an unfavorable postoperative OS in ICPN and IPNB. Recognition of glandular involvement may thus prevent overestimation of invasive carcinoma in ICPN and IPNB.

Pathologic patterns of invasive carcinoma associated with intraductal papillary neoplasms of bile duct (IPNB).

The pathologic features of invasive carcinoma associated with IPNB remain to be clarified. By using 82 cases of IPNB, the pathologic spectrum of associated invasive carcinoma and its correlation with their post-operative overall survival (OS) were examined. Invasive carcinoma was found in 52 cases (63 %) of IPNB and was classifiable into three patterns (patterns A, B and C). Pattern A was characterized by microscopic foci of invasive carcinoma in the fibrovascular stalks or confined to the bile duct mucosa and wall beneath the intraluminal pre-invasive neoplastic components of IPNB (23 cases) and pattern B by invasive carcinoma in the periductal connective tissue and in the adjacent organ(s) mainly near or beneath the intraluminal component(s) of IPNB (15 cases). Pattern C showed nodular invasive carcinoma considerably involving the intraluminal pre-invasive components and the bile duct mucosa and wall adjacent to the intraluminal pre-invasive components of IPNB (14 cases). Recognition of these three patterns of invasive carcinoma associated with IPNB may expand the pathologic spectrum of IPNB. IPNBs without invasive carcinoma showed a favorable post-operative-OS compared with those with invasion as a whole and those of pattern B and C, respectively, but showed a similar post-operative-OS to that of pattern A. IPNB of pattern B and C showed an unfavorable post-operative outcome, though there was no difference between pattern B and C. Understanding of the pathologic spectrum of associated invasive carcinoma may facilitate further pathological analysis of IPNB.

Association of precursors with invasive adenocarcinoma of the gallbladder: A clinicopathological study.

BACKGROUND: The current WHO classification proposed high-grade biliary intraepithelial neoplasm (BilIN) and intracholecystic papillary neoplasm (ICPN) as precursors of the gallbladder carcinoma (GBC). Herein, conventional GBCs (cGBCs) were pathologically examined with respect to these two precursors. METHODS: Forty-seven cases of GBC with grossly visible invasions were collected from Fukui Saiseikai Hospital. The association of two precursors was analyzed referring to pathologic features of cGBCs and post-operative survival. RESULTS: 20 cGBCa (42.6%) were associated with either of two precursors in the surrounding mucosa: high-grade BilIN in 15 cases (31.9%) or ICPN in 5 cases (10.6%). Association of precursors was not related to gross types of and histological differentiation of cGBC. cGBCs without precursors showed frequent vascular/perineural invasion and lymph node metastasis, though cGBCs with and without precursors presented a similar post-operative survival. High-grade BilIN and ICPN associated with cGBCs showed more complicated cytoarchitectural features compared with those with no or focal invasion. CONCLUSION: More than 40% of cGBCs were associated with high-grade BilIN or ICPN, and the former was a frequent precursor. cGBCs without precursors showed aggressive pathologic features. Clinical detection of these precursors may make early treatment of cGBCs possible.

Pathological features of pyloric gland adenoma of the gallbladder in comparison with gastric subtype of intracholecystic papillary neoplasm.

BACKGROUND AND AIMS: Pyloric gland adenoma (PGA) of the gallbladder is a polypoid, preinvasive epithelial neoplasm composed of uniform back-to-back, pyloric glands in a tubular configuration. Intracholecystic papillary neoplasm (ICPN), another preinvasive grossly visible neoplasm of the gallbladder, is subdividable into four subtypes, including gastric subtype. In this study, PGA was reappraised referring to gastric subtype of ICPN (gICPN). MATERIALS AND METHODS: PGA and gICPN pathologically defined by WHO 2019 classification were surveyed in a total of 104 cases of gallbladder epithelial neoplasms of our Hospital (2002 January to 2021 May) and were pathologically and immunohistochemically compared. RESULTS: PGA (7 cases) was characterized by i) a well-demarcated, polypoid lesion and ii) packed tubular components resembling pyloric glands. gICPNs (14 cases) were subdivided into i) pyloric gland predominant (2 cases), ii) foveola predominant (6 cases) and iii) mixed foveola and pyloric gland type (6 cases). gICPNs were also divided into a solitary, polypoid lesion with well demarcation from the surrounding mucosa (5 cases) and a conglomerated polypoid and granular lesions with poor demarcation (9 cases). PGA shared gross and histologic features with solitary, polypoid gICPNs, and PGA could be regarded as solitary gICPN predominantly composed of pyloric glands. Nuclear expression of ß-catenin was found in 6 of 7 PGA, but absent in gICPN, including solitary, polypoid gICPN. CONCLUSION: PGA could correspond to a solitary gICPN mainly composed of pyloric glands, but may undergo a different molecular pathway from gICPN.

Pathological characterization of intracholecystic papillary neoplasm: A recently proposed preinvasive neoplasm of gallbladder.

Intracholecystic papillary neoplasm (ICPN) is a recently proposed gallbladder neoplasm. Its prevalence and pathologies remain to be clarified. A total of 38 ICPN cases (28 ICPNs identified among 1904 cholecystectomies (1.5%) and in 100 surgically resected primary gallbladder neoplasms (28%) in Fukui Prefecture Saiseikai Hospital, Japan, and other 10 ICPNs) were examined pathologically and immunohistochemically. They were composed of 21 males and 17 females with a mean age of 75 years old, and presented intraluminal growth of papillary lesions with fine fibrovascular stalks. ICPNs were relatively frequent in the fundus (n = 11) and body (n = 9). Grossly, the conglomerated sessile type (n = 30) was more frequent than the isolated polypoid type (n = 8). All cases were classified as high-grade dysplasia, and they were further divided into 22 cases presenting irregular structures and 16 cases presenting regular structures. The former showed frequent complicated lesions and stromal invasion (54.5%) compared to the latter (12.5%). Twenty-four cases showed predominantly either of four subtypes (11 gastric, 7 intestinal, 4 biliary and 2 oncocytic subtype), while the remaining14 cases showed mixture of more than two subtypes. In conclusion, ICPN presented unique preinvasive neoplasm with characteristic histopathologies. Irregular histologies and complicated lesions of ICPN were related to stromal invasion.

Efficacy and safety of ustekinumab in East Asian patients with moderately to severely active ulcerative colitis: a subpopulation analysis of global phase 3 induction and maintenance studies (UNIFI).

BACKGROUND/AIMS: We aimed to evaluate the efficacy and safety of ustekinumab (UST) in the East-Asian population with moderate to severely active ulcerative colitis (UC). METHODS: This sub-analysis was conducted on data from East-Asian patients included in the UNIFI program (NCT02407236). UNIFI consisted of two double-blind, placebo-controlled trials: an 8-week induction study and a 44-week randomized withdrawal maintenance study. RESULTS: Of 133 East-Asian patients (Japanese: 107, Korean: 26) who underwent randomization, 131 completed induction study and 111 entered maintenance study. In the maintenance study, 78 patients were randomized. Patients who received UST 130 mg and UST 6 mg/kg showed numerically higher clinical remission at week 8 in the induction study (5/44 [11.4%] and 5/45 [11.1%], respectively) compared with those who received placebo (0/44, 0%). The proportion of patients achieved clinical remission at week 44 was numerically higher in the UST 90 mg q12w group (10/21, 47.6%), but similar in the UST 90 mg q8w group (5/26, 19.2%) compared to placebo (7/31, 22.6%). Serious adverse events were reported in 1 patient in UST 130 mg group, but no patient in UST 6 mg/kg group through week 8 in the induction study, and 1 patient in UST 90 mg q12w group and 5 patients in the UST 90 mg q8w group in the maintenance study. No deaths were reported in East-Asian patients throughout the study. CONCLUSIONS: UST induction and maintenance treatments were effective in East-Asian patients with moderate to severe UC; the efficacy and safety profiles were consistent with the overall population.

The Pathologic and Genetic Characteristics of the Intestinal Subtype of Intraductal Papillary Neoplasms of the Bile Duct.

The present study aimed to identify the pathologic and genetic characteristics of intestinal subtype of intraductal papillary neoplasm of the bile duct (iIPNB) showing columnar cells with pseudostratified, cigar-shaped nuclei, and basophilic or amphophilic cytoplasm with the diffuse immunohistochemical expression of CK20 and/or CDX2. A total of 34 cases of iIPNB were pathologically examined according to their anatomic location (the bile duct) and were then compared with the intestinal subtype of intraductal papillary mucinous neoplasm (iIPMN) of the pancreas (n=22). Mutations of 26 somatic genes were examined in formalin-fixed paraffin-embedded tissue specimens from 21 cases of iIPNB using the TruSight Tumor 26 gene panel and next-generation sequencing. iIPNB cases were divided into intrahepatic (n=6) and extrahepatic (n=28) categories. Intrahepatic IPNBs showed a less-complicated villous-papillary pattern, while extrahepatic IPNBs showed a papillary pattern with tubular and/or villous components and predominant high-grade dysplasia with complicated architectures. MUC5AC was frequently and extensively expressed in intrahepatic iIPNBs and iIPMNs but not in extrahepatic iIPNBs. CD10 was frequently expressed in extrahepatic IPNBs but not in intrahepatic iIPNBs or iIPMN. Genetic mutations of TP53 and PIK3CA, which were infrequent or absent in iIPMNs, were frequently detected in extrahepatic iIPNBs, while KRAS and GNAS, which were commonly observed in iIPMNs, were frequently detected in intrahepatic iIPNBs. Intrahepatic iIPNBs showed villous-papillary growth with features reminiscent of iIPMNs, while extrahepatic iIPNBs showed papillary growth with tubular and/or villous components, complicated histology and variable differences from iIPMNs, suggesting differences in the tumorigenesis of iIPNBs along the biliary tree.

A large-scale, prospective, observational study of leukocytapheresis for ulcerative colitis: treatment outcomes of 847 patients in clinical practice.

BACKGROUND AND AIMS: Leukocytapheresis is an extracorporeal therapy for ulcerative colitis. However, no large-scale study on leukocytapheresis has been reported. This large-scale, prospective, observational study aimed to evaluate the treatment outcomes of leukocytapheresis for active ulcerative colitis in clinical practice. METHODS: Patients with active ulcerative colitis treated with leukocytapheresis using a Cellsorba E column between May 2010 and December 2012 were enrolled from 116 medical facilities in Japan. RESULTS: A total of 847 patients were enrolled, and 623 were available for efficacy analysis. Out of 847 patients, 80.3% of the patients had moderate to severe disease activity, and 67.6% were steroid refractory. As concomitant medications, 5-aminosalicylic acids, corticosteroids, and thiopurines were administered to 94.8%, 63.8%, and 32.8% of the patients, respectively. In addition, infliximab and tacrolimus were concomitantly used in 5.8% and 12.3%, respectively. Intensive leukocytapheresis (≥4 leukocytapheresis sessions within the first 2 weeks) was used in >70% of the patients. Adverse events were seen in 10.3% (87/847), which were severe in only 5 patients (0.6%). Any concomitant medications did not increase the incidence of adverse events. Intensive leukocytapheresis was as safe as the conventional weekly procedure. The overall clinical remission rate was 68.9% (429/623), and the mucosal healing rate was 62.5% (145/232). Clinical remission was achieved more frequently and rapidly in the intensive group than in the weekly group. CONCLUSIONS: This large-scale study indicates that leukocytapheresis, including intensive procedure, is a safe and effective therapeutic option for active ulcerative colitis.

Anti-hypoalbuminemic effect of branched-chain amino acid granules in patients with liver cirrhosis is independent of dietary energy and protein intake.

AIM: A multicenter prospective intervention study was conducted in 204 patients with uncompensated liver cirrhosis to explore the influence of dietary intake and patient clinical characteristics on improvement of hypoalbuminemia at weeks 12 and 24 of treatment with branched-chain amino acid (BCAA) granules. METHODS: The primary endpoint set in this study was improvement of hypoalbuminemia in patients with liver cirrhosis. The dietary energy and protein intake per day were estimated based on the results of a survey on diet during a 3-day period preceding the start of the study. RESULTS: As for the primary endpoint, the mean serum albumin level increased significantly at weeks 12 and 24 of BCAA treatment, compared with the baseline level. The mean Child-Pugh score decreased significantly at weeks 12 and 24 of treatment as compared to the mean baseline score. There was a significant increase in the serum albumin level following treatment with BCAA granules regardless of energy intake and of protein intake. The incidence of ascites and edema significantly decreased in the overall patient population both at weeks 12 and 24 of treatment, compared with the baseline incidence. A subgroup analysis conducted in patients stratified according to changes in the serum albumin level at week 12 of treatment as against baseline showed that the incidence of ascites/edema was significantly reduced not only in the increased albumin group but in the unchanged albumin group. CONCLUSION: The present data suggest that the anti-hypoalbuminemic effect of BCAA treatment in patients with liver cirrhosis is independent of dietary intake.