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Odontogenic keratocysts (OKCs) are developmental cysts of the jaws that require proper diagnosis due to their potential for local aggressive growth and recurrences. OKCs have a typical parakeratotic epithelium demonstrating transepithelial cytokeratin 17 (CK17) and basal bcl2 staining on immunohistochemistry (IHC), which distinguishes them from other common jaw cysts. Secondary to inflammation, the epithelial lining may be altered and loses the typical IHC phenotype. The aim of the present study was to analyse a series of consecutive jaw cysts for their expression of CK17 and bcl2 and assess how these IHC stains may help in their diagnosis. All cysts were retrospectively assessed for available clinical, radiological and pathological findings and diagnoses were revised whenever needed. 85 cysts from 72 patients were collected from two departments. The series had 21 OKCs, the remaining non-OKCs included radicular/residual, dentigerous, paradental, lateral periodontal, botryoid odontogenic cysts. OKCs with typical epithelium showed the typical IHC phenotype, which was generally lost in inflammation-associated altered epithelium. Contrarily to earlier descriptions, a wide variety of CK17 positivity was seen in the majority of non-OKCs, including focal transepithelial staining. Basal bcl2 staining was also seen in 16 non-OKCs. These stainings were never as strong in intensity as seen in OKCs. One case was histopathologically identified as OKC due to focally maintained IHC profile. CK17 and bcl2 IHC may help in the diagnosis of OKCs, but must be interpreted with caution and is not a yes or no tool in the diagnostic puzzle. Electronic supplementary material The online version of this article (10.1007/s12253-020-00866-4) contains supplementary material, which is available to authorized users.

The spread through air spaces (STAS) has a main role in local recurrence of stage I lung adenocarcinomas (LAs), therefore its presence might question sublobar resection as a therapeutic option. The aim of our study was to evaluate the distribution of STAS in stage I LAs, to stratify patients according to local recurrence and to identify a group of patients who might be suitable for sublobar surgery. Patients resected with LA were included. The presence of STAS was recorded on hematoxylin eosin stained slides and clinicopathological data were obtained from medical charts. Overall survival (OS) and disease-free survival (DFS) were registered. Statistical methods included Kruskal-Wallis tests, Kaplan-Meier analyses, log-rank tests and Cox-regressions. 292 patients were included. STAS was identified in 38.7% and 95.7% of micropapillary carcinomas showed STAS. Significant correlation was found between STAS and high-grade patterns. Significant differences were found between OS and DFS estimates of STAS0 and STAS1 cases (5-y-OS: 80.0% vs. 68.4%; 5-y-DFS: 71.1% vs. 57.1%). The presence of STAS was associated with unfavorable prognosis in low and intermediate architectural grades, but not in high-grade. Multivariate analysis revealed that architectural grade (HR(OS):2.09; HR(DFS):1.52) and STAS (HR(OS):1.51; HR(DFS):1.48) were independent prognostic markers in stage I LA. Architectural grade combined with STAS was superior to other prognostic grades. The combination of architectural grade and STAS proved to be a prognostic factor that is superior to previously introduced grading systems. Patients having low and intermediate grade LAs without STAS might be eligible for sublobar resection. Electronic supplementary material The online version of this article (10.1007/s12253-020-00855-7) contains supplementary material, which is available to authorized users.

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model.

Stromal tumour infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple negative breast cancer (TNBC). Consistency scoring sTILs is good and was excellent when an internet-based scoring aid developed by the TIL-WG was used to score cases in a reproducibility study. This study aimed to evaluate the reproducibility of sTILs assessment using this scoring aid in cases from routine practice and to explore the potential of the tool to overcome variability in scoring. Twenty-three breast pathologists scored sTILs in digitized slides of 49 TNBC biopsies using the scoring aid. Subsequently, fields of view (FOV) from each case were selected by one pathologist and scored by the group using the tool. Inter-observer agreement was good for absolute sTILs (ICC 0.634, 95% CI 0.539–0.735, p &lt, 0.001) but was poor to fair using binary cutpoints. sTILs heterogeneity was the main contributor to disagreement. When pathologists scored the same FOV from each case, inter-observer agreement was excellent for absolute sTILs (ICC 0.798, 95% CI 0.727–0.864, p &lt, 0.001) and good for the 20% (ICC 0.657, 95% CI 0.561–0.756, p &lt, 0.001) and 40% (ICC 0.644, 95% CI 0.546–0.745, p &lt, 0.001) cutpoints. However, there was a wide range of scores for many cases. Reproducibility scoring sTILs is good when the scoring aid is used. Heterogeneity is the main contributor to variance and will need to be overcome for analytic validity to be achieved.

Simple Summary Invasive lobular breast cancer (ILC) is a special type of breast cancer (BC) that was first described in 1941. The diagnosis of ILC is made by microscopy of tumor specimens, which reveals a distinct morphology. This review recapitulates the developments in the microscopic assessment of ILC from 1941 until today. We discuss different concepts of ILC, provide an overview on ILC variants, and highlight advances which have contributed to a better understanding of ILC as a special histologic spectrum of tumors. Abstract Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in CDH1-deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research.

We report on a breast carcinoma with medullary features diagnosed by core needle biopsy in a 72-year-old woman. Both the primary tumour and its fine needle aspiration-proven, rapidly growing axillary metastasis regressed completely in less than 2 months, by the time surgery was performed. The biopsy of the primary tumour demonstrated a dense stromal infiltrate of CD8+/granzyme B+ activated cytotoxic T-cells suggestive of a robust antitumour immune response. Paradoxically, both tumour cells and tumour infiltrating immune cells demonstrated a diffuse PD-L1 expression, revealing that antitumour immune response has the ability to spontaneously overcome inhibitory mechanisms induced by cancerous growth.

Simple Summary Breast cancers that lack expression of the predictive markers oestrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 are known as triple-negative breast cancers (TNBCs) and are generally considered to have a poor prognosis. As available targeted treatments are not effective, aggressive chemotherapy is frequently advocated for patients with TNBC. It is now becoming apparent that TNBC is not one entity but constitutes a range of malignancies with different clinical behaviour. This paper reviews 7 distinct histological subtypes of TNBC where the overall prognosis is favourable, and aggressive systemic treatment is generally not indicated. Their recognition and separation from the larger group of no special type TNBC are important. The members of the European Working Group for Breast Screening Pathology review the morphology, known molecular features and reported outcomes, and formulate a consensus statement regarding the approach to the subtypes that are associated with a favourable prognosis. Abstract Triple-negative breast cancers (TNBC), as a group of tumours, have a worse prognosis than stage-matched non-TNBC and lack the benefits of routinely available targeted therapy. However, TNBC is a heterogeneous group of neoplasms, which includes some special type carcinomas with a relatively indolent course. This review on behalf of the European Working Group for Breast Screening Pathology reviews the literature on the special histological types of BC that are reported to have a triple negative phenotype and indolent behaviour. These include adenoid cystic carcinoma of classical type, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, low-grade mucoepidermoid carcinoma, secretory carcinoma, acinic cell carcinoma, and tall cell carcinoma with reversed polarity. The pathological and known molecular features as well as clinical data including treatment and prognosis of these special TNBC subtypes are summarised and it is concluded that many patients with these rare TNBC pure subtypes are unlikely to benefit from systemic chemotherapy. A consensus statement of the working group relating to the multidisciplinary approach and treatment of these rare tumour types concludes the review.

Purpose For optimal management of ductal carcinoma in situ (DCIS), reproducible histopathological assessment is essential to distinguish low-risk from high-risk DCIS. Therefore, we analyzed interrater reliability of histopathological DCIS features and assessed their associations with subsequent ipsilateral invasive breast cancer (iIBC) risk. Methods Using a case-cohort design, reliability was assessed in a population-based, nationwide cohort of 2767 women with screen-detected DCIS diagnosed between 1993 and 2004, treated by breast-conserving surgery with/without radiotherapy (BCS ± RT) using Krippendorff’s alpha (KA) and Gwet’s AC2 (GAC2). Thirty-eight raters scored histopathological DCIS features including grade (2-tiered and 3-tiered), growth pattern, mitotic activity, periductal fibrosis, and lymphocytic infiltrate in 342 women. Using majority opinion-based scores for each feature, their association with subsequent iIBC risk was assessed using Cox regression. Results Interrater reliability of grade using various classifications was fair to moderate, and only substantial for grade 1 versus 2 + 3 when using GAC2 (0.78). Reliability for growth pattern (KA 0.44, GAC2 0.78), calcifications (KA 0.49, GAC2 0.70) and necrosis (KA 0.47, GAC2 0.70) was moderate using KA and substantial using GAC2; for (type of) periductal fibrosis and lymphocytic infiltrate fair to moderate estimates were found and for mitotic activity reliability was substantial using GAC2 (0.70). Only in patients treated with BCS-RT, high mitotic activity was associated with a higher iIBC risk in univariable analysis (Hazard Ratio (HR) 2.53, 95% Confidence Interval (95% CI) 1.05–6.11); grade 3 versus 1 + 2 (HR 2.64, 95% CI 1.35–5.14) and a cribriform/solid versus flat epithelial atypia/clinging/(micro)papillary growth pattern (HR 3.70, 95% CI 1.34–10.23) were independently associated with a higher iIBC risk. Conclusions Using majority opinion-based scores, DCIS grade, growth pattern, and mitotic activity are associated with iIBC risk in patients treated with BCS-RT, but interrater variability is substantial. Semi-quantitative grading, incorporating and separately evaluating nuclear pleomorphism, growth pattern, and mitotic activity, may improve the reliability and prognostic value of these features.

Apocrine encapsulated papillary carcinoma (EPC) of the breast is a rare neoplasm, and only 10 cases have been reported in the literature to date. Although EPC by definition lacks a peripheral myoepithelial layer, all previously published apocrine EPC cases were clinically indolent and lacked a conventional invasive component. Herein, we report the 11th case of apocrine EPC, which had a conventional invasive carcinoma component and provides evidence of the malignant potential of this entity. We postulate that apocrine EPC is most likely a morphological variant of conventional EPC, with the same unpredictable malignant potential as non-apocrine cases.

Background: A deleterious, late-onset side effect of thoracic radiotherapy is the development of radiation-induced heart disease (RIHD). It covers a spectrum of cardiac pathology including also heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction. MicroRNA-212 (miR-212) is a crucial regulator of pathologic LVH via FOXO3-mediated pathways in pressure-overload-induced heart failure. We aimed to investigate whether miR-212 and its selected hypertrophy-associated targets play a role in the development of RIHD. Methods: RIHD was induced by selective heart irradiation (50 Gy) in a clinically relevant rat model. One, three, and nineteen weeks after selective heart irradiation, transthoracic echocardiography was performed to monitor cardiac morphology and function. Cardiomyocyte hypertrophy and fibrosis were assessed by histology at week 19. qRT-PCR was performed to measure the gene expression changes of miR-212 and forkhead box O3 (FOXO3) in all follow-up time points. The cardiac transcript level of other selected hypertrophy-associated targets of miR-212 including extracellular signal-regulated kinase 2 (ERK2), myocyte enhancer factor 2a (MEF2a), AMP-activated protein kinase, (AMPK), heat shock protein 40 (HSP40), sirtuin 1, (SIRT1), calcineurin A-alpha and phosphatase and tensin homolog (PTEN) were also measured at week 19. Cardiac expression of FOXO3 and phospho-FOXO3 were investigated at the protein level by Western blot at week 19. Results: In RIHD, diastolic dysfunction was present at every time point. Septal hypertrophy developed at week 3 and a marked LVH with interstitial fibrosis developed at week 19 in the irradiated hearts. In RIHD, cardiac miR-212 was overexpressed at week 3 and 19, and FOXO3 was repressed at the mRNA level only at week 19. In contrast, the total FOXO3 protein level failed to decrease in response to heart irradiation at week 19. Other selected hypertrophy-associated target genes failed to change at the mRNA level in RIHD at week 19. Conclusions: LVH in RIHD was associated with cardiac overexpression of miR-212. However, miR-212 seems to play a role in the development of LVH via FOXO3-independent mechanisms in RIHD. As a central regulator of pathologic remodeling, miR-212 might become a novel target for RIHD-induced LVH and heart failure.

BackgroundChemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes, but the clinical relevance of this triggered immune response is not known.We decided to investigate, whether treatment with various chemotherapeutic agents with significantly different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in the clinical setting.Methods112 breast carcinoma cases treated with pre-operative chemotherapy were selected for the study. According to chemotherapy regimen 28/112 patients received platinum-based, 42/112 cyclophosphamide-based and 42/112 anthracycline-based chemotherapy. The percentage of stromal tumor-infiltrating lymphocytes (StrTIL) was evaluated on hematoxylineosin stained slides of pre-treatment core biopsy (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL), according to the most recent recommendation of International TILs Working Group. In survival analyses, TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL.ResultsOf the 112 cases, 58.0% (n=65) were hormone receptor (HR) positive and 42.0% (n=47) were HR negative. There was a trend of higher post-StrTIL compared to pre-StrTIL (median 6.25% vs. 3.00%; pConclusionsStrTIL expression might be stimulated by highly (platinum), moderately (cyclophosphamide) and marginally (taxane, anthracycline) mutagenic chemotherapeutic agents. Increase in StrTIL in residual cancer compared to pre-treatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.

BACKGROUND: Several studies have demonstrated a prognostic role for stromal tumour infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). The reproducibility of scoring sTILs is variable with potentially excellent concordance being achievable using a software tool. We examined agreement between breast pathologists across Europe scoring sTILs on H&E-stained sections without software, an approach that is easily applied in clinical practice. The association between sTILs and response to anthracycline-taxane NACT was also examined. METHODOLOGY: Pathologists from the European Working Group for Breast Screening Pathology scored sTILs in 84 slides from 75 TNBCs using the immune-oncology biomarker working group guidance in two circulations. There were 16 participants in the first and 19 in the second circulation. RESULTS: Moderate agreement was achieved for absolute sTILs scores (intraclass correlation coefficient (ICC) = 0.683, 95% CI 0.601-0.767, p-value

Inflammatory breast cancer (IBC) is a clinico-pathological entity, which has specific features of inflammation and pathological evidence of cancer, most often involving dermal lymphatics. This review looks at IBC from the pathologists point of view. The diagnostic criteria and differential diagnosis are summarized first. The staging implications are described next. Despite the overall poor prognosis of IBC, it is heterogeneous in terms of most prognostic and predictive factors (such as histological type, grade, receptor status, intrinsic subtype, inflammatory infiltrate). It seems that some molecular features (genes expressed) are unique to IBC, and this may help to identify them as IBC at the molecular level. The key carcinogenetic pathways activated in IBC, the inflammatory pathways present in the disease as well as the relation of IBC to cancer stem cells are also briefly covered. Due to the relative rarity of IBC, preclinical trials are very important in the study of this entity, and models with stromal and microenvironmental elements are expected to outperform the traditional models without these features, as the microenvironment seems to be a key component of IBC. (C) 2018 Elsevier Ltd, BASO - The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Aims Solid papillary breast carcinoma resembling the tall cell variant of papillary thyroid neoplasms (BPTC), also known as solid papillary carcinoma with reverse polarity, is a rare histological type of breast cancer that resembles morphologically the tall cell variant of papillary thyroid carcinoma. BPTCs are characterised by IDH2 R172 hotspot somatic mutations or mutually exclusive TET2 somatic mutations, concurrently with mutations affecting PI3K pathway-related genes. We sought to characterise their histology and investigate the frequency of IDH2 and PIK3CA mutations in an independent cohort of BPTCs, as well as in conventional solid papillary carcinomas (SPCs). Methods and results Six BPTCs, not previously analysed molecularly, and 10 SPCs were reviewed centrally. Tumour DNA was extracted from microdissected histological sections and subjected to Sanger sequencing of the IDH2 R172 hotspot locus and exons 9 and 20 of PIK3CA. All six BPTCs were characterised by solid, papillary and follicular architecture with circumscribed, invasive tumour nodules composed of epithelial cells with reverse polarity. IDH2 mutations were identified in all six BPTCs (three R172S, two R172T and one R172G), four of which also harboured PIK3CA mutations (two H1047R, one Q546K and one Q546R). By contrast, all SPCs lacked IDH2 mutations, while one of 10 harboured a PIK3CA mutation (H1047R). Conclusion We validated the presence of IDH2 R172 hotspot mutations and PIK3CA hotspot mutations in 100% and 67% BPTCs tested, respectively, and documented absence of IDH2 R172 mutations in SPCs. These findings confirm the genotypical-phenotypical correlation reported previously in BPTC, which constitutes an entity distinct from conventional SPC.

Background Postanalytic issues of Ki67 assessment in breast cancers like counting method standardisation and interrater bias have been subject of various studies, but little is known about analytic variability of Ki67 staining between pathology labs. Our aim was to study interlaboratory variability of Ki67 staining in breast cancer using tissue microarrays (TMAs) and central assessment to minimise preanalytic and postanalytic influences. Methods Thirty European pathology labs stained serial slides of a TMA set of breast cancer tissues with Ki67 according to their routine in-house protocol. The Ki67-labelling index (Ki67-LI) of 70 matched samples was centrally assessed by one observer who counted all cancer cells per sample. We then tested for differences between the labs in Ki67-LI medians by analysing variance on ranks and in proportions of tumours classified as luminal A after dichotomising oestrogen receptor–positive cancers into cancers showing low (

Male breast cancer (MBC) is rare. We assembled 446 MBCs on tissue microarrays and assessed clinicopathological information, together with data from 15 published studies, totalling 1984 cases. By immunohistochemistry we investigated 14 biomarkers (ERα, ERβ1, ERβ2, ERβ5, PR, AR, Bcl-2, HER2, p53, E-cadherin, Ki67, survivin, prolactin, FOXA1) for survival impact. The main histological subtype in our cohort and combined analyses was ductal (81%, 83%), grade 2; (40%, 44%), respectively. Cases were predominantly ERα (84%, 82%) and PR positive (74%, 71%), respectively, with HER2 expression being infrequent (2%, 10%), respectively. In our cohort, advanced age (>67) was the strongest predictor of overall (OS) and disease free survival (DFS) (p = 0.00001; p = 0.01, respectively). Node positivity negatively impacted DFS (p = 0.04). FOXA1 p = 0.005) and AR p = 0.009) were both positively prognostic for DFS, remaining upon multivariate analysis. Network analysis showed ERα, AR and FOXA1 significantly correlated. In summary, the principle phenotype of MBC was luminal A, ductal, grade 2. In ERα+ MBC, only AR had prognostic significance, suggesting AR blockade could be employed therapeutically.

Thirteen cases of invasive solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms (BPTC) are reported here. Some cases had long-term follow-up. BPTC is a special type of primary breast neoplasm showing a triple-negative profile but low aggressive potential. Knowledge on BPTC is still scanty; therefore, the aim of the present paper was to report on the features of an additional 13 cases. All the patients were female individuals, and the mean age at presentation was 62.6 years; nodule sizes ranged from 0.6 to 2.5 cm (average, 1.6 cm). All the cases were characterized on histology by papillary, follicular as well as solid structures. The cells were columnar, eosinophilic mostly with granular cytoplasms, rich in mitochondria, with the features of oncocytes in no fewer than 7 cases. Estrogen and progesterone receptors as well as HER2 were consistently negative. The Ki67 proliferative index was low. Markers consistent with thyroid origin, such as TTF1 and thyroglobulin, were negative. Five cases stained for mammoglobin and GATA 3 were positive. All cases proved to be invasive and 2 cases each experienced metastases to 1 lymph node (axillary and intramammary). One case of the latter had a local recurrence. Nevertheless, all the patients are alive, free of disease 24 to 132 months after surgery, of which 8 are without further treatment The present series confirms that BPTC is a primary breast tumor of low malignant potential.

To identify markers of non-response to neoadjuvant chemotherapy (NAC) that could be used in the adjuvant setting. Sixteen pathologists of the European Working Group for Breast Screening Pathology reviewed the core biopsies of breast cancers treated with NAC and recorded the clinico-pathological findings (histological type and grade; estrogen, progesterone receptors, and HER2 status; Ki67; mitotic count; tumor-infiltrating lymphocytes; necrosis) and data regarding the pathological response in corresponding surgical resection specimens. Analyses were carried out in a cohort of 490 cases by comparing the groups of patients showing pathological complete response (pCR) and partial response (pPR) with the group of non-responders (pathological non-response: pNR). Among other parameters, the lobular histotype and the absence of inflammation were significantly more common in pNR (p

The Ki67 labelling index (LI – proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5. The Ki67 labelling index (LI - proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5. © 2014 Elsevier Ltd.

Purpose Application of current nodal status classification is complicated in lobular breast carcinoma metastases. The aim of this study was to define the optimal interpretation of the pTNM classification in sentinel node (SN) –positive patients to select patients with limited or with a high risk of non-SN involvement. Patients and Methods SN metastases of 392 patients with lobular breast carcinoma were reclassified according to interpretations of the European Working Group for Breast Screening Pathology (EWGBSP) and guidelines by Turner et al, and the predictive power for non-SN involvement was assessed. Results Reclassification according to definitions of EWGBSP and Turner et al resulted in different pN classification in 73 patients (19%). The rate of non-SN involvement in the 40 patients with isolated tumor cells according to Turner et al and with micrometastases according to EWGBSP was 20%, which is comparable to the established rate for micrometastases. The rate of non-SN involvement in the 29 patients with micrometastases according to Turner et al and with macrometastases according to EWGBSP was 48%, which is comparable to the established rate for macrometastases. Therefore, the EWGBSP method to classify SN tumor load better reflected the risk of non-SN involvement than the Turner et al system. Conclusion Compared with the guidelines by Turner et al, the EWGBSP definitions better reflect SN metastatic tumor load and allow better differentiation between patients with lobular breast carcinoma who have a limited or a high risk of non-SN metastases. Therefore, we suggest using the EWGBSP definitions in these patients to select high-risk patients who may benefit from additional local and/or systemic therapy.

The optimal pathological assessment of sentinel nodes (SLNs) in breast cancer is a matter of debate. Currently, multilevel histological evaluation and immunohistochemistry (IHC) are recommended, but alternative RT-PCR procedures have been developed. To assess the reliability of these different procedures, we devised a step-sectioning protocol at 100 micron-intervals of 74 SLNs using methacarn fixation. mRNA was extracted from sections collected from levels 4 to 5. Mammaglobin, CEA and CK19 were used for RT-PCR. mRNA extraction was successful in 69 SLNs. Of these, 7 showed macrometastases (>2mm), 2 showed micrometastases (

Background: Core needle biopsies represent only a small portion of a breast lesion. Rare lesions with overlapping features may be underestimated in such small samples. Case

Background Two recently developed clinical prediction rules aim to anticipate the lack of nonsentinel lymph node metastases and the involvement of less than 4 lymph nodes in breast cancer patients with positive sentinel lymph nodes (SLNs). Methods The University of Louisville Breast SLN Study clinical prediction rules were validated on an independent set of SLN-positive patients with tumors ≤15 mm. Results The data on 475 and 473 patients, respectively, were used for the validation. The areas under the receiver operating characteristic curves were similar to the originals for both predictive tools (.70 and .76). The lowest score of 1 identified 5 of 7 patients with disease limited to the SLNs and 161 of 165 as having less than 4 involved lymph nodes. Conclusions A subset of patients with SLN-only involvement and less than 4 metastatic lymph nodes can probably be identified by means of the Louisville clinical prediction rules, but prediction of the lack of non-SLN metastasis seems less reliable.

Contains fulltext : 57809.pdf (Publisher’s version ) (Closed access) AIMS: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. METHODS: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. RESULTS: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. CONCLUSIONS: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

This review surveys the staging systems used for the classification of colorectal carcinomas, including the TNM system, and focuses on the assessment of the nodal stage of the disease. It reviews the quantitative requirements for a regional metastatic work up, and some qualitative features of lymph nodes that may help in the selection of positive and negative lymph nodes. Identification of the sentinel lymph nodes (those lymph nodes that have direct drainage from the primary tumour site) is one such qualitative feature that is claimed to allow the upstaging of colorectal carcinomas via an oriented, enhanced pathological work up. Current evidence in favour of a change in the requisite of assessing as may lymph nodes as is possible, and concentrating the efforts on only a selected number of lymph nodes, is weak.

Our objective was the elaboration of a new animal model for the free transplantation of an omental flap and the examination of its viability in dogs. The cooled omental flap from the abdomen was freely transplanted to the lateral cervical region, and its blood supply was established with microsurgical anastomoses. The technique was developed in 5 dogs, and short-term survival examinations were later carried out in 3 cases by means of this method. Postoperative viability was assessed by angiography, methylene blue testing, and histology. Of the 3 transplanted grafts, 2 still survived 1 week after the operation. For technical reasons, 1 flap thrombotized. For determination of the viability of the transplanted graft, histology proved best. Vital reactions, including granulation tissue and angiogenesis, were present on the histological slides. The short-term survival of an omental flap can be ensured with microsurgical transplantation in dogs.

Aims: To evaluate two detailed step sectioning protocols for sentinel lymph nodes (SLNs). Methods: After vital dye or combined dye and radiocolloid guided biopsy, SLNs were fixed in formalin and embedded in paraffin wax. In protocol A, SLNs from 123 patients were sectioned in steps of 50–100 μm, whereas in protocol B, SLNs from 123 patients were sectioned at steps of 250 μm. Epithelial marker immunohistochemistry (IHC) was performed on multiple levels in cases with negative haematoxylin and eosin findings. Results: In groups A and B, 74 and 47 patients were found to have tumour cells in their axillary SLNs, and 19 (28%) and 18 (19%) patients, respectively, were upstaged as compared with the standard histological assessment. Nodal involvement detected by deeper sections was often micrometastatic or in isolated tumour cells Conclusions: Serial sectioning and IHC are recommended for the evaluation of SLNs. The optimal extent of the histopathological work up should be studied further.

AIM: To assess the value of the intensive histological work up of axillary sentinel lymph nodes (SLN) to demonstrate regional metastatic disease. METHODS: From a series of 58 successful lymphatic mapping procedures, 78 SLN were analysed by serial sections (mean of 49 levels/SLN) and by immunostaining to cytokeratin and epithelial membrane antigen, and the results compared with those obtained by assessing the central cross section. RESULTS: The central cross section would have failed to detect metastases in eight of 26 lymph nodes (31%) in patients with breast cancer metastasising to the SLN only. This would have led to a false negative node status in six of 21 patients (29%). Two micrometastases were detected with the aid of immunostains. CONCLUSIONS: The results suggest the need to examine SLN at multiple levels and to use immunohistochemistry in negative cases. Serial sections are also useful in the case of micrometastases, as some of these may convert to macrometastases at deeper levels. Multiple level investigation of SLN and immunohistochemistry in the event of the negativity of standard stains would result in improved staging and an increase in the proportion of node positive disease detected.

AIMS: To test the hypothesis that a correct qualitative assessment of axillary nodal status can be established by examining only a limited number of lymph nodes. METHODS: Slides from 499 pN1 or pN0 axillary dissection specimens relating to symptomatic breast cancer cases operated on at our institution between 1991 and 1996 were reviewed. Nodes were ranked in descending order on the basis of their estimated size and lymphoid or metastatic tissue content. After ranking, all nodes were studied microscopically; 265 axillary clearance specimens were positive. RESULTS: Assessment of the 3-6 largest/firmest nodes can lead to the detection of 93-98% of node positive patients and can give a correct qualitative assessment of axillary node status in 96-99%. CONCLUSIONS: Sampling the 4-6 largest/firmest nodes seems to be a reliable alternative for the staging of symptomatic breast cancer. These results suggest a reconsideration of the generally held view that a minimum of 10 nodes is required for adequate identification of the pN0 category.

AIM: To implement an audit scheme to increase the lymph node yield from axillary clearance specimens. METHODS: Two pathologists cut up each specimen after weighing it. The number of nodes and the dimensions of the largest and smallest nodes were recorded, together with the number of non-lymph node structures recovered. Fifty consecutive audited cases were compared with 50 consecutive cases assessed before the audit process. RESULTS: It proved possible to increase the median number of lymph nodes from 10 to 22. There was an obvious learning period, during which the number of nodes recovered during the second pathologist9s cut-up gradually decreased, while the total number remained relatively constant. The increase in lymph node yield resulted from the recovery of smaller nodes. The identification of lymph nodes also improved, and fewer non-lymph node structures were recovered by the end of the study. CONCLUSIONS: Such an audit scheme can be recommended for all institutions where the lymph node yield of axillary clearance specimens seems suboptimal. The relevance of recovering more nodes remains to be determined; from this small series, it seems to have no clinical impact.

Contains fulltext : 152476.pdf (Publisher’s version ) (Open Access) BACKGROUND: Pleomorphic invasive lobular cancer (pleomorphic ILC) is a rare variant of ILC that is characterized by a classic ILC-like growth pattern combined with an infiltrative ductal cancer (IDC)-like high nuclear atypicality. There is an ongoing discussion whether pleomorphic ILC is a dedifferentiated form of ILC or in origin an IDC with a secondary loss of cohesion. Since gene promoter hypermethylation is an early event in breast carcinogenesis and thus may provide information on tumor progression, we set out to compare the methylation patterns of pleomorphic ILC, classic ILC and IDC. In addition, we aimed at analyzing the methylation status of pleomorphic ILC. METHODS: We performed promoter methylation profiling of 24 established and putative tumor suppressor genes by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) analysis in 20 classical ILC, 16 pleomorphic ILC and 20 IDC cases. RESULTS: We found that pleomorphic ILC showed relatively low TP73 and MLH1 methylation levels and relatively high RASSF1A methylation levels compared to classic ILC. Compared to IDC, pleomorphic ILC showed relatively low MLH1 and BRCA1 methylation levels. Hierarchical cluster analysis revealed a similar methylation pattern for pleomorphic ILC and IDC, while the methylation pattern of classic ILC was different. CONCLUSION: This is the first report to identify TP73, RASSF1A, MLH1 and BRCA1 as possible biomarkers to distinguish pleomorphic ILC from classic ILC and IDC.