Emerging and under-recognised patterns of colorectal carcinoma morphologies: a comprehensive review.

While the overwhelming majority of colorectal carcinomas (CRC) are diagnosed as adenocarcinoma not otherwise specified, there are numerous under-recognised morphologic patterns of CRC. These patterns are recognised by the WHO, appear in reporting manuals for the American Joint Committee of Cancer, and/or are listed on synoptic reports, while many other variants have either fallen out of favour or are emerging as future bona fide patterns. Herein, we discuss 13 variants: serrated adenocarcinoma, micropapillary adenocarcinoma, medullary carcinoma, neuroendocrine carcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, adenosquamous carcinoma, adenoma-like adenocarcinoma, lymphoglandular complex-like CRC, carcinoma with sarcomatoid components, cribriform-comedo-type adenocarcinoma, undifferentiated carcinoma and low-grade tubuloglandular adenocarcinoma. The purpose of this review is to scrutinise these variants by assessing their clinical characteristics, morphologic cues, as well as pitfalls, and address their prognostic significance. Our analysis aims to bring clarity and updated understanding to these variants, offering valuable insights for pathologists. This contributes to more nuanced CRC diagnosis and treatment strategies, highlighting the importance of recognising a broad spectrum of morphologic patterns in CRC.

Addition of cribriform pattern 4 and intraductal prostatic carcinoma into the CAPRA-S tool improves post-radical prostatectomy patient stratification in a multi-institutional cohort.

AIMS: Pre-surgical risk classification tools for prostate cancer have shown better patient stratification with the addition of cribriform pattern 4 (CC) and intraductal prostatic carcinoma (IDC) identified in biopsies. Here, we analyse the additional prognostic impact of CC/IDC observed in prostatectomies using Cancer of Prostate Risk Assessment post-surgical (CAPRA-S) stratification. METHODS: A retrospective cohort of treatment-naïve radical prostatectomy specimens from three North American academic institutions (2010-2018) was assessed for the presence of CC/IDC. Patients were classified, after calculating the CAPRA-S scores, into low-risk (0-2), intermediate-risk (3-5) and high-risk (6-12) groups. Kaplan-Meier curves were created to estimate biochemical recurrence (BCR)-free survival. Prognostic performance was examined using Harrell's concordance index, and the effects of CC/IDC within each risk group were evaluated using the Cox proportional hazards models. RESULTS: Our cohort included 825 prostatectomies (grade group (GG)1, n=94; GG2, n=475; GG3, n=185; GG4, n=13; GG5, n=58). CC/IDC was present in 341 (41%) prostatectomies. With a median follow-up of 4.2 years (range 2.9-6.4), 166 (20%) patients experienced BCR. The CAPRA-S low-risk, intermediate-risk and high-risk groups comprised 357 (43%), 328 (40%) and 140 (17%) patients, and discriminated for BCR-free survival (p<0.0001). For CAPRA-S scores 3-5, the addition of CC/IDC status improved stratification for BCR (HR 2.27, 95% CI 1.41 to 3.66, p<0.001) and improved the overall c-index (0.689 vs 0.667, analysis of variance p<0.001). CONCLUSION: The addition of CC/IDC into the CAPRA-S classification significantly improved post-radical prostatectomy patient stratification for BCR among the intermediate-risk group (CAPRA-S scores 3-5). The reporting of CC and IDC should be included in future prostate cancer stratification tools for improved outcome prediction.

Impact of cellular morphology and three-tiered nuclear grade on progression of conventional renal cell carcinoma.

AIMS AND METHODS: The aims of this study were to evaluate the prognostic impact of cytomorphology and three-tiered grading on tumour-free survival of patients with conventional renal cell carcinoma (cRCC). Formalin-fixed, paraffin-embedded samples from 710 patients were assessed and the results were evaluated according to the clinical data. RESULTS: Kaplan-Meier regression model showed that 90.9% of patients with clear cell, and 50.9% with pure eosinophilic cRCC were free of metastasis during follow-up. The three-triered grading showed a good correlation with progression as 95.2% of patients with of G1 tumours, 66.1% with G2 tumours and only 25.3% with G3 tumours were tumour free (p<0.001). The grading was correlated with cytomorphology and coagulation necrosis. In multivariate analysis, tumour grade and stage were independent prognostic markers (p<0.001). CONCLUSIONS: The three-tiered grading predicts the progression of cRCC irrespectively of cytomorphology. However, the cytomorphology and necrosis show a good correlation with three-tiered grading in estimate disease progression.

Comprehensive characterisation of acinar cystic transformation of the pancreas: a systematic review.

AIMS: Acinar cystic transformation (ACT) of the pancreas is a rare pancreatic cystic lesion. Owing to its rarity, comprehensive histomolecular characterisation of this entity is still lacking. We aim to perform a systematic review on this controversial entity. METHODS: We searched PubMed, SCOPUS and Embase through May 2023 to identify all studies on ACTs. Clinicopathological, immunohistochemical (IHC) and molecular data have been extracted and analysed. RESULTS: Overall, there were 121 cases of ACTs in the literature. ACT had a female predominance (65.3% of patients), and a mean size of 4.8 cm. ACT was more often unifocal (71.9%) and multiloculate (61.2%). Histologically, the cysts were lined by an acinar epithelium, sometimes harbouring ductal-like areas (18.2%). In five cases (4.1%), an intralesional pancreatic intraepithelial neoplasia (PanIN) was reported. Preoperative diagnosis is challenging. After surgical resection, all patients were alive and disease free during follow-up except one patient who developed a second ACT after resection. By IHC, all lesions were positive for acinar markers; cytokeratin 7 and 8/18/19 were usually positive, and Ki-67 was invariably ≤3%. At the molecular level, three cases demonstrated genetic alterations: one showed multiple chromosomal gains, and other two harboured somatic mutations of KRAS and SMO genes (one mutation per case). CONCLUSIONS: Globally considered, our findings demonstrated that ACT is a benign entity, without the need of surgical resection with the exception of symptomatic lesions. The rare occurrence of intracystic PanINs and driver mutations suggest considering follow-up if a preoperative diagnosis of ACT can be made.

Analytical validation of white blood cell differential and platelet assessment on the Sysmex DI-60 digital morphology analyzer.

INTRODUCTION: Digital morphology analyzers are increasingly replacing light microscopy in laboratory hematology practice. This study aimed to perform the analytical validation of the white blood cell (WBC) differential and of reliability of platelet assessment on Sysmex DI-60 (Kobe, Japan). METHODS: Validation included determination of within-run and between-run precision for WBC differential according to the CLSI EP15-A3 protocol, accuracy and method comparison with light microscopy and with the automated WBC differential from the Sysmex XN-10 hematology analyzer, reliability of platelet clump detection and platelet count estimation. RESULTS: Standard deviations of both pre- and post-classification mostly satisfied manufacturer's criteria for imprecision. Accuracy assessment revealed that only eosinophil count (1.4%) in one peripheral blood smear (PBS) remained outside the declared range (2-10%) after reclassification. Method comparison between DI-60 and light microscopy yielded Spearman's correlation coefficients from 0.37 (basophils) to 0.94 (neutrophils and lymphocytes), minor proportional difference for bands, constant difference for monocytes, both constant and proportional difference for lymphocytes and statistically significant biases for bands, lymphocytes, monocytes and basophils. Diagnostic sensitivity (Se) and specificity (Sp) of DI-60 in detecting immature/pathological cells were 88.7% (95%CI:81.1-94.0) and 83.0% (95%CI:78.7-86.7), respectively, with the area under the curve (AUC) of 0.86 (95%CI:0.82-0.89). Agreement in detection of platelet clumps was 94.8% (kappa coefficient = 0.67, 95%CI:0.53-0.80). Se and Sp of DI-60 to detect platelet clumps were 65.7% (95%CI: 47.8-80.9) and 96.9% (95%CI: 93.9-98.6), respectively, while AUC was 0.81 (95%CI: 0.76-0.86). CONCLUSION: DI-60 provides reliable WBC differential and platelet assessment. In doubtful cases, the use of light microscopy is still mandatory.

Cambios morfométricos en pacientes con enfermedad renal crónica fallecidos relacionados con diabetes mellitus, hipertensión arterial y obesidad

Fundamento: la enfermedad renal crónica ha incrementado su incidencia, no existen estudios en Cuba ni en la provincia sobre morfometría renal en pacientes con enfermedad renal crónica a los que se les ha practicado autopsia. Objetivo: determinar variaciones morfométricas renales en pacientes fallecidos a los que se les ha practicado autopsia en el Hospital General Universitario Dr. Gustavo Aldereguía Lima de Cienfuegos. Método se realizó un estudio descriptivo, longitudinal y retrospectivo. El universo lo conformaron 85 pacientes fallecidos a los que se les practicó autopsia y que tenían diagnóstico clínico de enfermedad renal crónica en cualquier estadio. Se trabajó con el total del universo. Las variables estudiadas fueron: edad, sexo, peso y talla para el cálculo del índice de masa corporal, antecedentes patológicos personales, el estadio clínico de la enfermedad renal crónica y la morfometría renal a cada órgano por separado, las mensuraciones realizadas fueron: peso, diámetro longitudinal, diámetro transversal, espesor o grosor de la corteza renal. Los datos se procesaron en el paquete estadístico de SSPS v. 11.5 presentándose tablas en números absolutos y porcientos. Resultados predominó el sexo femenino, en edades entre 70-79 años, con estadio clínico I y IV de la enfermedad renal crónica, los obesos representaron el 57,6 %, los hipertensos el 67,1 % y los diabéticos el 25,8 %. Hubo disminución de todas las variables morfométricas en ambos riñones, destacándose el espesor de la corteza renal. Conclusiones: existió relación entre la hipertensión, la diabetes mellitus y la obesidad con las variables morfométricas renales.

Background: chronic kidney disease has increased its incidence, there are no studies in Cuba or in the province on renal morphometry in patients with chronic kidney disease who have undergone autopsy. Objective: to determine renal morphometric variations in deceased patients who have undergone autopsy at the Dr. Gustavo Aldereguía Lima University General Hospital of Cienfuegos. Method: a descriptive, longitudinal and retrospective study was carried out. The universe was made up of 85 deceased patients who underwent autopsy with a clinical diagnosis of chronic kidney disease at any stage. We worked with the whole universe. The variables studied were: age, sex, weight and height for the calculation of the body mass index, personal pathological history, the clinical stage of chronic kidney disease and renal morphometry to each organ separately, the measurements made were: weight, longitudinal diameter, transverse diameter, thickness or thickness of the renal cortex. The data was processed in the statistical package of SSPS v. 11.5 presenting tables in absolute numbers and percentages. Results: the female sex predominated, aged between 70-79 years, with clinical stage I and IV of chronic kidney disease, the obese represented 57.6 %, the hypertensive 67.1 % and the diabetic 25.8 %. There was a decrease in all morphometric variables in both kidneys, highlighting the thickness of the renal cortex. Conclusions: there was a relationship between hypertension, diabetes mellitus and obesity with renal morphometric variables.

[Salivary gland tumors-an overview : Advances in molecular characterization: Part II]. / Speicheldrüsenkarzinome ­ ein aktueller Überblick : Fortschritte in der molekularen Typisierung Teil II.

The second part of the article is devoted to the molecular characteristics of epithelial-myoepithelial carcinoma, polymorphous adenocarcinoma, myoepithelial carcinoma, basal cell adenocarcinoma, and salivary duct carcinoma. In addition, the new entities mucinous adenocarcinoma, sclerosing microcystic adenocarcinoma, and microsecretory adenocarcinoma are summarized. The molecular genotype can also be very helpful in diagnosing most of these entities. In this regard, overexpression of the androgen receptor and/or human epidermal growth factor receptor 2 (HER2)/neu can support diagnosis in the appropriate histopathologic context and may serve as a potential target for therapy in salivary duct carcinoma.

Chondroblastoma: clinicopathological analyses of 307 cases from a single institution in China and the diagnostic value of the H3F3 K36M mutant antibody.

AIMS: To elucidate the clinicopathological features and the diagnostic value of mutation specific antibody H3F3 K36M of chondroblastoma (CB) in China. METHODS: Clinicopathological profiles were retrieved, and immunohistochemistry was performed on 185 CB specimens and the control group. RESULTS: Our series included 307 patients with a mean age of 22.1 years. Long tubular bones (63.8%, 196/307) were most commonly involved, followed by short bones of the hands and feet (22.1%, 68/307), sesamoid bones (8.1%, 25/307), flat bones and irregular bones (5.9%, 18/307). The most commonly involved site was the proximal femur, followed by distal femur, proximal humerus and calcaneus. The average age in the long bones group (20.3 years) was significantly younger than the short bones group (24.9 years) (p<0.001), sesamoid bones group (24.4 years) (p=0.02) and flat bones and irregular bones group (29.1 years) (p<0.001). Microscopically, aneurysmal bone cyst-like change (63.6%, 117/184), necrosis (43.5%, 80/184) and chicken-wire calcification (26.1%, 48/184) were variably noted. In rare cases, cortical destruction, soft tissue and lymphovascular invasion were identified. Positive immunoreaction with H3F3 K36M was examined in all non-decalcified, all EDTA decalcified, 87.1% hydrochloric acid (HCl) decalcified CB samples and the high-grade sarcoma secondary to CB, but not the control group. CONCLUSIONS: CB usually involves the long tubular bones in younger age group. H3F3 K36M can identify K36M mutation with 100% specificity and 100% sensitivity in non-decalcified and EDTA decalcified samples, more than 80% sensitivity in HCl decalcified samples. Virtually, all CBs harbour an H3K36M mutation.

Performance of the CellaVision DC-1 digital cell imaging analyser for differential counting and morphological classification of blood cells.

AIMS: Recently, a new automated digital cell imaging analyser (Sysmex CellaVision DC-1), intended for use in low-volume and small satellite laboratories, has become available. The purpose of this study was to compare the performance of the DC-1 with the Sysmex DI-60 system and the gold standard, manual microscopy. METHODS: White blood cell (WBC) differential counts in 100 normal and 100 abnormal peripheral blood smears were compared between the DC-1, the DI-60 and manual microscopy to establish accuracy, within-run imprecision, clinical sensitivity and specificity. Moreover, the agreement between precharacterisation and postcharacterisation of red blood cell (RBC) morphological abnormalities was determined for the DC-1. RESULTS: WBC preclassification and postclassification results of the DC-1 showed good correlation compared with DI-60 results and manual microscopy. In addition, the within-run SD of the DC-1 was below 1 for all five major WBC classes, indicating good reproducibility. Clinical sensitivity and specificity were, respectively, 96.7%/95.9% compared with the DI-60% and 96.6%/95.3% compared with manual microscopy. The overall agreement on RBC morphology between the precharacterisation and postcharacterisation results ranged from 49% (poikilocytosis) to 100% (hypochromasia, microcytosis and macrocytosis). CONCLUSIONS: The DC-1 has proven to be an accurate digital cell imaging system for differential counting and morphological classification of WBCs and RBCs in peripheral blood smears. It is a compact and easily operated instrument that can offer low-volume and small satellite laboratories the possibilities of readily available blood cell analysis that can be stored and retrieved for consultation with remote locations.

Beyond the routine CBC: machine learning and statistical analyses identify research CBC parameter associations with myelodysplastic syndromes and specific underlying pathogenic variants.

AIMS: Given the time, expense and clinical expertise required for a myelodysplastic syndrome (MDS) diagnosis, there is a clear need for a cost-effective screening laboratory test that can rapidly and accurately distinguish patients with cytopenias related to MDS from other causes. METHODS: We measured conventional and research use only complete blood cell (CBC) parameters using the Sysmex XN-series haematology analyser in 102 MDS patients (70 patients with active MDS and 32 patients in remission), 43 patients with cytopenia without morphological evidence of MDS and 484 age-adjusted controls. A variety of algorithms, including random forest machine learning, were used to construct parameter-based models to predict the presence of MDS using both CBC and molecular data or CBC data alone and correlated individual pathogenic variants/genetic pathways with CBC parameters changes. RESULTS: Using the CBC parameters alone, our predictive model for active MDS showed a 0.86 receiver operating characteristic curve (ROC)/area under the ROC curve (AUC), with 0.87 sensitivity and 0.72 specificity; with the addition of the molecular and demographic status, the ROC/AUC improved to 0.93, sensitivity to 0.89 and specificity to 0.84. The most discriminatory MDS parameters were reflective of dysplastic neutrophil morphology, red cell count fragmentation and degree of platelet immaturity. Specific patterns of parameters were associated with individual gene pathogenic variants or affected pathways. CONCLUSIONS: CBC research parameters can be used as an adjunct to the haematological workup of cytopenia(s) to help screen for patients with high likelihood of MDS.

[Salivary gland tumors-an overview : Advances in molecular characterization: Part I]. / Speicheldrüsenkarzinome ­ ein aktueller Überblick : Fortschritte in der molekularen Typisierung: Teil I.

In recent years, the characterization of salivary gland tumors has undergone a major transformation. Morphologically defined entities could to a large extent also be characterized molecularly with an often distinct genotype. The first part of this article reviews the advances in the molecular characteristics of mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, secretory carcinoma, intraductal carcinoma, and hyalinizing clear cell carcinoma. The molecular genotype can be particularly useful in classifying unusual morphologic variants. Recurrent NTRK or RET gene fusions can be used not only as a diagnostic tool but also for potential targeted therapy.

Oral Lichen Planus: Associations Between Histomorphometric Characteristics and White and Red Lesions.

Histomorphometry seems to provide more rigid quantitative elements for histological analysis and to bring less subjectivity to the diagnosis of oral lichen planus lesions (OLP). This study aimed to verify the association between white and red lesions and histomorphometric characteristics of OLP lesions. This retrospective cross-sectional study assessed 48 hematoxylin- and eosin-stained histological sections from incisional biopsies obtained from OLP cases. A single previously calibrated evaluator performed the light microscopy analyses to evaluate morphological and morphometric parameters. Analyses of associations among variables were performed using the Fisher's exact test. Morphometric variables were assessed using the Mann-Whitney non-parametric test. Comparisons among the three groups (age range) were performed using the Kruskal-Wallis test. In this study, 81.2% of the participants were women aged < 50 years. Keratosis, acanthosis, and inflammatory infiltrates were noted in 10.4, 10.4, and 37.5% of moderate/severe cases, respectively. Inflammatory infiltrate (52.1%), papillary projections (54.2%), saw teeth (12.5%), basal layer degeneration (39.6%), and Civatte bodies (68.8%) were also observed. There was no significant association between lesion type and clinicopathological variables (p > 0.05) or between lesion type and histological (p > 0.05) and morphometric variables (p > 0.05). Furthermore, the morphometric variables analyzed did not differ between white and red lesions (p > 0.05) or in their associations with clinicopathological variables (p > 0.05). The results of this investigation showed no associations between white and red OLP lesions and the histomorphometric characteristics evaluated.

Cerium dioxide, a Jekyll and Hyde nanomaterial, can increase basal and decrease elevated inflammation and oxidative stress.

It was hypothesized that the catalyst nanoceria can increase inflammation/oxidative stress from the basal and reduce it from the elevated state. Macrophages clear nanoceria. To test the hypothesis, M0 (non-polarized), M1- (classically activated, pro-inflammatory), and M2-like (alternatively activated, regulatory phenotype) RAW 264.7 macrophages were nanoceria exposed. Inflammatory responses were quantified by IL-1ß level, arginase activity, and RT-qPCR and metabolic changes and oxidative stress by the mito and glycolysis stress tests (MST and GST). Morphology was determined by light microscopy, macrophage phenotype marker expression, and a novel three-dimensional immunohistochemical method. Nanoceria blocked IL-1ß and arginase effects, increased M0 cell OCR and GST toward the M2 phenotype and altered multiple M1- and M2-like cell endpoints toward the M0 level. M1-like cells had greater volume and less circularity/roundness. M2-like cells had greater volume than M0 macrophages. The results are overall consistent with the hypothesis.

GTF2I mutation in micronodular thymoma with lymphoid stroma.

AIMS: Micronodular thymoma with lymphoid stroma is a rare subtype of thymoma with characteristic clinical and pathological features. Some of the features, such as indolent nature, principally spindle morphology and no significant association to myasthenia gravis, are shared with type A and AB thymoma, which is closely linked to GTF2I mutation. However, not much is known regarding the molecular genetics of this thymoma subtype. In this study, the GTF2I mutation status was investigated in 16 cases of micronodular thymoma. METHODS: 16 micronodular thymomas were retrieved and the GTF2I mutation was tested by Sanger sequencing. The clinicopathological findings were documented. RESULTS: GTF2I c.1271T>A p.(Leu424His) mutation within exon 15 was detected in 14 out of 16 tumours (87.5%). Two patients died of other causes while all others remained alive with no evidence of recurrence during the follow-up period ranging from 19 to 188 months (median: 100 months). CONCLUSIONS: GTF2I mutation status and presence of spindle cell morphology may indicate that type A and AB thymoma, and micronodular thymoma represent a group biologically distinct from type B thymomas, which generally lack this mutation.

Atypical lymphoid cells circulating in blood in COVID-19 infection: morphology, immunophenotype and prognosis value.

AIMS: Atypical lymphocytes circulating in blood have been reported in COVID-19 patients. This study aims to (1) analyse if patients with reactive lymphocytes (COVID-19 RL) show clinical or biological characteristics related to outcome; (2) develop an automatic system to recognise them in an objective way and (3) study their immunophenotype. METHODS: Clinical and laboratory findings in 36 COVID-19 patients were compared between those showing COVID-19 RL in blood (18) and those without (18). Blood samples were analysed in Advia2120i and stained with May Grünwald-Giemsa. Digital images were acquired in CellaVisionDM96. Convolutional neural networks (CNNs) were used to accurately recognise COVID-19 RL. Immunophenotypic study was performed throughflow cytometry. RESULTS: Neutrophils, D-dimer, procalcitonin, glomerular filtration rate and total protein values were higher in patients without COVID-19 RL (p<0.05) and four of these patients died. Haemoglobin and lymphocyte counts were higher (p<0.02) and no patients died in the group showing COVID-19 RL. COVID-19 RL showed a distinct deep blue cytoplasm with nucleus mostly in eccentric position. Through two sequential CNNs, they were automatically distinguished from normal lymphocytes and classical RL with sensitivity, specificity and overall accuracy values of 90.5%, 99.4% and 98.7%, respectively. Immunophenotypic analysis revealed COVID-19 RL are mostly activated effector memory CD4 and CD8 T cells. CONCLUSION: We found that COVID-19 RL are related to a better evolution and prognosis. They can be detected by morphology in the smear review, being the computerised approach proposed useful to enhance a more objective recognition. Their presence suggests an abundant production of virus-specific T cells, thus explaining the better outcome of patients showing these cells circulating in blood.

Quantitative morphometrics reveals glomerular changes in patients with infrequent segmentally sclerosed glomeruli.

AIMS: Detection of one segmentally sclerosed glomerulus (SSG) identifies patients with focal segmental glomerulosclerosis (FSGS) but rare SSGs may be missed in kidney biopsies. It is unknown whether alterations of unaffected glomeruli in patients with infrequent SSG can be detected by quantitative morphometrics. METHODS: We determined SSG frequency and obtained quantitative morphometrics in glomeruli without a pathologic phenotype in large kidney sections of non-involved kidney tissue from 137 patients undergoing total nephrectomy. We used multivariate modelling to identify morphometrics independently associated with increasing frequency of SSG and Receiver Operator Curve (ROC) analysis to determine the ability of quantitative morphometrics to identify patients with FSGS. We used the geometric distribution to estimate the sensitivity and specificity of a needle biopsy to identify patients with FSGS. RESULTS: In seventy-one patients (51.8%), at least one SSG was observed, and of those, 39 (54.9%) had an SSG lesion in less than 2% of all glomeruli (mean of 249 glomeruli per specimen). Increasing percent of SSG was independently associated with decreasing podocyte density and increasing mesangial index in multivariate modelling. For infrequent SSG lesions (<1% of glomeruli), kidney biopsy could miss FSGS diagnosis more than 74% of the time, and podocyte density had an area under the curve (AUC) of 0.77, and mesangial index, an AUC of 0.79 to identify patients with FSGS. CONCLUSIONS: More than half of patients had FSGS, although 30% had infrequent SSG. Quantitative morphometrics in glomeruli without pathology, such as podocyte density and mesangial index, identified patients with infrequent SSG and may serve as clinical markers to identify patients with FSGS.

Specific cell differentiation in breast cancer: a basis for histological classification.

Breast parenchyma progenitor cells show a high degree of phenotypic plasticity reflected in the wide range of morphology observed in benign and malignant breast tumours. Although there is evidence suggesting that all breast cancer (BC) arises from a common epithelial progenitor or stem cell located at the terminal duct lobular units (TDLUs), BC shows a broad spectrum of morphology with extensive variation in histological type and grade. This is related to the complexity of BC carcinogenesis including initial genetic changes in the cell of origin, subsequent genetic and epigenetic alterations and reprogramming that occur at various stages of BC development and the interplay with the surrounding microenvironment, factors which influence the process of differentiation. Differentiation in BC determines the morphology, which can be measured using histological grade and tumour type. Histological grade, which measures the similarity to the TDLUs, reflects the degree of differentiation whereas tumour type reflects the type of differentiation. Understanding BC phenotypic differentiation facilitates the accurate diagnosis and histological classification of BC with corresponding clinical implications in terms of disease behaviour, prognosis and management plans. In this review, we highlight the potential pathways that BC stem cells follow resulting in the development of different histological types of BC and how knowledge of these pathways impacts our ability to classify BC in diagnostic practice. We also discuss the role of cellular differentiation in producing metaplastic and neuroendocrine carcinomas of the breast and how the latter differ from their counterparts in other organs, with emphasis on clinical relevance.

Improving the management of early colorectal cancers (eCRC) by using quantitative markers to predict lymph node involvement and thus the need for major resection of pT1 cancers.

BACKGROUND: Since implementing the NHS bowel cancer screening programme, the rate of early colorectal cancer (eCRC; pT1) has increased threefold to 17%, but how these lesions should be managed is currently unclear. AIM: To improve risk stratification of eCRC by developing reproducible quantitative markers to build a multivariate model to predict lymph node metastasis (LNM). METHODS: Our retrospective cohort of 207 symptomatic pT1 eCRC was assessed for quantitative markers. Associations between categorical data and LNM were performed using χ2 test and Fisher's exact test. Multivariable modelling was performed using logistic regression. Youden's rule gave the cut-point for LNM. RESULTS: All significant parameters in the univariate analysis were included in a multivariate model; tumour stroma (95% CI 2.3 to 41.0; p=0.002), area of submucosal invasion (95% CI 2.1 to 284.6; p=0.011), poor tumour differentiation (95% CI 2.0 to 358.3; p=0.003) and lymphatic invasion (95% CI 1.3 to 192.6; p=0.028) were predictive of LNM. Youden's rule gave a cut-off of p>5%, capturing 18/19 LNM (94.7%) cases and leading to a resection recommendation for 34% of cases. The model that only included quantitative factors were also significant, capturing 17/19 LNM cases (90%) and leading to resection rate of 35% of cases (72/206). CONCLUSIONS: In this study, we were able to reduce the potential resection rate of pT1 with the multivariate qualitative and/or quantitative model to 34% or 35% while detecting 95% or 90% of all LNM cases, respectively. While these findings need to be validated, this model could lead to a reduction of the major resection rate in eCRC.