Dysplastic crypt-rings in tandem: A novel histologic parameter in tubular adenomas.

Descriptions of the various dysplastic crypt phenotypes occurring in TA have remained unattended in the literature. Recently, new crypt-phenotypes, characterized by crypt rings in tandem (CRT), and by dysplastic crypt rings in tandem (DCRT) were described in IBD, and in in IBD-associated dysplasia, respectively. Here, we report the occurrence of DCRT in 40.4 % (n = 59) out of 146 consecutive tubular adenomas of the colorectum (TA). The number of DCRT varied: 10 TA had two DCRT, seven TA had three DCRT, two TA, four DCRT and the remaining two TA had ≥ five DCRT. The frequency of DCRT was influenced by TA-size; larger TA (≥ 5 mm) had significantly more DCRT than smaller TA (<5 mm). Conversely, the frequency of TA with DCRT was not influenced by age, gender, or localization. Since only 1 or 2 sections were available per TA, the number of DCRT in the entire TA should be higher than those shown in Results. Historical controls in human and rodent normal colorectum showed no CRT. Moreover, DCRT were not found in 781 historical non-polypoid colorectal adenomas. The present finding might encourage searching for DCRT, the final goal being to achieve a more elaborated microscopic narrative of TA, the most prevalent of all colorectal adenomas.

Microenvironment-induced restoration of cohesive growth associated with focal activation of P-cadherin expression in lobular breast carcinoma metastatic to the colon.

Invasive lobular carcinoma (ILC) is a special breast cancer type characterized by noncohesive growth and E-cadherin loss. Focal activation of P-cadherin expression in tumor cells that are deficient for E-cadherin occurs in a subset of ILCs. Switching from an E-cadherin deficient to P-cadherin proficient status (EPS) partially restores cell-cell adhesion leading to the formation of cohesive tubular elements. It is unknown what conditions control EPS. Here, we report on EPS in ILC metastases in the large bowel. We reviewed endoscopic colon biopsies and colectomy specimens from a 52-year-old female (index patient) and of 18 additional patients (reference series) diagnosed with metastatic ILC in the colon. EPS was assessed by immunohistochemistry for E-cadherin and P-cadherin. CDH1/E-cadherin mutations were determined by next-generation sequencing. The index patient's colectomy showed transmural metastatic ILC harboring a CDH1/E-cadherin p.Q610* mutation. ILC cells displayed different growth patterns in different anatomic layers of the colon wall. In the tunica muscularis propria and the tela submucosa, ILC cells featured noncohesive growth and were E-cadherin-negative and P-cadherin-negative. However, ILC cells invading the mucosa formed cohesive tubular elements in the intercryptal stroma of the lamina propria mucosae. Inter-cryptal ILC cells switched to a P-cadherin-positive phenotype in this microenvironmental niche. In the reference series, colon mucosa infiltration was evident in 13 of 18 patients, one of which showed intercryptal EPS and conversion to cohesive growth as described in the index patient. The large bowel is a common metastatic site in ILC. In endoscopic colon biopsies, the typical noncohesive growth of ILC may be concealed by microenvironment-induced EPS and conversion to cohesive growth.

Sporadic Colorectal Tubular Adenomas Thrive in Symbiosis With Underlying Nondysplastic Branching Crypts.

BACKGROUND/AIM: Nondysplastic crypt branching (NDCB), mostly asymmetric branching (NDCAB), was previously found beneath the dysplastic epithelium of colorectal tubular adenomas (TA) in Swedish patients. This study examined the frequency of NDCB and NDCAB beneath the dysplastic epithelium of TA, in German patients. PATIENTS AND METHODS: From a collection of 305 TA, 121 TA fulfilled the prerequisites for inclusion. All NDCB were registered. RESULTS: Of 673 NDBCs, 572 (85%) NDCABs and 101 (15%) NDCSs, were found beneath the neoplastic tissue in the 121 TA. When the frequency of NDCB was challenged against the TA size, a linear correlation was found in the 121 TA (p<0.05, p=0.020172). Most NDCB were NDCAB (p<0.05, p=0.00001). The frequency of NDCB correlated with increasing TA size, implying that the higher frequency of both NDCB, dysplastic crypt branching, and their dysplastic offspring crypts were the most probable sources of TA enlargement. The frequency of NDCB underneath TA was not influenced by increasing age, sex or TA localization. CONCLUSION: Similar findings as those reported here were previously found in TA in Swedish patients. The similarity between these two populations, located in disparate geographical areas and subjected to dissimilar microenvironmental conditions suggests that NDBC in TA might be a ubiquitous unreported phenomenon. According to the literature, normal colon cells often harbor somatic mutations. Consequently, NDCB underneath TA may be mutated nondysplastic branching crypts upon which the dysplastic epithelium in TA eventually develops.

Morphological subtypes of colorectal low-grade intraepithelial neoplasia: diagnostic reproducibility, frequency and clinical impact.

AIMS: Special histomorphological subtypes of colorectal low-grade intraepithelial neoplasia (LGIN) with variable prognostic impact were recently described in patients with inflammatory bowel disease (IBD) referred to as non-conventional dysplasia. However, they can also be found in patients without IBD. We aimed to analyse the reproducibility, frequency and prognostic impact of non-conventional colorectal LGIN in patients with and without IBD. METHODS: Six pathologists evaluated 500 specimens of five different LGIN-cohorts from patients with and without IBD. Non-conventional LGIN included hypermucinous, goblet cell-deficient, Paneth cell-rich and crypt cell dysplasia. A goblet cell-rich type and non-conventional LGIN, not otherwise specified were added. Results were compared with the original expert-consented diagnosis from archived pathology records. RESULTS: Four or more pathologists agreed in 86.0% of all cases. Non-conventional LGIN was seen in 44.4%, more frequently in patients with IBD (52%; non-IBD: 39.3%, p=0.005). In patients with IBD non-conventional LGIN associated with more frequent and earlier LGIN relapse (p=0.006, p=0.025), high-grade intraepithelial neoplasia (p=0.003), larger lesion size (p=0.001), non-polypoid lesions (p=0.019) and additional risk factors (p=0.034). Results were highly comparable with expert-consented diagnoses. In patients without IBD, non-conventional LGIN may indicate a higher risk for concurrent or subsequent colorectal carcinoma (CRC, p=0.056 and p=0.061, respectively). Frequencies and association with high-grade intraepithelial neoplasia or CRC varied between the different LGIN subtypes. CONCLUSIONS: Non-conventional histomorphology in colorectal LGIN is frequent and highly reproducible. Our results indicate an increased risk for CRC in patients with non-conventional LGIN, probably independent of IBD. We recommend reporting non-conventional LGIN in routine pathology reports.

The Number of Colon Crypts in Digital Mucosal Samples: A New Independent Parameter for Diagnosing Ulcerative Colitis.

Background/Aim: It has been demonstrated that most routine biopsies from the colon and rectum display cross-cut crypts (CCC). The aim was to assess the number of CCC in microscopic isometric digital samples (0.500 mm2) from routine colon biopsies. Patients and Methods: Colon biopsies from 224 patients were investigated: 99 in patients with ulcerative colitis (UC), 31 UC in remission (UCR), 28 infectious colitis (IC), 7 resolved IC (RIC), 19 diverticular sigmoiditis (DS), and 40 normal colon mucosa (NCM). Results: A total of 8,024 CCC were registered: 2,860 (35.6%) in UC, 1,319 UCR (16.4%), 849 (10.6%) in IC, 340 (4.2%) in RIC, 795 (9.9%) in DS, and 1,861 (23.2%) in NCM. The CCC frequencies in UC and IC were significantly lower (p<0.05) than those in UCR, RIC, DS, and NCM. Conclusion: By the simple algorithm of counting CCC in standardized isometric microscopic digital circles measuring 0.500 mm2, it was possible to differentiate between UC (long-lasting inflammation) and IC (short-lasting inflammation) on the one hand, and UCR, RIC, DS (persistent inflammation), and NCM, on the other. The counting of CCC in the algorithm by five pathologists working in three disparate European Countries, was found to be reproducible.

Tumor-Stroma Ratio in Colorectal Cancer-Comparison between Human Estimation and Automated Assessment.

The tumor-stroma ratio (TSR) has been repeatedly shown to be a prognostic factor for survival prediction of different cancer types. However, an objective and reliable determination of the tumor-stroma ratio remains challenging. We present an easily adaptable deep learning model for accurately segmenting tumor regions in hematoxylin and eosin (H&E)-stained whole slide images (WSIs) of colon cancer patients into five distinct classes (tumor, stroma, necrosis, mucus, and background). The tumor-stroma ratio can be determined in the presence of necrotic or mucinous areas. We employ a few-shot model, eventually aiming for the easy adaptability of our approach to related segmentation tasks or other primaries, and compare the results to a well-established state-of-the art approach (U-Net). Both models achieve similar results with an overall accuracy of 86.5% and 86.7%, respectively, indicating that the adaptability does not lead to a significant decrease in accuracy. Moreover, we comprehensively compare with TSR estimates of human observers and examine in detail discrepancies and inter-rater reliability. Adding a second survey for segmentation quality on top of a first survey for TSR estimation, we found that TSR estimations of human observers are not as reliable a ground truth as previously thought.

Is the Routine Histopathologic Diagnosis of Ulcerative Colitis Based on Cross-cut Sections or on Well-oriented Sections?

BACKGROUND/AIM: For many years, it was empirically estimated that the majority of the routine colon biopsies in Swedish patients with ulcerative colitis (UC), exhibited cross-cut crypts. The aim of the present study was to assess the frequency of cross-cut crypts (CCC) and well-oriented crypts in routine colon biopsies in German patients with UC. PATIENTS AND METHODS: In total, 447 colon biopsies: 376 with UC and 71 controls were investigated. RESULTS: Out of 376 colon biopsies with UC, 73% exhibited ≥60% CCC. Out of the 237 biopsies showing ≥80% CCC, as many as 71% exhibited 100% CCC in individual biopsies. Similar percentages were found in control biopsies. CONCLUSION: The majority of the routine colon biopsies with UC, as well as control biopsies in German patients displayed CCC. Thus, an unnoticed, consequent, and systematic cutting technical hitch was introduced during the laboratory processing of colon biopsies. The reason(s) behind the similar histologic processing mode of colon biopsies at the two geographically disparate laboratories (Sweden and Germany) remains elusive. The cross-cutting mode influenced the narrative of biopsies in UC, inasmuch as some histological parameters listed among well-oriented colon sections were not present in sections displaying CCC.

Crypt-rings in tandem detected in infectious colitis, in IBD and in IBD-associated noninvasive neoplasia.

AIMS: Recently, eight novel histologic structures in colon mucosa with inflammation were described. Here, we assessed the frequency of one of them: crypt rings in tandem (CRT), in patients with infectious colitis (IC), IBD (ulcerative colitis; UC or Crohn colitis; CrC) and UC in remission (UCR). In addition, the frequency of dysplastic CRT (DCRT) in IBD-associated noninvasive neoplasia (IBDNIN) were also calculated. METHODS: Colon biopsies in 578 cases were reviewed: 42 cases with IC, 280 with IBD (180 UC and 100 CrC), 100 UCR and the remaining 156, IBDNIN. RESULTS: The proportions of CRT in IC was 16.7%, in IBD 14.3% %, in UCR 3%, and of DCRT in IBDNIN, 20%. No differences were recorded between the proportions of CRT in IC, UC and CrC. Conversely, the difference in CRT frequency between UC and UCR, and between CRT and DCRT were significant (P = 0.006, and p = 0.05, respectively). CONCLUSIONS: CRT evolved in IC and in IBD. The finding of CRT in IC strongly suggest that those characteristic crypts were shaped at the early stages of mucosal inflammation. CRT persisted in IBD with protracted inflammation but plummeted in UCR, that is when the mucosal inflammation waned. The proportion of DCRT was significantly higher than that of CRT. It is submitted that DCRT might had developed in IBDNIN using CRT as scaffolds. This is the first study in which a characteristic pathologic aberration of cryptogenesis was tracked in colon biopsies from patients with IBD and with IBD-associated neoplastic transformation.

Frequency of Her2-low in colorectal cancer and its relations with the tumor microenvironment.

BACKGROUND: To date, little is known regarding human epithelial growth factor receptor (HER2) low-expressing colorectal cancer (CRC). Due to promising rising therapies with HER2-antibody-drug conjugates we aimed to analyze the frequency of HER2-low in patients with CRC. Additionally we characterized the clinicopathologic background of this group and its potential relationship with the tumor microenvironment represented by budding and tumor infiltrating lymphocytes (TILs). METHODS: 319 patients with CRC, stages I-IV, were enrolled. HER2-immunohistochemistry (IHC) as well as fluorescence in situ hybridization (FISH) were performed on tissue microarrays. IHC was evaluated semiquantitatively and software-assisted using the HERACLES Diagnostic Criteria for CRC. HER2-low was defined as IHC 1 + or 2 +/FISH negative. HER2-IHC results were compared with budding, TILs and their combinations. RESULTS: The HER2 low-expressing subset represented almost one half of all CRC (47.1 %). Assessment was highly reproducible with different methods. HER2-low cases were significantly more often lower T-, N-, and tumor stage and had less L1 compared with HER2-0. Additionally, they showed more often TILs > 5 % (p = 0.001). The difference between HER2-0 and HER2-low was highly significant between the four budding/TILs-groups (p < 0.001). Cases with low budding/high TILs were more often HER2-low. The highest difference was seen between the low budding/high TILs-group and the low budding/low TILs-group (p < 0.001). CONCLUSIONS: HER2-low expression in CRC is frequent and involves nearly one half of all patients. We could show a relationsship between HER2-low expression and the tumor microenvironment. Special attention should be paid to the low budding/high TILs group in future research.

The frequency of dysplastic branching crypts in colorectal polypoid tubular adenomas.

Dysplastic crypt branching (DCB) was recently found in ulcerative colitis-associated dysplasia. The aim was to assess the frequency and the branching phenotype of DCB in polypoid colorectal tubular adenomas (TA). A total of 3956 DCB were found in the 139 TA: 98% were in asymmetric branching (DCAB) and the remaining 2% in symmetric branching (DCSB). A linear correlation was found between DCB frequency and the increasing digital size in TA (p < .05). Using a digital ruler, adenomas were divided into small TA (<5 mm) and larger TA (≥5 mm). The difference between the frequency of DCB in small TA (n = 75) vs. larger TA (n = 64), was significant (p < .05). DCB frequency was not influenced by age, gender or TA localization. In the normal colorectal mucosa (≈2 m2 ), only occasional CSB is found and no CAB. And yet, multiple DCB (mean 16.7 DCB), mostly DCAB, was found in small TA, occupying <5 mm of the mucosal area. In larger TA, as many as 42.1 DCB (mean), mostly DCAB, occurred in merely 7.8 mm (mean) of the colon mucosa. Thus it is suggested that DCB is a standard histologic element of TA. The natural expansion of the adenomatous tissue in larger TA appears to be follow on from newly produced, mostly DCAB, by DCSB and by the accumulation of their dysplastic offspring's progenies. The findings strongly suggest that DCB is a central microstructure in the histological events unfolding in polypoid colorectal TA.

Novel histological repertoire of crypt-associated anomalies in inflamed colon mucosa.

AIMS: Studying crypt branching in ulcerative colitis (UC) and in infectious colitis (IC), we detected previously unreported crypt-associated anomalies (CAAs). The objective was to describe, illustrate and assess the frequency of CAAs in inflamed colon mucosa in patients with UC and IC. METHODS: Sections from 100 consecutive biopsies with UC, in 50 with IC and in 27 with UC in remission (UCR) were reviewed. The following CAAs were identified: crypt eosinophilia, intracryptal epithelial hyperplasia, intracryptal epithelial budding, intracryptal supernumerary crypts, intracryptal epithelial bridges, crypt rings in rows and off-centre epithelial budding. RESULTS: The frequency of crypts with extensive crypt eosinophilia and with intracryptal epithelial budding was significantly higher in UC than in IC and UCR (p<0.05); the frequency in the remaining histological parameters was similar in UC, IC and UCR. CONCLUSIONS: CAAs were found interspersed with branching crypts. CAAs persisted in long-lasting UC mucosal inflammation, but declined when the inflammation waned. Since similar anomalies are not present in normal colon mucosa, the results suggest that CAAs had been boosted by the ongoing mucosal inflammation. The development of these previously unreported CAAs in the colon mucosa with inflammation might embody pathological aberrations of cryptogenesis.

Further Study on Field Cancerization in the Human Colon.

BACKGROUND/AIM: Nearly 70 years ago, Slaughter launched the hypothesis of field cancerization for oral carcinomas; that hypothesis was subsequently also claimed for carcinomas in other organs. We previously found in the colon mucosa adjacent to nonpolypoid adenomas, branching crypts lined by normal epithelium (BCNE). Here, we explored whether BCNE could also be found in the colon mucosa adjacent to sporadic polypoid tubular adenomas (TA), the most prevalent of all colon adenomas. PATIENTS AND METHODS: Nondysplastic mucosa adjacent to TA was found in 103 out of 131 TA. All BCNE adjacent to TA were recorded. RESULTS: In 98 (95.1%) out of 103 TA having nondysplastic adjacent mucosa, 645 BCNE were registered: 82.6% were in asymmetric branching and 17.4% in symmetric branching. Thus, BCNE in asymmetric branching predominated. The frequency of BCNE adjacent to TA was influenced by the adenoma size and degree of dysplasia severity. Contrarywise, the frequency of BCNE adjacent to TA was neither influenced by the age or sex of the patients, nor by the colon localization of TA. CONCLUSION: BCNE often occur in the normal mucosa adjacent to TA. BCNE emerge as integral components of TA. The majority of the BCNE were in asymmetric branching, considered as aberrations of cryptogenesis. We propose that the accretion of asymmetric BCNE adjacent to TA supports Slaughter's hypothesis of field cancerization.

Dysplastic crypts in asymmetric branching found in ulcerative colitis-associated dysplasia.

BACKGROUND: Biopsies from patients with ulcerative colitis (UC) often show crypt branching´s (CB). AIMS: The purpose was to analyze the frequency of CB in biopsies with dysplasia in UC (D-UC). METHODS: Digitalized-sections from 49 consecutive D-UC cases were reviewed and all CB were recorded. Potential confounders such as gender, age, UC-duration, localization in the colorectum, degree of epithelial dysplasia and number of mucosal samples/biopsy, were investigated. RESULTS: A total of 334 dysplastic CB (DCB) were recorded in the 49 D-UC cases; 321 (96.1%) DCB were in asymmetric branching (DCAB), and the remaining 13 (3.9%), in symmetric branching (DCSB). Out of the 49 D-UC cases, 41% had 1-4 DCAB, 43% 5-9 DCAB, 10% 10-15 DCAB, and the remaining 6%, ≥ 16 DCAB. Low-grade dysplasia (LGD) was present in 44 (90%) of the 49 D-UC cases, and high-grade dysplasia (HGD) in the remaining 5 (10%). The frequency of DCAB was not influenced by age, gender, biopsy site (right colon, left colon, or rectum), number of mucosal samples/biopsy, degree of dysplasia or UC duration. CONCLUSIONS: Two novel histologic phenotypes of DCB in UC-associated dysplasia are reported, namely DCAB and DCSB. The wide variation in DCAB-frequency in UC-associated dysplasia suggests potential biological differences between cases.

Crypts in Asymmetric Branching in Patients With Ulcerative Colitis in Remission.

BACKGROUND/AIM: To report the frequency of crypts in asymmetric branching (CAB) in biopsies from all colorectal segments in patients with ulcerative colitis in remission (UCR). PATIENTS AND METHODS: Biopsies in 100 UC patients were investigated: 50 with UCR and 50 with ongoing long-lasting UC (LLU; i.e., controls). RESULTS: The frequency of CAB was significantly lower in UCR than in LLUC, both in the right colon and left colorectum. CAB frequency was not influenced by two important confounders: the age and sex of patients. CONCLUSION: CAB is a pathologic aberration of colorectal cryptogenesis evoked by chronic mucosal inflammation. When chronic inflammation waned in UCR, the production of CAB plummeted or ceased. Chronic inflammation and protracted disease-duration in LLUC increase the risk for colorectal dysplasia or carcinoma. Importantly, dysplastic CAB were recently detected in LLUC-associated dysplasia. Whether the abrogation of CAB is instrumental in reducing the neoplastic risk in UCR patients, deserves further investigation.

pT3 colorectal cancer revisited: a multicentric study on the histological depth of invasion in more than 1000 pT3 carcinomas-proposal for a new pT3a/pT3b subclassification.

BACKGROUND: Pathological TNM staging (pTNM) is the strongest prognosticator in colorectal carcinoma (CRC) and the foundation of its post-operative clinical management. Tumours that invade pericolic/perirectal adipose tissue generally fall into the pT3 category without further subdivision. METHODS: The histological depth of invasion into the pericolic/perirectal fat was digitally and conventionally measured in a training cohort of 950 CRCs (Munich). We biostatistically calculated the optimal cut-off to stratify pT3 CRCs into novel pT3a (≤3 mm)/pT3b (>3 mm) subgroups, which were then validated in two independent cohorts (447 CRCs, Bayreuth/542 CRCs, Mainz). RESULTS: Compared to pT3a tumours, pT3b CRCs showed significantly worse disease-specific survival, including in pN0 vs pN+ and colonic vs. rectal cancers (DSS: P < 0.001, respectively, pooled analysis of all cohorts). Furthermore, the pT3a/pT3b subclassification remained an independent predictor of survival in multivariate analyses (e.g. DSS: P < 0.001, hazard ratio: 4.41 for pT3b, pooled analysis of all cohorts). While pT2/pT3a CRCs showed similar survival characteristics, pT3b cancers remained a distinct subgroup with dismal survival. DISCUSSION: The delineation of pT3a/pT3b subcategories of CRC based on the histological depth of adipose tissue invasion adds valuable prognostic information to the current pT3 classification and implementation into current staging practices of CRC should be considered.

Dysplastic Crypts in Asymmetric Branching in Ulcerative Colitis: A Preliminary Report.

AIM: To report the detection of dysplastic crypts in asymmetric branching (DCAB) in biopsies from patients with ulcerative colitis (UC). PATIENTS AND METHODS: One hundred consecutive endoscopic biopsies from patients with UC undergoing surveillance were reviewed. RESULTS: Three biopsy/cases showed DCAB. The frequency of DCAB varied from two in one case, three in another case, and five in the remaining case. CONCLUSION: The final outcome of DCAB is to generate two or more dysplastic asymmetric offspring-crypts. Repeated DCAB offspring formation, together with new DCAB, would boost the pool of dysplastic crypts, resulting in an exponential expansion of the mucosal area occupied by dysplasia in UC.

Diagnostic Impact of Crypt Branching in Patients With Crohn's Disease: A Validation Study.

BACKGROUND/AIM: Crypt branching in inflammatory bowel diseases (IBD) was previously classified into symmetric (CSB) and asymmetric branching (CAB). We aimed to validate the inter-rater agreement of the assessment of crypt branching (also called crypt fission) in patients with Crohn's disease (CD) and to elucidate its potential diagnostic impact. PATIENTS AND METHODS: A total of 100 colon biopsies from patients with active CD were analyzed. Two cohorts of patients with ulcerative colitis (UC) and infectious colitis, respectively, served as controls (UC-controls/infectious controls). Three pathologists scored the total number of branching crypts (TBC) as well as the number of CSB and CAB. RESULTS: Inter-rater agreement ranged from moderate to good for TBC and CAB in the study cohort. The study cohort showed significantly higher counts of TBC, CSB, and CAB than the infectious controls (p<0.001 for TBC, p=0.008 for CSB, and p<0.001 for CAB). Cases with CD showed more TBC and CAB compared to cases with UC (p=0.001 each). CONCLUSION: Inter-rater agreement for crypt branching is reliable in patients with CD. Crypt branching was shown to be an additional histologic feature to distinguish active CD from infectious colitis. Additionally, it could be helpful in the distinction between CD and UC.

Diagnostic and Prognostic Impact of Crypt Branching in Patients With Ulcerative Colitis: A Validation Study.

BACKGROUND/AIM: This study aimed to validate the inter-rater agreement of the assessment of crypt branching (also called crypt fission) in patients with ulcerative colitis (UC) and to elucidate its potential diagnostic and prognostic impact. PATIENTS AND METHODS: A total of 100 biopsies from patients with UC were analyzed. Two cohorts of 50 patients each served as controls [infectious controls/controls with low grade intraepithelial neoplasia (LGIN) in UC alio loco]. Three pathologists scored the number of total crypts in fission as well as the number of crypts in symmetric (CSF) and asymmetric fission (CAF). RESULTS: Inter-rater agreement ranged from good to excellent in the study cohort. The number of crypts in fission correlated significantly with UC-activity (p=0.001; p<0.001). The study cohort showed higher mean counts of crypts in fission and significant more total and CAF than the infectious controls (p=0.007 and p=0.008), especially in male patients (p<0.001) The LGIN-control cohort showed significant more CSF (p=0.012). CONCLUSION: Inter-rater agreement for crypt branching was reliable in the study cohort. Crypt branching proved as an additional histologic feature to distinguish active UC against infectious colitis. Higher amounts of CSF may help identifying patients at higher risk for neoplasia.

Branching crypts in inflammatory bowel disease revisited.

Histologic sections from patients with inflammatory bowel disease (IBD) usually exhibit crypts with architectural distortions and branching crypts. It has been postulated that crypt branching should be assessed only in well-oriented, upright crypts. However, those crypts are mostly found in sections from colectomy specimens and colon mucosectomies. Sections from endoscopic biopsies are fortuitously cut in a horizontal plane, a procedure mostly revealing cross-cut crypt rings. In endoscopic biopsies from UC patients we previously detected cross-cut crypts heralding the crest domain of branching crypts. Recently, the scrutiny of biopsies from IBD patients revealed that branching-crest domains concurred either with crypts in symmetric branching, typified by twin, amalgamating back-to-back isometrics crypt-rings, or with crypts in asymmetric branching, characterized by ≥2 amalgamating anisometric crypt-rings; both symmetric and asymmetric branching-crest domains were encased by a thin muscularis mucosae. Quantitative studies in biopsies from Swedish and German patients with IBD showed that crypts in asymmetric branching outnumbered those in symmetric branching. Because crypt-branching seldom occurs in the normal colon in adults and considering that colon crypts typically divide once or twice during a lifetime, the accruing of asymmetric branching crypts in IBD biopsies emerges as a significant histologic parameter. Although the biological significance of asymmetric crypt-branching in IBD remains at present elusive, their occurrence deserves to be further investigated. The future policy will be to include in our pathologic reports, the number of crypts in asymmetric branching, in order to monitor their frequency in prospective surveillance biopsies in patients with IBD.