Histological Patterns and Mammographic Presentation of Invasive Lobular Carcinoma Show No Obvious Associations.

Invasive lobular carcinoma of the breast has different mammographic appearances, including spiculated or lobulated masses, architectural distortion, increased breast density, and the possibility of also being occult. Histologically, the morphology is also variable, as several patterns have been described beside the classical one, including the solid, the alveolar, the trabecular, the one with tubular elements, and others. Of 146 ILC cases, 141 were reviewed for mammographic appearance and 136 for histological patterns by two radiologist and two pathologists, respectively; 132 common cases were analyzed for possible associations between mammographic presentation and the histological patterns. Interobserver agreement on the presence or absence of a given mammographic morphology ranged from 45% (increased density) to 95% (occult lesion); the most common radiomorphology was that of a spiculated mass. Interobserver agreement on the presence or absence of a given histological pattern ranged between 79% (solid) and 99% (classical) but was worse when semi-quantification was also included. The mammography-pathology correlation was less than optimal. Multifocality was more commonly detected by histology. The identification of a mammographic mass lesion often coincided with a mass-like lesion on the histological slides and vice versa, but nearly half of the mammographically occult lesions were felt to have masses on histological slides assessed grossly. Histological patterns showed no obvious associations with one or the other mammographic appearance.

ONEST (Observers Needed to Evaluate Subjective Tests) Analysis of Stromal Tumour-Infiltrating Lymphocytes (sTILs) in Breast Cancer and Its Limitations.

Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopathology specimens is influenced by several factors and is subject to issues of reproducibility. ONEST (Observers Needed to Evaluate Subjective Tests) helps in determining the number of observers that would be sufficient for the reliable estimation of inter-observer agreement of TIL categorisation. This has not been explored previously in relation to TILs. ONEST analyses, using an open-source software developed by the first author, were performed on TIL quantification in breast cancers taken from two previous studies. These were one reproducibility study involving 49 breast cancers, 23 in the first circulation and 14 pathologists in the second circulation, and one study involving 100 cases and 9 pathologists. In addition to the estimates of the number of observers required, other factors influencing the results of ONEST were examined. The analyses reveal that between six and nine observers (range 2-11) are most commonly needed to give a robust estimate of reproducibility. In addition, the number and experience of observers, the distribution of values around or away from the extremes, and outliers in the classification also influence the results. Due to the simplicity and the potentially relevant information it may give, we propose ONEST to be a part of new reproducibility analyses.

ONEST (Observers Needed to Evaluate Subjective Tests) suggests four or more observers for a reliable assessment of the consistency of histological grading of invasive breast carcinoma: A reproducibility study with a retrospective view on previous studies.

Histological grade is one of the most important prognosticators of breast cancer which is available for nearly all cases. It also makes part of several multivariable analysis derived combined prognostic profiles despite concerns about its reproducibility. The aims included a reproducibility study of grading in the light of a recently described statistical approach, ONEST (Observers Needed to Evaluate Subjective Tests) and review earlier reproducibility studies in the light of the ONEST analysis. Nine pathologists reviewed 50 core needle biopsies and 50 slides from different excision specimens and recorded the scores for gland (tubule) formation, nuclear pleomorphism and mitotic activity as well as histological grade. Overall percent agreement, Fleiss kappa and the intraclass correlation coefficient (ICC) were used for the analysis of reproducibility. ONEST data and curves were generated from 100 random permutations of the participants. ONEST suggested a minimum of 4 observers for the reliable evaluation of reproducibility for both the scored components and grade in either type of specimen. Our results suggested moderate or moderate to good reproducibility of grading (kappa values of 0.51 for excisions, and 0.54 for biopsies and ICCs of 0.70 and 0.69, respectively) with gland formation being the most and nuclear pleomorphism the worst consistently evaluated feature. In studies with sufficient participants (at least 4) and non-pairwise comparisons in the analysis, the reproducibility of histological grading is fair to moderate, whereas studies with fewer participants or pairwise kappa analysis suggest moderate to almost prefect agreement of the results. ONEST is a valuable complementation of reproducibility analyses.

The additional value of ONEST (Observers Needed to Evaluate Subjective Tests) in assessing reproducibility of oestrogen receptor, progesterone receptor, and Ki67 classification in breast cancer.

The reproducibility of assessing potential biomarkers is crucial for their implementation. ONEST (Observers Needed to Evaluate Subjective Tests) has been recently introduced as a new additive evaluation method for the assessment of reliability, by demonstrating how the number of observers impact on interobserver agreement. Oestrogen receptor (ER), progesterone receptor (PR), and Ki67 proliferation marker immunohistochemical stainings were assessed on 50 core needle biopsy and 50 excision samples from breast cancers by 9 pathologists according to daily practice. ER and PR statuses based on the percentages of stained nuclei were the most consistently assessed parameters (intraclass correlation coefficients, ICC 0.918-0.996), whereas Ki67 with 5 different theoretical or St Gallen Consensus Conference-proposed cut-off values demonstrated moderate to good reproducibility (ICC: 0.625-0.760). ONEST highlighted that consistent tests like ER and PR assessment needed only 2 or 3 observers for optimal evaluation of reproducibility, and the width between plots of the best and worst overall percent agreement values for 100 randomly selected permutations of observers was narrow. In contrast, with less consistently evaluated tests of Ki67 categorization, ONEST suggested at least 5 observers required for more trustful assessment of reliability, and the bandwidth of the best and worst plots was wider (up to 34% difference between two observers). ONEST has additional value to traditional calculations of the interobserver agreement by not only highlighting the number of observers needed to trustfully evaluate reproducibility but also by highlighting the rate of agreement with an increasing number of observers and disagreement between the better and worse ratings.

[Laparoscopic and open complete mesocolic excision in right-sided colon cancer compared with open and laparoscopic surgery]. / Laparoszkópos és nyitott komplett mezokólikus excízió összehasonlítása nyitott és laparoszkópos konvencionális mutéttel jobb oldali vastagbéldaganatoknál ­ retrospektív feldolgozás, kezdeti tapasztalatok.

Introduction: In 2009, Hohenberger translated the concept of total mesorectal excision to colon cancer surgery and he named it complete mesocolic excision (CME). The principle of CME is based on wide mesenteric excision in the embriologic plane to remove mesenteric lymph nodes, central vascular ligation without damage of the peritoneal layer. CME can be performed by laparoscopic and open methods. Aim: To make sure that we are capable of performing right laparoscopic hemicolectomy with similar results to the open method. Results: A cohort of 156 consecutive patients were operated on with malignant right-sided colon tumours from 01.09.2016 to 30.06.2019. 143 curative resections were performed in 63 men and 80 women. The average age of men and women were 71.5 and 72.75 years, respectively. 84 laparoscopic and 59 open operations were performed. 84 patients underwent CME surgery and 56 conventional resections. The average length of the specimen was 22.34 cm in the conventional and 24.97 cm in CME surgery (p = 0.18) and the average lymph node number were 15.4 and 16.9, respectively (p = 0.24). The average duration of the operation was 111 minutes for the conventional and 136 minutes for the CME group (p = 0.0014), while the average length of stay were 7.47 days and 5.65 days (p = 0.0004) respectively for the cases without complications. Conclusion: We are yet in the learning period, but based on the early results, it might be concluded that the operation can be performed by laparoscopic methods as well with similar results to the open operation but with shorter length of stay.

The Petersen prognostic index revisited in Dukes B colon cancer--Inter-institutional differences.

A prognostic index (Petersen index, PI) was created for patients with pT3-4 pN0 M0 (Stage II, Dukes' B) colon cancers to distinguish between patients with better and worse outcome, and to help in recommending adjuvant chemotherapy for high risk patients in this stage. The prognostic value of the PI was evaluated in two independent retrospective series of stage II (Dukes' B) colon cancer patients. The parameters defining the PI (venous invasion, peritoneal involvement, circumferential margin involvement, perforation through the tumour) and performance of the PI were compared in two institutions. The two series of patients consisted of 127 and 87 patients. Venous invasion was more frequently detected at one of the centres (p<0.01) and tumour perforation was more frequent at the other (p<0.01). There were no significant differences in the 5-year survival estimates of all patients (p=0.19), and of either the low PI value groups (p=0.52) or that of the high PI value groups (p=0.99) between the two sites. In contrast, there were significant differences in the survival estimates between patients of the low PI category and those of the high PI category altogether (p<0.01) and in either centre. Although, it was expected that differences in the frequency of the parameters involved in the PI would influence its performance, this was not confirmed by the data. Our results suggest that using the PI may be of value in prognostic factor based therapy selection of colon carcinoma patients.

The role of sentinel node biopsy in male breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a standard procedure in women with breast cancer. The risk of morbidity related to axillary lymph node dissection (ALND) is similar for men and women with breast cancer and SLNB could minimize this risk. METHODS: Between January 2004 and August 2013, 25 men with primary breast cancer were operated on at the Bács-Kiskun County Teaching Hospital. These were reviewed retrospectively. SLNB was performed following lymphoscintigraphy with intraoperative gamma probe detection and blue dye mapping. RESULTS: SLNB was successful in all 16 male patients (100 %), in whom it was attempted. The SLNs were negative in 4 cases (25 %) and were involved in 12. Intraoperative imprint cytology was positive in 9 of the 12 involved cases (75 %) and resulted immediate completion ALND. In 7 patients, the intraoperative imprint cytology was negative, with 3 false-negative results that resulted in delayed completion ALND. After a median follow-up of 48 months, there was only one axillary recurrence after ALND and none in the SLNB group. CONCLUSIONS: SLNB is successful and accurate in male breast cancer patients too. Although compared to women a larger proportion of men have positive nodes, for men with negative nodes, ALND-related morbidity may be reduced by SLNB. We recommend SLNB in male patients with breast cancer and clinically negative axilla.

[Interobserver reproducibility of Gleason grading in prostate biopsy samples]. / A Gleason-osztályozás reprodukálhatóságának vizsgálata prosztata-tubiopsziás mintákban.

INTRODUCTION: Gleason grading is the most common method of prostate cancer classification. AIM: The aim of the authors was to assess the reproducibility of Gleason grading among pathologists using the same needle biopsy samples. METHOD: 23 pathologists examined 37 prostate cancer biopsies stained with hematoxylin and eosin. Gleason scores were categorised into 4 groups (2-4, 5-6, 7 and 8-10). Kappa statistics were used to reflect interobserver agreement. RESULTS: Considering all participating pathologists, grouping into one of the 4 categories resulted in an overall kappa value of 0.49. For the individual categories, the worst agreement (kappa = 0.15) was seen with well differentiated carcinomas, and the best (kappa = 0.65) with poorly differentiated ones. CONCLUSIONS: These results suggest that Gleason grading in biopsy samples is moderately reproducible. The kappa values vary according to the differentiation of the cancer, and there is not much difference between the results of the present study and those published in the literature. To increase reproducibility, trainings should be organised, and this could improve the quality of grading.

Multi-institutional comparison of non-sentinel lymph node predictive tools in breast cancer patients with high predicted risk of further axillary metastasis.

Although axillary lymph node dissection (ALND) has been the standard intervention in breast cancer patients with sentinel lymph node (SLN) metastasis, only a small proportion of patients benefit from this operation, because most do not harbor additional metastases in the axilla. Several predictive tools have been constructed to identify patients with low risk of non-SLN metastasis who could be candidates for the omission of ALND. In the present work, predictive nomograms were used to predict a high (>50 %) risk of non-SLN metastasis in order to identify patients who would most probably benefit from further axillary treatment. Data of 1000 breast cancer patients with SLN metastasis and completion ALND from 5 institutions were tested in 4 nomograms. A subset of 313 patients with micrometastatic SLNs were also tested in 3 different nomograms devised for the micrometastatic population (the high risk cut-off being 20 %). Patients with a high predicted risk of non-SLN metastasis had higher rates of metastasis in the non-SLNs than patients with low predicted risk. The positive predictive values of the nomograms ranged from 44 % to 64 % with relevant inter-institutional variability. The nomograms for micrometastatic SLNs performed much better in identifying patients with low risk of non-SLN involvement than in high-risk-patients; for the latter, the positive predictive values ranged from 13 % to 20 %. The nomograms show inter-institutional differences in their predictive values and behave differently in different settings. They are worse in identifying high risk patients than low-risk ones, creating a need for new predictive models to identify high-risk patients.

Limited lymph-node recovery based on lymph-node localisation is sufficient for accurate staging.

AIMS: To assess the reliability of nodal staging in colorectal carcinomas (CRCs) when only lymph nodes close to the tumour are recovered and examined histologically. METHODS: Lymph nodes from CRC resection specimens were recovered into two fractions: one from around the tumour and the 3 cm sidelong bowel segment associated with it in the proximal and distal directions, and another from the remaining part of the resection specimen. RESULTS: Of the 762 CRCs (239 right colon, 251 left colon, 257 rectum, 15 unspecified localisation) there were 393 node-negative and 369 node-positive cases. The median number of LNs examined was 18. The assessment of the LNs located in the close fraction (median 13) yielded an adequate qualitative nodal status in 756 patients (99.2%). In four cases (two rectal and two right colic), no LN metastases could be identified in the close-fraction lymph nodes, but nodes from the distant fraction contained metastases. Of the node-positive carcinomas which had at least one positive lymph node in the close fraction, 203 belonged to the pN1 category and 162 to the pN2 category of the Tumour Node Metastasis staging system. Only 14 cases (10 rectal, two right and two left colic tumours) were misclassified as pN1 (on the basis of lymph nodes recovered from the close fraction) although they were of the pN2 category. CONCLUSIONS: In general, nodal status of CRCs may be adequately assessed by examining the lymph nodes from the close fraction around the tumour and the 3 cm sidelong bowel segment in both directions.

Venous invasion demonstrated by orcein staining of colorectal carcinoma specimens is associated with the development of distant metastasis.

AIMS: To assess venous invasion (VI) and its relation to distant metastases in colorectal cancer (CRC). METHODS: Primary untreated CRC cases were assessed for VI. All tumour blocks were stained with H&E and orcein. The presence of VI and nodal status were then correlated with the presence of synchronous or metachronous distant metastases. RESULTS: VI was detected more frequently with the orcein stain (18% versus 71%). Eleven tumours (nine node-positive tumours, all VI positive) were associated with synchronous distant metastasis. During a median follow-up of 17 months nine further cases were diagnosed with distant metastasis (six node-positive tumours, all VI positive). The specificity and sensitivity of the presence of nodal metastasis for predicting distant metastasis were 0.56 and 0.75, respectively. The same values for orcein-detected VI were 0.39 and 1, respectively. CONCLUSIONS: Elastic stains such as the orcein stain enable the detection of clinically relevant VI with greater frequency than conventionally stained histological slides. If nodal involvement is an indication for systemic chemotherapy, the data presented here suggest that VI detected by the orcein stain should also be an indication for systemic chemotherapy.

[Analysis of predictive tools for further axillary involvement in patients with sentinel-lymph-node-positive, small (< or =15 mm) invasive breast cancer]. / A hónalji nyirokcsomók további érintettségére vonatkozó modellek elemzése kisméretu (< / =15 mm) ôrszemnyirokcsomó-áttétes emlôrákokban.

Small breast cancers often require different treatment than larger ones. The frequency and predictability of further nodal involvement was evaluated in patients with positive sentinel lymph nodes and breast cancers < or =15 mm by means of 8 different predictive tools. Of 506 patients with such small tumors 138 with positive sentinel nodes underwent axillary dissection and 39 of these had non-sentinel node involvement too. The Stanford nomogram and the micrometastatic nomogram were the predictive tools identifying a small group of patients with low probability of further axillary involvement that might not require completion axillary lymph node dissection. Our data also suggest that the Tenon score can separate subsets of patients with a low and a higher risk of non-sentinel node metastasis. Predictive tools based on multivariate models can help in omitting completion axillary dissection in patients with low risk of non-sentinel lymph node metastasis based on their small tumor size.

Predicting non-sentinel lymph node status after positive sentinel biopsy in breast cancer: what model performs the best in a Czech population?

Several models have previously been proposed to predict the probability of non-sentinel lymph node (NSLN) metastases after a positive sentinel lymph node (SLN) biopsy in breast cancer. The aim of this study was to assess the accuracy of two previously published nomograms (MSKCC, Stanford) and to develop an alternative model with the best predictive accuracy in a Czech population. In the basic population of 330 SLN-positive patients from the Czech Republic, the accuracy of the MSKCC and the Stanford nomograms was tested by the area under the receiver operating characteristics curve (AUC). A new model (MOU nomogram) was proposed according to the results of multivariate analysis of relevant clinicopathologic variables. The new model was validated in an independent test population from Hungary (383 patients). In the basic population, six of 27 patients with isolated tumor cells (ITC) in the SLN harbored additional NSLN metastases. The AUCs of the MSKCC and Stanford nomograms were 0.68 and 0.66, respectively; for the MOU nomogram it reached 0.76. In the test population, the AUC of the MOU nomogram was similar to that of the basic population (0.74). The presence of only ITC in SLN does not preclude further nodal involvement. Additional variables are beneficial when considering the probability of NSLN metastases. In the basic population, the previously published nomograms (MSKCC and Stanford) showed only limited accuracy. The developed MOU nomogram proved more suitable for the basic population, such as for another independent population from a mid-European country.

Heterogeneity of pT3 colorectal carcinomas according to the depth of invasion.

Colorectal carcinomas (CRCs) infiltrating through the muscularis propria layer without infiltration of adjacent structures, organs or the serosa-i.e. the pT3 tumors, compose the largest subset of large intestinal carcinomas treated by surgical resection. They are heterogeneous in terms of prognosis. CRCs treated by surgery in a period of 69 months were prospectively classified as pT3a tumors (invading to a maximum of 5 mm beyond the muscularis propria) and pT3b tumors (invading deeper). Their nodal status, incidence of vascular invasion and the presence or absence of distant metastases were analyzed in relation to the depth of invasion. Of the 593 CRCs primarily treated by surgery 429 were pT3 tumors. CRCs categorized as pT3a had significantly lower rates of nodal involvement (44% vs 75%), massive nodal involvement (pN2) (9% vs 39%), venous invasion (17% vs 30%) and distant metastasis (11% vs 28%) than pT3b tumors. Significant differences in these prognostic variables in pT3a and pT3b cancers were observed both for carcinomas of the colon and those of the rectum. Such differences were not obvious in further 66 ypT3 cases of rectal carcinoma receiving neoadjuvant treatment before surgery. Tumors in the pT3a category are associated with a better prognostic profile than pT3b tumors. This subdivision might be useful in both prognostication and treatment planning.

Basal phenotype in breast carcinoma occurring in women aged 35 or younger.

Breast cancer in the young is considered a special clinical presentation of the disease. Sixty-nine breast cancer cases diagnosed at or before the age of 35 were analyzed for common morphological and immunophenotypical features of basal-like carcinomas. Sixteen carcinomas displayed the immunophenotypical characteristics (estrogen receptor and HER2 negativity and positivity for at least one of the following basal markers: cytokeratin 5 or 14, epidermal growth factor receptor, p63) of basal-like carcinomas, and most of them demonstrated characteristic histological features (pushing borders, lymphocytic peritumoral infiltrate, central hypocellular zone or necrosis, high mitotic rate) too. These tumors were more likely to be high-molecular-weight cytokeratin: 34betaE12 and p53 positive by immunohistochemistry. The presence of a basal-like phenotype can be important as concerns systemic treatment issues and could theoretically be associated with a higher rate of BRCA1 mutations in the young, because of the overlap of BRCA1 mutation associated breast carcinomas and the basal-like phenotype.

Vascular invasion demonstrated by elastic stain-a common phenomenon in benign granular cell tumors.

Granular cell tumor is generally benign, but rare malignant cases have been documented. Features of malignancy include necrosis, cellular spindling, vesicular nuclei with large nucleoli, increased mitotic activity, high nuclear to cytoplasmic ratio, and pleomorphism, but not vascular invasion. Venous invasion was incidentally identified with the orcein elastic stain in an otherwise benign granular cell tumor (propositus case). Four further benign granular cell tumors were also analyzed; venous invasion was discovered in three. It is suggested that vascular invasion is not uncommon in granular cell tumors and should not lead to the classification of the tumor as malignant or atypical. It is likely that in most cases there is only invasion of the vascular wall. It is also suggested that some cases of vascular invasion identified by elastic stains in tumors such as colorectal carcinomas (where these stains are recommended for routine use) may also represent invasion of vascular structures without the propensity of metastasis.

Sentinel lymph node biopsy and non-sentinel node involvement in special type breast carcinomas with a good prognosis.

This study aimed at identifying factors related to sentinel lymph node (SLN) involvement in patients with tubular, cribriform, mucinous or papillary breast carcinoma and those related to non-SLN metastases if an SLN was positive. Multivariate analyses involved logistic and stepwise regressions. The SLNs harboured metastases in 85 of 572 cases, 78 of whom underwent axillary dissection; 19 presented non-SLN positive disease. Lack of lymphovascular invasion, a tumour size < or = 10 mm and a single SLN removed were the factors predicting an SLN metastasis rate <10%, and patients with these features could be candidates for no surgical axillary staging. A positive SLN proportion of < or = 50% and no lymphovascular invasion were associated with a <10% rate of non-SLN invasion; patients with a positive SLN and these features could be candidates for the omission of completion axillary dissection. The opposite presentation of these factors would mandate SLN biopsy and axillary dissection, respectively.

The impact of the largest metastasis size on nodal tumor burden in colorectal carcinomas: implications for the sentinel lymph node theory in cancers of the large intestine.

BACKGROUND AND OBJECTIVES: Successful sentinel lymph node (SLN) biopsy has been reported in colorectal cancer (CRC), but its results are still controversial. The SLN theory suggests that there is an orderly spread from the primary tumor to the SLNs first, and from the SLNs to further nodes later. This study examines the influence of nodal metastasis size on further nodal involvement. METHODS: CRC resection specimens with nodal metastasis have been evaluated for the maximum nodal metastasis size for a period of 5 years. All lymph nodes (LNs) were submitted to standard histological examination. RESULTS: Two hundred thirty-five CRC specimens with a single invasive tumor were assessed. The mean numbers of LNs examined and involved were 18 and 4, respectively. The largest metastasis size ranged from 0.14 to 22.1 mm. There was a significant correlation between this parameter and the number or the ratio of LNs involved (Spearman's Rho: 0.517, and 0.382, respectively; P < 0.0001). A cluster analysis identified three relatively distinct groups of low, intermediate, and extensive nodal involvement. CONCLUSIONS: The correlation of the largest metastasis size with the number and the ratio of involved nodes may be an indirect proof of the sequential spread from first echelon LNs to further nodes. However, the data suggest a more complex process: with increasing metastasis size, the number of involved nodes and its variability increase more than might be expected. This suggests a recruitment or cascade process, which becomes more unpredictable as nodal tumor burden increases.

Sentinel lymph node biopsy in staging small (up to 15 mm) breast carcinomas. Results from a European multi-institutional study.

Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early breast cancer, but controversy exists regarding its universal use and consequences in small tumors. 2929 cases of breast carcinomas not larger than 15 mm and staged with SLN biopsy with or without axillary dissection were collected from the authors' institutions. The pathology of the SLNs included multilevel hematoxylin and eosin (HE) staining. Cytokeratin immunohistochemistry (IHC) was commonly used for cases negative with HE staining. Variables influencing SLN involvement and non-SLN involvement were studied with logistic regression. Factors that influenced SLN involvement included tumor size, multifocality, grade and age. Small tumors up to 4 mm (including in situ and microinvasive carcinomas) seem to have SLN involvement in less than 10%. Non-SLN metastases were associated with tumor grade, the ratio of involved SLNs and SLN involvement type. Isolated tumor cells were not likely to be associated with further nodal load, whereas micrometastases had some subsets with low risk of non-SLN involvement and subsets with higher proportion of further nodal spread. In situ and microinvasive carcinomas have a very low risk of SLN involvement, therefore, these tumors might not need SLN biopsy for staging, and this may be the approach used for very small invasive carcinomas. If an SLN is involved, isolated tumor cells are rarely if ever associated with non-SLN metastases, and subsets of micrometastatic SLN involvement may be approached similarly. With macrometastases the risk of non-SLN involvement increases, and further axillary treatment should be generally indicated.