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Lesions identified during breast imaging often require microscopic verification. Current recommendations imply the classification of radiological, clinical, cytology and core biopsy findings into one of five predefined categories. The Decker system also includes a classification of both the correlation between radiology and pathology and the actions required on this basis.To report on the five-year results of the implementation of the Decker system in our pretreatment multidisciplinary breast team.Retrospective analysis of patients operated on because of breast diseases or appearing at the multidisciplinary breast team during the period between 2000 and 2014.Of 1716 cases discussed, 1531 were solved by non-operative diagnostics, 157 required diagnostic excisions; 1122 cases (65%) proved to be malignant. Malignancy was diagnosed by core needle biopsies in 69% of the cases. The non-operative approach was unsuccessful, delayed or wrong in 14 cases.Breast lesions need to be evaluated in a multidisciplinary setting. The Decker-system is suitable for the recording and analysis of the correlation between radiologic/physical and microscopy findings, and of the ensuing diagnostic/therapeutic actions. Orv Hetil. 2017; 158(28): 1100-1108.

Sarcoidosis is a systemic granulomatous disease of unknown aetiology, which is characterized by bilateral hilar lymphadenopathy and pulmonary disease. Clinically detected cardiac involvement occurs in 5% of sarcoid patients, although cardiac manifestations are discovered in 25% of the cases at autopsy. Sarcoid heart disease frequently causes atrioventricular block. The authors present the case of a 44-year-old man with bradycardia. On admission, second degree Mobitz II, then third degree atrioventricular block was diagnosed. Coronarography showed normal coronary arteries. 2.5 years following artificial Biotronik Entovis DR type pacemaker implantation, sudden cardiac death occurred. Autopsy revealed sarcoidosis with cardiac, pulmonary, splenic, renal and lymph node involvement. In case of young or middle-aged patients with atrioventricular block, it is best to search for other causes if the most common coronary origin can be excluded. Orv Hetil. 2017; 158(27): 1067-1070.

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.

Aim The aim of the present study was to evaluate the risk of axillary non-sentinel lymph-node metastases (ALN) in breast cancer patients presenting macrometastasis (Mac-m) in the sentinel lymph node (SN). Materials and methods A retrospective series of 1464 breast cancers from patients who underwent ALN dissection following the diagnosis of Mac-m in the sentinel node (SN) was studied. In all the cases the MAC-m linear size was evaluated and correlated with presence or absence of non-SN ALN metastases. Results Non-SN metastases were detected in 644∖1464 cases (43.98%). The risk of further axillary metastases ranged from 20.2% (37/183) in cases with Mac-m between 2 and 2.9 mm, to 65.3% (262/401) in cases with Mac-m measuring > 10 mm. The risk of non-SN ALN metastases showed a 3% increase, parallel to each mm increment in SN metastasis size. The data evaluated with the receiver operating characteristic (ROC) curve showed that the Mac-m could be subdivided according to a new cut-off of 7 mm. pT1 tumours, with Mac-m < 7 mm had a risk of non-SN ALN metastases of

Invasive lobular carcinoma of the breast is known to produce intracellular mucin and has been recognized in single-case reports to show extracellular mucin production, as well. This latter morphology is not only rare but must also be under- or misdiagnosed. The aim was to better characterize this entity. Cases of lobular cancers demonstrating extracellular mucin formation were identified in a multi-institutional effort and their clinical and morphologic features were assessed. Immunohistochemistry was used to characterize the E-cadherin-membrane complex, neuroendocrine differentiation, and to some extent, mucin formation. All but one of the eight cases occurred in postmenopausal patients. Extracellular mucin production was present in 5 to 50% of the tumour samples and rarely also appeared in nodal and distant metastases. The tumours were completely E-cadherin negative and showed cytoplasmic p120 positivity. The majority (n = 6/8) was also completely negative for beta-catenin, but two tumours displayed focal beta-catenin positivity in the mucinous area. MUC1 and MUC2 expression was observed in all and 7/8 tumours, respectively; neuroendocrine differentiation was present in only one. Invasive lobular carcinoma with extracellular mucin formation is a rare morphologic variant of lobular carcinoma prone to be misdiagnosed and warranting further studies.

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.

Axillary lymph node dissection has been traditionally perceived as a therapeutic and a staging procedure and unselectively removes all axillary lymph nodes. There still remains some controversy as concerns the survival benefit associated with axillary clearance. Sentinel lymph node biopsy removes the most likely sites of regional metastases, the lymph nodes directly connected with the primary tumour. It allows a more accurate staging and a selective indication for clearing the axilla, restricting this to patients who may benefit of it. Axillary dissection was performed in all patients during the learning phase of sentinel lymphadenectomy, but later only patients with metastasis to a sentinel node underwent this operation. Currently, even some patients with minimal sentinel node involvement, including some with macrometastasis may skip axillary clearance. This review summarizes the changes that have occurred in the surgical management of the axilla, the evidences and controversies behind these changes, along with current recommendations.Az axillaris blokkdissectio emlőrákos betegeknél tradicionálisan egy terápiás és stádiummeghatározó műtét, amely során a hónalji nyirokcsomókat szelektivitás nélkül távolítják el. A mai napig ellentmondásos annak a megítélése, hogy a hónalji nyirokcsomók eltávolításának van-e túlélést befolyásoló szerepe. Az őrszemnyirokcsomó-biopszia során a regionális áttétek legvalószínűbb helyét, a primer tumorral direkt összeköttetésben álló nyirokcsomókat távolítják el, ami lehetőséget ad részletesebb stagingvizsgálatokra, és lehetővé teszi a hónalji blokkdissectio szelektívvé tételét, azon betegeknél indikálva azt, akiknél úgy véljük, ennek haszna lehet. Kezdetben a tanulási fázis alatt minden betegnél, majd csak az őrszemnyirokcsomóban áttétes betegeknél végeztek blokkdissectiót, de újabban bizonyos körülmények között, minimális érintettség mellett akár őrszemnyirokcsomó-makrometasztázisok esetén is biztonságosnak tartják a blokkdissectio elhagyását. Jelen közlemény a hónalj sebészi kezelésének változásait, az ezek mögött álló evidenciákat és ellentmondásokat, valamint az ezekkel kapcsolatos ajánlásokat foglalja össze. Orv. Hetil., 2014, 155(6), 203–215.

Different classes of breast cancers were explored for their positivity for growth hormone-releasing hormone receptors (GHRH-R) in this pilot study, as no systematic evaluation of such tumors has been performed to date. Seventy-two small primary breast carcinomas were evaluated for GHRH-R expression by immunohistochemistry using a polyclonal antibody and a cutoff value of 10% staining. GHRH-R positivity was detected in 58% of all cases, 20/23 (87%) of invasive lobular carcinomas (ILC) and 22/46 (48%) of invasive ductal carcinomas (IDC). GHRH-R positivity was more frequent in grade 2 tumors (86%), as compared to grade 1 (18%) or grade 3 (47%) cancers. GHRH-R expression was not associated with mitotic scores, the Ki-67 labeling indices or nodal status. IDCs with casting-type calcifications on the mammogram showed positivity for GHRH-R in 9/12 (75%) cases. Most importantly, apocrine epithelium, and all 10 apocrine carcinomas added later to the study were GHRH-R-positive. These preliminary results suggest a greater than average GHRH-R expression in ILCs and IDCs associated with casting-type calcifications on the mammogram. Apocrine carcinomas seem uniformly positive for GHRH-R. Whether these findings could indicate a potential role of GHRH-antagonists in targeted treatment of these types of breast cancer requires further studies.

AimsThere is no internationally accepted grading system for lung adenocarcinoma despite the new WHO classification. The architectural grade, the Kadota grade and the Sica score were evaluated and compared with overall (OS) and disease-free survival (DFS).MethodsComprehensive histological subtyping was used in a series of resected stage I lung adenocarcinoma to identify subtypes of adenocarcinomas, the architectural grade, the Kadota grade, the Sica grade, the mitotic count, nuclear atypia, the presence of lymphovascular, vascular and airway propagation, necrosis, and micropapillary or solid growth pattern in any percentage. Statistical models fitted included Kaplan-Meier estimates and Cox proportional hazard regression models.Results261 stage I adenocarcinomas were included. The 5-year survivals of different subtypes were as follows: lepidic (n=40, OS: 92.5%; DFS 91.6%), acinar (n=54, OS: 81.8%; DFS: 68.6%), papillary (n=49, OS: 73.6%; DFS: 61.0%), solid (n=95, OS: 64.7%; DFS: 57.8%) and micropapillary (n=23, OS: 34.8%; DFS: 33.5%). Concerning the architectural grade, there were significant differences between OS and DFS of low and intermediate (pOS=0.005, pDFS<0.001), low and high (pOS<0.001, pDFS<0.001) and intermediate and high grades (pOS=0.002, pDFSConclusionsOf the three grading systems compared, the architectural grade makes the best distinction between the outcome of low-grade, intermediate-grade and high-grade stage I adenocarcinomas.

The proportion of Ki-67 immunostained cells (Ki-67 labeling index, LI) is one of the most commonly used histology methods for estimating proliferation of breast carcinomas. Although the Ki-67 LI is used in treatment decision making, its reproducibility shows variation in different studies, and is generally less then optimal. The aim of the present study was to investigate how the use of a standardized, partially digitalized counting method could affect reproducibility of determining the Ki-67 LI. Thirty breast cancer core-biopsy samples were stained with B-56, SP-6 and MIB-1 monoclonal Ki-67 antibodies. Each sample was represented by a single digital photograph taken with a x20 objective. Four investigators determined the Ki-67 LI on these digital images by estimation, then by counting with the help of a grid overlaid on the same images. Altogether 720 evaluations were made by 4 independent pathologists. Good to excellent correlation was found between estimations and calculations of each observer. Kappa values >0.6 suggest substantial inter-observer agreement when classifying the cases into a 15 % and 30 % cut-off determined three-tiered or a 4-quarter-based four-tiered categorization, which is better than the fair reproducibility gained on the real slides in a previous study. The results also suggest that the type of the antibody may also impact on the consistency of both estimating and calculating the Ki-67 LIs. The results indicate that counting on digital images may significantly improve reproducibility of determining the KI-67 LI. Interestingly, estimation on the same images is not worse, but is obviously faster and more convenient.

Gleason grading is the most common method of prostate cancer classification.The aim of the authors was to assess the reproducibility of Gleason grading among pathologists using the same needle biopsy samples.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.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.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.Bevezetés: A Gleason-gradingrendszer jelenleg a legáltalánosabban elterjedt és ajánlott osztályozás prosztatakarcinóma esetében. Célkitűzés: A szerzők célja a Gleason-osztályozás reprodukálhatóságának felmérése, a patológusok közötti egyetértés vizsgálata volt prosztata-tűbiopszás mintákon. Módszer: 23 patológus vizsgált meg 37 prosztatakarcinómát tartalmazó biopsziás mintát hematoxilin-eozinnal festett metszetekben. A Gleason-pontszámokat (score) négy kategóriába sorolták (2–4, 5–6, 7 és 8–10). A vizsgálók közti egyetértés meghatározására kappa-statisztikát használtak. Eredmények: Az összes vizsgálóra vonatkoztatva, a Gleason-pontszámok alapján kialakított kategóriákba történő besorolás reprodukálhatóságát jellemző kappa-érték 0,49 volt. Az egyes kategóriákra és az összes vizsgálóra vonatkoztatva a legkisebb egyetértést (kappa = 0,15) a jól differenciált karcinómáknál, a legnagyobbat (kappa = 0,65) pedig a rosszul differenciált rákoknál találták. Következtetések: Az eredmények alapján a Gleason-pontszám (score) meghatározása a részt vevő magyar patológusok között mérsékelten reprodukálhatónak bizonyult. A különböző kappa-értékek a daganatok differenciáltságának megfelelően változtak, az irodalmi adatoktól lényegében nem tértek el. A reprodukálhatóság növelése érdekében célzott továbbképzés bevezetése mérlegelendő, ami a leletezés minőségének javulását eredményezhetné. Orv. Hetil., 2013, 154, 1219–1225.

Blood and lymphatic vessel invasion (BLVI) has been long recognised as a category I prognostic factor in colorectal carcinomas (CRC) along with the pT and pN categories of the Tumour-Node-Metastasis system, preoperative carcinoembryonal antigen levels and the residual tumour (R) classification.1 Small vessel involvement includes the invasion of capillary-type vessels (figure 1A), where a reliable distinction between lymphatic and blood capillaries cannot be made on H&E-stained or general endothelial marker (eg, CD31, CD34) immunostained sections. Theoretically, the two types of capillary invasion lead to different consequences: lymphatic vessel invasion (LI) precedes and may be predictive of lymph node metastasis, whereas blood capillaries may be the source of systemic dissemination.2–4 The development of lymphatic endothelial markers like podoplanin (D2-40) or lymphatic endothelial hyaluronan receptor (LYVE-1) enables a distinction between lymphatic and blood capillaries: lymphatics can be defined as D2-40, LYVE-1, CD31 and CD34 positive capillaries, whereas blood capillaries are D2-40 and LYVE-1 negative but can be highlighted by CD31 or CD34 antibodies.4–7 Without such a distinction, small vessel invasion is best recorded as (lympho-)vascular invasion (LVI) or angiolymphatic invasion.1 The impact of LI or LVI is mainly seen in patients with conservative removal (eg, polypectomy) of invasive carcinomas without a resection allowing the histopathologic assessment of the lymph nodes. Figure 1 Types of vessel invasion in colorectal carcinomas. (A) Small vessel (ie, capillary) invasion corresponding to (lympho-)vascular invasion. (B and C) Venous invasion (VI) stained by orcein and elastica van Gieson, respectively. Right to the vein invaded by carcinoma is an accompanying artery, which helps the recognition of VI. (D) Invasion of an artery. ((A) CD34 ×400, (B) Orcein ×100, (C) Elastica van Gieson ×100, (D) Orcein ×100). This figure is only reproduced in colour in the online version. By contrast, large vessel invasion includes venous invasion (VI) …

Multifocality of invasive breast carcinoma has been associated with prognostic disadvantage. Unifocal, multifocal and diffuse distributions have been recently defined for both inasive carcinomas and in situ components, and these have been combined into categories of prognostic relevance. Eight observers analyzed the same series of 30 megaslides from 29 carcinomas, and had to classify the lesions into the three distribution patterns of unifocal, multifocal or diffuse (or not present/non influential). The reproducibility of the distribution patterns of invasive carcinomas was better than that of the in situ carcinoma components, but was still only fair to moderate on the basis of kappa values. The reproducibility of DCIS was poor to slight with some kappa values reflecting agreement by chance only. The results suggest the definitions of these distribution patterns require refinements for a more reliable and reproducible diagnosis if one wants to associate prognostic information with this variable.

Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor. Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12–2.8 and P = 0.035; HR = 1.68, 1.03–2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26–5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18–4.8), eIF5 P = 0.022; HR = 2.55 (1.14–5.7); coexpression P = 0.001; HR = 7.04 (2.22–22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival. Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575–83. ©2016 AACR.

There have been relevant changes in the diagnosis and treatment of breast cancer to implement the updating of the 2010 recommendations made during the 2nd national consensus conference on the disease. Following a wide interdisciplinary consultation, the present recommendations have been finalized after their public discussion at the 3rd Hungarian Consensus Conference on Breast Cancer. The recommendations cover non-operative and intraoperative diagnostics, the work-up of operative specimens, the determination of prognostic and predictive markers and the content of the cytology and histology reports. Furthermore, it touches some special issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, some relevant points about the future.A 2009. évben megtartott II. Emlõrák Konszenzus Konferencia óta a betegség diagnosztikájában és kezelésében is történtek olyan változások, amelyek indokolttá tették a 2010. évben megjelent szakmai ajánlások megújítását. Széles körû szakmaközi szakértõi egyeztetést követõen, a jelen útmutatás a III. Emlõrák Konszenzus Konferencia résztvevõinek nyilvánossága elõtti vitát követõen került véglegesítésre. A szakmai ajánlás külön érinti a non-operatív diagnosztikát, az intraoperatív diagnosztikát, a mûtéti anyagok feldolgozását, a prognosztikai és prediktív faktorok meghatározását, a citológiai, illetve szövettani lelet tartalmi elemeit és egyes speciális kérdéseket, mint a multigénes molekuláris vizsgálatok jelen hazai helyzetét, a patológusok klinikai vizsgálatokban vállalt szerepét és ennek feltételeit, valamint néhány, a jövõ szempontjából irányadó pontot.

Radiation-induced heart disease (RIHD) is a concern during radiotherapy. For its comprehensive study, an in vivo selective heart irradiation model was developed.Sprague-Dawley rats were irradiated with 50 Gy and functional imaging, biochemical (circulating growth differentiation factor-15 (GDF-15), transforming growth factor-beta (TGF-beta) and morphological (picrosirius red staining of the heart) objectives were tested.Signs and symptoms of RIHD occurred12 weeks after irradiation with tachypnea, systolic and diastolic dysfunction, cardiac hypertrophy and body development retardation. Plasma GDF-15 was increased 3, 12 and 26, while plasma TGF-beta was increased 12 weeks after irradiation. At autopsy, extensive pleural fluid was found in the irradiated animals. Interstitial fibrosis could be reliably detected and quantified in irradiated hearts after a follow-up time of 19 weeks.The studied parameters could be used in future experiments for testing protective agents for prevention of radiation heart injury.

The introduction of sentinel lymph node biopsy in early breast cancer patients has substantially changed the approach to axillary management traditionally consisting of lymph node dissection. It has also rendered it more sophisticated. Several factors influence the decision on whether a patient should be offered sentinel lymph node biopsy or axillary lymph node dissection after the biopsy or instead of it. The potential options have been combined into an algorithm, of which each step is explained with the most important evidences in support or against summarized.

The optimal locoregional treatment of patients diagnosed with sentinel node (SN) micrometastasis is controversial. A previously reported and validated nomogram was used to calculate the risk of non-SN metastasis in patients with SN micrometastasis over a period of 2 years. Patients were given detailed information about the risk, consequences and treatment options of non-SN involvement, the risk and potential complications of unnecessary completion axillary lymph node dissection (ALND), the imperfectness of the nomogram, and other factors that may influence their selection of further treatment. They also received a questionnaire to monitor factors influencing their decisions. Of the 25 patients participating in the study, 10 have opted for ALND. The only factor that seemed to influence their choice was fear from disease recurrence. Giving detailed information to SN micrometastatic patients is a patient-centered alternative to current recommendations on performing ALND in all such patients or omitting ALND in all of them.

Sentinel lymph node (SN) biopsy offers the possibility of selective axillary treatment for breast cancer patients, but there are only limited means for the selective treatment of SN-positive patients. Eight predictive models assessing the risk of non-SN involvement in patients with SN metastasis were tested in a multi-institutional setting. Data of 200 consecutive patients with metastatic SNs and axillary lymph node dissection from each of the 5 participating centres were entered into the selected non-SN metastasis predictive tools. There were significant differences between centres in the distribution of most parameters used in the predictive models, including tumour size, type, grade, oestrogen receptor positivity, rate of lymphovascular invasion, proportion of micrometastatic cases and the presence of extracapsular extension of SN metastasis. There were also significant differences in the proportion of cases classified as having low risk of non-SN metastasis. Despite these differences, there were practically no such differences in the sensitivities, specificities and false reassurance rates of the predictive tools. Each predictive tool used in clinical practice for patient and physician decision on further axillary treatment of SN-positive patients may require individual institutional validation; such validation may reveal different predictive tools to be the best in different institutions.

It is well accepted that detailed analysis of sentinel lymph nodes (SLNs) may upstage breast cancer, but generally involves the identification of low-volume metastases (including isolated tumor cells and clusters). Although several guidelines recommend therapeutic interventions for micrometastases, there is also evidence supporting therapeutic interventions only for macrometastases. There is also evidence in support of means of regional disease control other than axillary lymph node dissection (ALND). The pathologic evaluation of SLNs should consider the clinical setting. Intraoperative assessment is indicated only if ALND is an immediate interventional option for SLN positivity. Generally, hematoxylin and eosin-stained sections taken at 2-mm step intervals are sufficient to disclose macrometastases, but if micrometastases are also considered in further treatment planning, smaller intervals and immunohistochemistry as well as quantitative molecular methods may also be considered.

Male breast cancer remains understudied despite evidence of rising incidence. Using a co-ordinated multi-centre approach, we present the first large scale biomarker study to define and compare hormone receptor profiles and survival between male and female invasive breast cancer. We defined and compared hormone receptor profiles and survival between 251 male and 263 female breast cancers matched for grade, age, and lymph node status. Tissue microarrays were immunostained for ERα, ERβ1, -2, -5, PR, PRA, PRB and AR, augmented by HER2, CK5/6, 14, 18 and 19 to assist typing. Hierarchical clustering determined differential nature of influences between genders. Luminal A was the most common phenotype in both sexes. Luminal B and HER2 were not seen in males. Basal phenotype was infrequent in both. No differences in overall survival at 5 or 10 years were observed between genders. Notably, AR-positive luminal A male breast cancer had improved overall survival over female breast cancer at 5 (P = 0.01, HR = 0.39, 95% CI = 0.26-0.87) but not 10 years (P = 0.29, HR = 0.75, 95% CI = 0.46-1.26) and both 5 (P = 0.04, HR = 0.37, 95% CI = 0.07-0.97) and 10 years (P = 0.04, HR = 0.43, 95% CI = 0.12-0.97) in the unselected group. Hierarchical clustering revealed common clusters between genders including total PR-PRA-PRB and ERβ1/2 clusters. A striking feature was the occurrence of ERα on distinct clusters between genders. In female breast cancer, ERα clustered with PR and its isoforms; in male breast cancer, ERα clustered with ERβ isoforms and AR. Our data supports the hypothesis that breast cancer is biologically different in males and females suggesting implications for clinical management. With the incidence of male breast cancer increasing this provides impetus for further study.

Cserni G. Benign apocrine papillary lesions of the breast lacking or virtually lacking myoepithelial cells – potential pitfalls in diagnosing malignancy. APMIS 2012; 120: 249–52. Two cases of apocrine papillary lesions are presented, in which myoepithelial cells were not visualized on hematoxylin and eosin-stained slides. A complex sclerosing papillary lesion did not exhibit myoepithelial cells on p63 and CD10 immunostaining, although a thin rim of myoepithelial cell cytoplasm was revealed by smooth muscle actin, calponin, and S100 immunostains. In the other lesion, without sclerosis, myoepithelium was not detected in the central papillary cores or at the periphery of the cystic wall on hematoxylin and eosin-stained sections or with any of the myoepithelial markers tested, although two small wall areas did display the presence of myoepithelium. These two cases strengthen the view that the lack of myoepithelium alone in apocrine lesions cannot be equated with malignancy. As recent literature reports have demonstrated that myoepithelial cells may be missing from benign apocrine changes and proliferations of different types, a reconsideration of the diagnostic criteria of the malignancy of such lesions appears essential.

The TNM is the most widely used staging system for malignant disease. Its seventh edition has been updated in several respects, but there still remain controversial issues requiring further improvement. The current review highlights the items related to early breast cancer. It deals separately with contradictions found in the online resources, those related to the different categories, the stages, grade and finally it places the TNM in the milieu of biological markers often used to tailor individual patient treatment. Although TNM has lost its nearly unique role in assessing patient risk and in selecting systemic therapy for breast cancer, it is still of importance in reflecting the anatomic extent of disease in a categorical way, selecting surgical treatment and comparing similar tumours of different extent.

Isolated tumour cells and micrometastases represent two different staging categories and are often dealt with differently when identified in sentinel lymph nodes of breast cancer patients. The reproducibility of these categories was found to be suboptimal in several studies. The new edition of the TNM (Tumour Node Metastasis) is expected to improve the reproducibility of these categories. Fifty cases of possible low-volume nodal involvement were represented by one to four digital images and were analysed by members of the European Working Group for Breast Screening Pathology (EWGBSP). The kappa value for interobserver agreement of the pN (TNM) staging categories and of the isolated tumour cells category were 0.55 and 0.56 reflecting moderate reproducibility, and the kappa of the micrometastatic category (0.62) reflected substantial reproducibility. This is an improvement over the results gained on the basis of the previous edition of the TNM. Maximal adherence to the category definitions supplemented by explanatory texts in the staging manual should result in more homogeneous nodal staging of breast cancer.

Estrogen receptor (ER) testing has become an important part of breast cancer reporting as the ER status is a predictor of hormonal treatment efficacy. Progesteron receptors (PR) are often tested in parallel, and the best response to hormonal manipulations can be expected in tumors positive for both receptors. The existence of breast cancers with an ER negative and PR positive phenotype is controversial. A series of cases with this phenotype were reevaluated to clarify the existence and the frequency of this entity. A total of 205/6587 (3.1%; range of the rate per department: 0.3-7.1%.) cases reported to have the ER-negative and PR-positive status by immunohistochemistry were collected from 9 Hungarian departments. After careful reevaluation of the tumor slides and control tissues with a 1% cut-off for positivity and restaining of the questionable cases, all but 1 of the reevaluable 182 cases changed their original phenotype. Most cases converted to dual positives (n = 124) or dual negatives (n = 31) or unassessable / questionable. ER-negative and PR-positive breast cancers are very rare if existing. Such a phenotype should prompt reassessment.

The number of positive axillary nodes is a strong prognostic factor in breast cancer, but is affected by variability in nodal staging technique yielding varying numbers of excised nodes. The nodal ratio of positive to excised nodes is an alternative that could address this variability. Our 2006 review found that the nodal ratio consistently outperformed the number of positive nodes, providing strong arguments for the use of nodal ratios in breast cancer staging and management. New evidence has continued to accrue confirming the prognostic significance of nodal ratios in various worldwide population settings. This review provides an updated summary of available data, and discusses the potential application of the nodal ratio to breast cancer staging and prognostication, its role in the context of modern surgical techniques such as sentinel node biopsy, and its potential correlations with new biologic markers such as circulating tumor cells and breast cancer stem cells.

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.

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.

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.

Aims: To examine the frequency of extracapsular extension (ECE) of sentinel lymph node (SLN) metastases in breast cancer according to metastasis size, and to characterise ECE in micometastases. Methods: If initially negative, SLNs were examined by step-sectioning and immunohistochemistry. Non-SLNs were not subjected to enhanced pathology. Positive axillary SLNs were analysed for metastasis size and the presence of ECE. Results: Of 885 successful SLN biopsy cases, 343 (39%) exhibited SLN involvement, and 115 (34%) displayed ECE. Of the latter, 107 underwent axillary dissection, and 63 (59%) of these demonstrated non-SLN metastases. The presence of ECE correlated with metastasis size (coefficient 0.92). Eight (10%) of the 84 micrometastatic SLN cases had ECE, and two of these were associated with non-SLN metastases. Only ECE and only the intraparenchymal nodal part of the micrometastasis were seen in some sections of five cases each. The primary tumours of the micrometastatic cases with ECE were non-high-grade and often of tubular type. Conclusions: The frequency of ECE increases with increasing nodal metastasis size. Minimal nodal metastases with ECE may represent a distinct pattern of nodal involvement with a predominant capsular and extracapsular, but only minimal or no nodal parenchymal component, predominantly seen in non-poorly differentiated and/or tubular carcinomas. This presentation of nodal metastasis can sometimes pose differential diagnostic problems, and should be distinguished from massive metastases presenting with ECE because it does not seem to be so commonly associated with non-SLN metastases or a massive metastatic load to the axilla as ECE of SLN metastases in general.

Sentinel lymph node (SN) biopsy has become increasingly used for the staging of breast carcinoma, resulting in the upstaging of this disease, and this has led to concerns with regard to what should be considered a positive SN. Factors influencing the positive staging of an SN include metastasis size, the method used for metastasis detection, the definition of metastasis and the individual pathologist. Until evidence to the contrary emerges, an SN should be considered positive if metastases (nodal involvement >0.2mm in the largest dimension) are detected in it by histology. A target size should be identified, and SNs, as the most likely sites of nodal metastases, should be searched systematically to find (nearly) all of the targeted metastases. The European guidelines for SN assessment have set two such target sizes: as a minimum, all metastases >2mm should be identified, and optimally all micrometastases should also be sought.

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

Objective: The identification of myoepithelial cells (MEC) is a valuable clue in the differential diagnosis of breast lesions. A series of breast lesions with occasional absence of or decrease in the staining for some MEC markers was analyzed for the expression of a novel marker, p40, and results were compared to the p63 staining profile. Methods: Samples (n = 34) from patients with benign sclerosing lesions (n = 11), ductal carcinoma in situ (n = 13) and adenomyoepithelial lesions (n = 10) and associated normal breast tissues (n = 31) were selected to evaluate the differential expression of p40 and p63 using immunohistochemistry. Triple-negative, cytokeratin 5 (CK5)-expressing invasive breast carcinomas (n = 19) were also assessed for p40 expression. Results: Normal structures showed similar diffuse and strong MEC positivity using p40 and p63 in all 31 cases. The two antibodies performed similarly in all 34 breast lesions acknowledged to present altered expression of MEC markers; focal losses of expression occurred in a parallel fashion. CK5-positive carcinomas expressed p40 more frequently than p63 (18/19 vs. 8/19) and the staining was more marked. Conclusions: It seems that both antibodies can be used interchangeably for MEC identification, but show differences in the labeling at least in a subset of tumor cells in triple-negative carcinomas.

Sentinel lymph nodes (SLNs) are the most likely site of regional metastasis. Their step sectioning and cytokeratin immunohistochemistry (IHC) result in the upstaging of breast cancer. The heterogeneity of histologic methods is partially responsible for differences in nodal upstaging of the disease in different reports. Intraoperative assessment might be done by both frozen sections and imprint cytology; both methods have advantages and disadvantages. Several guidelines relating to the histopathology of sentinel nodes, including the recent European Working Group for Breast Screening Pathology guidelines, are briefly summarized. These latter advocate multilevel assessment of grossly or intraoperatively negative sentinel nodes with levels separated by a maximum of 1 mm and allow IHC in their assessment, although this latter method is not mandatory. Both methods of intraoperative evaluation are allowable. There are also minimum requirements for the reports on sentinel node histology. For example, the reports should include the extent of nodal involvement, the method used for their identification, and preferably the method used for investigating the sentinel nodes, even if the results are negative. These guidelines are intended to form the basis for national guidelines in European countries.

Summary The reproducibility of diagnosing isolated tumor cells (ITC) and micrometastases has been recently tested by expert breast pathologists, but might be different in a community setting. Digital images of 50 cases of low volume nodal involvement were circulated among pathologists from the Piedmont region (Italy) and from the Helios Medical Center in Berlin. Participants were asked to categorize the lesions into micrometastasis, ITC or others. The test was performed on the basis of a previous consensus statement. Kappa statistics were used for the assessment of interobserver variability. The kappa values for the consistency of categorizing cases were 0.47 and 0.57 for the regional and the institutional tests, respectively. Our study suggests that the reproducibility of diagnosing micrometastases and ITC in a community setting may reach that of experts, but is in the moderate range, and this may interfere with studies trying to solve the prognostic significance of these diagnostic categories.

SUMMARY. We aim to elaborate upon a basically new animal model for esophageal resection. A total of 17 operations on 10 dogs were performed in order to develop a model in which resection of the cervical part of the esophagus involves two steps. The first step comprises omental flap transplantation from the abdomen to the cervical region by a microsurgical method, this omental flap improving the blood supply to the organ (prevascularization). The second step is segmental resection of the esophagus 14 days later. Of the five transplanted grafts, four still survived one week after the operation; for technical reasons, one flap had thrombotized. In the two long-term survival cases with esophageal resection after prevascularizastion, there were no major complications: the resections were successful, and the omental flap ‘grew into’ the tissue structure of the esophagus, assisting the healing of the anastomosis. Segmental resection of the cervical part of the esophagus was performed successfully via a new type of operation on dogs.

Sentinel lymph node biopsy is an accurate method for the detection of axillary metastases in cases of breast carcinoma and is of value as a replacement for axillary dissection. There is variation, however, in the methods and protocols used for the histopathological evaluation of sentinel lymph nodes, standardisation of which will be required if results of sentinel lymph node analysis are to be used to stratify patients into prognostic groups. The significance of micrometastases, isolated tumour cells (ITCs) and the value of immunohistochemistry are also matters for further definition. In this Expert Opinion we present reviews from two authors, providing American and European perspectives on the approach to sentinel lymph node evaluation.

SUMMARY BACKGROUND DATA: The purpose of this study was to determine the type of relationship between tumor size and mortality in early breast carcinoma. METHODS: The data was abstracted from 83,686 cases registered in the Surveillance, Epidemiology, and End Results Program of women diagnosed with primary breast carcinoma between 1988 and 1997 presenting with a T1-T2 lesion and no metastasis in whom axillary node dissection was performed: 58,070 women were node-negative (N0) and 25,616 were node-positive (N+). End point was death from any cause. Tumor size was modeled as a continuous variable by proportional hazards using a generalized additive models procedure. RESULTS: Functionally, a Gompertzian expression exp(-exp(-(size-15)/10)) provided a good fit to the effect of tumor size (in millimeters) on mortality, irrespective of nodal status. Quantitatively, for tumor size between 3 and 50 mm, the increase of crude cumulative death rate (number of observed deaths divided by the number of patients at risk) increased with size from 10% to 25% for N0 and from 20% to 40% for N+. CONCLUSIONS: The functional relationship of tumor size with mortality is concordant with current knowledge of tumor growth. However, its qualitative and quantitative independence of nodal status is in contradiction with the prevailing concept of sequential disease progression from primary tumor to regional nodes. This argues against the perception that nodal metastases are caused by the primary tumor.

BACKGROUND The latest edition of the tumor-lymph node-metastasis (TNM) classification of malignant tumors distinguishes between isolated tumor cells (pN0) and micrometastases (pN1mi). The reproducibility of these categories has not been assessed previously. METHODS Digital images from 50 cases with low-volume lymph node involvement from axillary sentinel lymph nodes were circulated twice for evaluation (Evaluation Rounds 1 and 2) among the members of the European Working Group for Breast Screening Pathology, and the members were asked to categorize lesions as micrometastasis, isolated tumor cells, or something else and to classify each case into a pathologic lymph node (pN) category of the pathologic TNM system. Methods for improving the low reproducibility of the categorizations were discussed between the two evaluation rounds. κ Statistics were used for the assessment of interobserver variability. RESULTS The κ value for the consistency of categorizing low-volume lymph node load into micrometastasis, isolated tumor cells, or neither of those changed from 0.39 to 0.49 between Evaluation Rounds 1 and 2, but it was slightly lower for the pN categories (0.35 and 0.44, respectively). Interpretation of the definitions of isolated tumor cells (especially with respect to their localization within the lymph node), lack of guidance on how to measure them if they were multiple, and lack of any definitions for multiple simultaneous foci of lymph node involvement were listed among the causes of discordant diagnoses. CONCLUSIONS The results of the current study indicated that the definitions available have minor contradictions and do not permit a reproducible distinction between micrometastases and isolated tumor cells. Refinement of these definitions, therefore, is required. One refinement that may improve reproducibility is suggested in this report. Cancer 2005. © 2004 American Cancer Society.

BackgroundThe need for further axillary treatment in patients with breast cancer with low-volume sentinel node (SN) involvement (micrometastases or smaller) is controversial.MethodsTwenty-five studies reporting on non-SN involvement associated with low-volume SN involvement were identified using Medline and a meta-analysis was performed.ResultsThe weighted mean estimate for the incidence of non-SN metastases after low-volume SN involvement is around 20 per cent, whereas this incidence is around 9 per cent if the SN involvement is detected by immunohistochemistry (IHC) alone. Subset analyses suggest that studies with axillary dissection after any type of SN involvement result in somewhat higher estimates than studies allowing omission of axillary clearance, as do studies with more detailed histological evaluation of the SN compared with those with a less intensive histological protocol. Higher-quality papers yield lower pooled estimates than lower-quality papers.ConclusionThe risk of non-SN metastasis with a low-volume metastasis in the SN is around 10–15 per cent, depending on the method of detection of SN involvement. This should be taken into account when assessing the risk of omission of axillary dissection after a positive SN biopsy yielding micrometastatic or immunohistochemically positive SNs.

Contains fulltext : 58820.pdf (Publisher’s version ) (Closed access) To assess the variability of oestrogen receptor (ER) testing using immunocytochemistry, centrally stained and unstained slides from breast cancers were circulated to the members of the European Working Group for Breast Screening Pathology, who were asked to report on both slides. The results showed that there was almost complete concordance among readers (kappa=0.95) in ER-negative tumours on the stained slide and excellent concordance among readers (kappa=0.82) on the slides stained in each individual laboratory. Tumours showing strong positivity were reasonably well assessed (kappa=0.57 and 0.4, respectively), but there was less concordance in tumours with moderate and low levels of ER, especially when these were heterogeneous in their staining. Because of the variation, the Working Group recommends that laboratories performing these stains should take part in a external quality assurance scheme for immunocytochemistry, should include a tumour with low ER levels as a weak positive control and should audit the percentage positive tumours in their laboratory against the accepted norms annually. The Quick score method of receptor assessment may also have too many categories for good concordance, and grouping of these into fewer categories may remove some of the variation among laboratories.

This report concerns a 56-year-old-woman presenting PM-SCL autoantibody positive scleroderma with dermatomyositis (scleromyositis) and concomitant interstitial lung fibrosis. The recently observed overlapping syndrome is characterized by the presence of specific autoantibodies, HLA-type association and benign course. A new skin symptom ("mechanic's hands") predicts the disease, in particular the interstitial lung pathology, which is its most relevant internal manifestation.