Publications by authors named "Isabel Amendoeira"

34 Publications

Axillary staging based on molecular analysis: Results of the B-CLOSER-II study.

Pathol Res Pract 2020 Nov 3;216(11):153197. Epub 2020 Sep 3.

Pathology Department, Hospital Universitari Vall d'Hebron, Passeig de la Vall d'Hebron 119-129 08035 Barcelona, Spain; Departament de Ciències morfològiques, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron 119-129 08035 Barcelona, Spain; Spanish Medical Research Network Centre in Oncology (CIBERONC), Spain. Electronic address:

Introduction: Axillary staging (pN) is a strong predictor of outcome in early stage breast cancer yet following the publication of the Z0011 trial there has been an increasing tendency to spare lymph node dissection. Automated molecular detection of cytokeratin 19mRNA by one-step nucleic acid amplification (OSNA) has been demonstrated to be an accurate method to assess sentinel lymph node (SLN) metastasis. In this study we compare histological and molecular methods following complete axillary lymph node dissection (cALND), determine whether molecular axillary staging affects survival, and evaluate the predictive and prognostic value of total tumor load in ALND (AD-TTL) and in all positive nodes (G-TTL).

Material And Methods: Axillary lymph nodes were collected from 102 patients with primary breast cancer with histological confirmation of axillary involvement (cN+) or positive SLN. The central 1-mm portion of each non-SLN was processed for hematoxylin-eosin staining and the remaining tissue was analyzed by OSNA.

Results: Non-SLNs were diagnosed as positive in 72 out of 102 patients (70.6 %) on OSNA compared with only 53 (52 %) on histology (p < 0.01). Thirteen patients would have changed staging if the diagnoses provided had been by molecular methods (p < 0.01), but without a change in prognosis. AD-TTL and G-TTL were predictive of recurrence and mortality.

Conclusions: Compared to molecular detection, histological examination significantly underestimates the frequency of axillary node metastases. However, the increase in pN did not show a clinical effect on survival in those patients.
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http://dx.doi.org/10.1016/j.prp.2020.153197DOI Listing
November 2020

Sentinel node total tumour load as a predictive factor for non-sentinel node status in early breast cancer patients - The porttle study.

Surg Oncol 2020 Mar 25;32:108-114. Epub 2019 Nov 25.

Centro Hospitalar e Universitário São João, Porto, Portugal.

OSNA is a molecular assay for the detection of sentinel node metastasis. TTL emerged as a concept that seems to accurately predict the status of the NSN. Authors tried to confirm this motion. This is a retrospective and multicentric study that analyzed 2164 patients, 579 of whom had positive SN and completion AD. Logistic regression models were performed in order to identify a suitable cutoff to identify patients who benefit from AD. Univariate and multivariate regression analysis showed a relationship between TTL>30000 and the presence of NSN metastasis (OR 2.84, CI 1.99-4.08, p < 0.001). Logistic regression indicated that the cutoff of 30000 copies/μL better discriminates patients with NSN positivity and allows wide use of these criteria. This cutoff value may safely assist clinicians and patients to decide to proceed or not with an AD.
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http://dx.doi.org/10.1016/j.suronc.2019.11.008DOI Listing
March 2020

[Tumors of the thyroid gland. Proposal for the management and study of samples from patients with thyroid neoplasms].

Rev Esp Patol 2020 Jan - Mar;53(1):27-36. Epub 2019 May 7.

IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Department of Pathology, Hospital de S. João, Porto, Portugal.

The recent changes in the classification and staging of thyroid tumors have arisen from the need to provide an adequate response to the exponential increase of thyroid cancer, which, however, has not been accompanied by an increase in mortality. These changes pretend to reduce overdiagnoses of malignancy, unnecessary treatment, side effects as well as cost for the health system. To this end, this article reviews recommendations for the management of thyroid surgical pathology samples with emphasis on the new terminology of the WHO classification. The basic criteria for the diagnosis of malignancy in well-differentiated thyroid carcinomas are reviewed and the criteria for NIFTP (non-invasive follicular tumor with papillary-like nuclear features) diagnosis are updated. Recommendations for the elaboration of the pathological report are also included.
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http://dx.doi.org/10.1016/j.patol.2019.03.003DOI Listing
March 2021

Pre-operative management of Pleomorphic and florid lobular carcinoma in situ of the breast: Report of a large multi-institutional series and review of the literature.

Eur J Surg Oncol 2019 Dec 5;45(12):2279-2286. Epub 2019 Jul 5.

Department of Histopathology, St. Vincent's University Hospital, Dublin, and School of Medicine, University College, Dublin, Ireland. Electronic address:

Background: Pleomorphic and Florid Lobular carcinoma in situ (P/F LCIS) are rare variants of LCIS, the exact nature of which is still debated.

Aim: To collect a large series of P/F LCIS diagnosed on preoperative biopsies and evaluate their association with invasive carcinoma and high grade duct carcinoma in situ (DCIS). Data obtained were compared with those reported in the literature.

Methods: A multi-institutional series of P/F LCIS was retrieved. All cases were diagnosed on pre-operative biopsies, which was followed by an open surgical excision. Data on post-operative histopathology were available. A literature review was performed.

Results: A total of 117 cases were collected; invasive carcinoma and/or DCIS was present in 78/117 cases (66.7%). Seventy cases of P/F LCIS were pure on biopsy and 31 of these showed pathological upgrade in post-surgical specimens. Pre-operative biopsy accuracy was 47/78 (60.3%); pre-operative biopsy underestimation of cancer was 31/78 (39,7.%). In the literature review papers, invasive carcinoma or DCIS was associated with 274 of 418 (65.5%) cases of P/F LCIS. Pre-operative biopsy accuracy was 66% (181/274) whereas pre-operative biopsy underestimation of cancer was 33.9% (93/274).

Conclusions: The data presented here indicate that P/F LCIS is frequently associated with invasive carcinoma or high grade DCIS and that pre-operative biopsy is associated with an underestimation of malignancy. Open surgery is indicated when P/F LCIS is diagnosed pre-operatively.
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http://dx.doi.org/10.1016/j.ejso.2019.07.011DOI Listing
December 2019

European Perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: Proceedings of an Interactive International Symposium.

Thyroid 2019 01 7;29(1):7-26. Epub 2019 Jan 7.

18 Department of Endocrinology and Metabolism, Endocrine Tumor Center at WTZ, Essen University Hospital, Essen, Germany.

Background: The American Thyroid Association (ATA) management guidelines for patients with thyroid nodules and differentiated thyroid cancer (DTC) are highly influential practice recommendations. The latest revision appeared in 2015 ("ATA 2015"). These guidelines were developed predominantly by North American experts. European experts frequently have different perspectives, given epidemiological, technological/methodological, practice organization, and medicolegal differences between the respective regions.

Summary: Divergent viewpoints were the focus of an invited symposium organized by the European Association of Nuclear Medicine involving 17 European thyroidologists, four ATA Guidelines Taskforce members, and an audience of 200 international experts. The group discussed the preoperative assessment of thyroid nodules, surgery and the role of pathology, radioiodine (RAI) therapy (RAIT), the assessment of initial therapy and dynamic risk stratification, and the treatment of persistent disease, recurrences, and advanced thyroid cancer. The dialogue resulted in this position paper contrasting European and ATA 2015 perspectives on key issues. One difference pertains to the permissiveness of ATA 2015 regarding lobectomy for primary tumors ≤4 cm. European panelists cited preclusion of RAIT, potential need for completion thyroidectomy, frequent inability to avoid chronic thyroid hormone replacement, and limitations of supportive evidence as arguments against widely applying lobectomy. Significant divergence involved ATA 2015's guidance regarding RAIT. European panelists favored wider use of postoperative RAIT than does ATA 2015. Rationales included the modality's association with favorable patient outcomes and generally limited toxicity, and lack of high-quality evidence supporting withholding RAIT. Additionally, European panelists favored recombinant human thyrotropin (rhTSH) in more settings than does ATA 2015, citing avoidance of hypothyroid morbidity and quality-of-life impairment, without apparent sacrifice in oncologic outcomes. Based on clinical evidence plus theoretical advantages, European experts advocated dosimetric versus fixed-activity RAIT approaches for advanced DTC. European panelists noted that the ATA 2015 risk-stratification system requires information sometimes unavailable in everyday practice. ATA 2015 recommendations regarding RAI-refractory DTC should consider potential palliative benefits of RAIT in patients who also have RAI-susceptible lesions.

Conclusions: European panelists suggested modifications to approximately one-third of ATA 2015 recommendations. Varying European and ATA 2015 perspectives can stimulate analysis and discussion of the literature and performance of primary research to resolve discrepant recommendations and potentially improve patient outcomes.
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http://dx.doi.org/10.1089/thy.2017.0129DOI Listing
January 2019

Cribriform-morular variant of thyroid carcinoma: a neoplasm with distinctive phenotype associated with the activation of the WNT/β-catenin pathway.

Mod Pathol 2018 08 21;31(8):1168-1179. Epub 2018 May 21.

i3S Instituto de Investigação e Inovação em Saúde, Porto, Portugal.

Cribriform-morular variant of thyroid carcinoma is classically associated with familial adenomatous polyposis but, it can also occur as a sporadic neoplasm. This neoplasm is much more frequently observed in women than in men (ratio of 61:1). In familial adenomatous polyposis patients, tumors are generally multifocal and/or bilateral (multinodular appearance), whereas in the sporadic cases tumors tend to occur as single nodules. The tumors are well delimited, and characteristically show a blending of follicular, cribriform, papillary, trabecular, solid, and morular patterns. Neoplastic cells are tall or cuboidal with the occasional nuclear features of classic papillary thyroid carcinoma. The morules include cells with peculiar nuclear clearing and show positivity for CDX2 and CD10. Angioinvasion and capsular invasion have been described in about 30 and 40% of cases, respectively, with lymph node metastases in less than 10% of patients and distant metastases in 6%. Although this tumor has good prognosis, neuroendocrine and/or poor differentiation have been associated with aggressive behavior. Tumor cells can be focally positive or negative for thyroglobulin, but are always positive for TTF-1, estrogen and progesterone receptors, and negative for calcitonin and cytokeratin 20. Nuclear and cytoplasmic staining for β-catenin is the hallmark of this tumor type; this feature plays a role in fine needle aspiration biopsy. Cribriform-morular variant of thyroid carcinoma has a peculiar endodermal (intestinal-like) type phenotype, activation of the WNT/β-catenin signaling pathway, and belongs to the non-BRAF-non-RAS subtype of the molecular classification of thyroid tumors. Elevated expression of estrogen and progesterone receptors and activation of the WNT/β-catenin pathway may prove useful as putative therapeutic targets in cases that do not respond to conventional therapy. Clinicians should be alerted to the possibility of familial adenomatous polyposis when a diagnosis of cribriform-morular variant of thyroid carcinoma is made. Instead of being considered as a variant of papillary thyroid carcinoma its designation as cribriform-morular thyroid carcinoma seems more appropriate.
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http://dx.doi.org/10.1038/s41379-018-0070-2DOI Listing
August 2018

The Curious Case of Pseudocysts in Breast Cancer Specimens: An Alteration Associated With Hydrogel-Based Breast Biopsy Markers.

Int J Surg Pathol 2019 Apr 24;27(2):189-191. Epub 2018 Apr 24.

1 Department of Pathology, Centro Hospitalar de São João, Porto, Portugal.

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http://dx.doi.org/10.1177/1066896918769377DOI Listing
April 2019

Breast sebaceous carcinoma-a rare entity. Clinico-pathological description of two cases and brief review.

Virchows Arch 2018 May 19;472(5):877-880. Epub 2018 Mar 19.

Department of Pathology, Centro Hospitalar São João, Porto, Portugal.

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http://dx.doi.org/10.1007/s00428-018-2327-zDOI Listing
May 2018

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): impact on the reclassification of thyroid nodules.

Endocr Relat Cancer 2018 04 9;25(4):R247-R258. Epub 2018 Feb 9.

Department of Pathology, Centro Hospitalar S. João, Porto, Portugal.

The 2017 edition of the WHO book on Classification of Tumours of Endocrine Organs includes a new section entitled 'Other encapsulated follicular-patterned thyroid tumours', in which the newly created NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) is identified and described in detail. Despite deleting the word 'carcinoma' from its name, NIFTP is not a benign tumor either and is best regarded as a neoplasm with 'very low malignant potential'. The main goal of the introduction of NIFTP category is to prevent overdiagnosis and overtreatment. Sampling constraints, especially when dealing with heterogeneous and/or large nodules, and difficulties in the invasiveness evaluation, are the major weaknesses of the histological characterization of NIFTP. At the cytological level, NIFTP can be separated from classic papillary carcinoma (cPTC) but not from encapsulated, invasive follicular variant PTC. The impact of NIFTP individualization for cytopathology is the drop of rates of malignancy for each Bethesda category in general and for indeterminate categories in particular. The biggest impact will be seen in institutions with a high frequency of FVPTC. The introduction of NIFTP has changed the utility of predictive values of molecular tests because mutations and rearrangements are frequently detected in NIFTP. This turns less promising the application of mutation detection panels as indicators of malignancy and will probably contribute to switch to a rule-out approach of molecular testing. Selection for surgery will go on being determined by a combined detection of clinical, cytological and ultrasound suspicious features.
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http://dx.doi.org/10.1530/ERC-17-0513DOI Listing
April 2018

Is Regression after Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer Different in Sentinel and Non-sentinel Nodes?

Pathol Oncol Res 2018 Jan 8;24(1):167-170. Epub 2017 Apr 8.

Department of Pathology, University of Szeged, Állomás u 1, Szeged, 6725, Hungary.

Tumor draining sentinel lymph nodes (SLNs) are the sites of selective changes as compared to non-SLNs. They show features of tumor-reactive lymphadenopathy, including increased total number of functional blood vessels, but a relative immunosuppressed status has also been described in them. We explored the hypothesis of a selective regression or non-regression in SLNs versus non-SLNs in 142 patients with 110 estrogen receptor-positive and 32 estrogen receptor-negative tumors undergoing both SLN biopsy and axillary lymph node dissection after neoadjuvant therapy by assessing the tumoral (metastatic) and regression statuses of SLNs and non-SLNs separately. Of the 89 cases with signs of nodal regression, 22 cases (25%) were in favor of a selective non-regression in SLNs, 18 cases (20%) were supportive of a selective and more pronounced regression in the SLNs and the remaining showed equal degrees of regression or non-regression in SLNs and non-SLNs. The results indicate that there is no obvious difference in the degree of regressive histological changes shown by SLNs and NSLNs. Therefore, this phenomenon may not be a major contributor to the higher false negative rate of SLN biopsy after neoadjuvant treatment.
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http://dx.doi.org/10.1007/s12253-017-0229-zDOI Listing
January 2018

P-cadherin: a useful biomarker for axillary-based breast cancer decisions in the clinical practice.

Mod Pathol 2017 05 13;30(5):698-709. Epub 2017 Jan 13.

Instituto de Investigação e Inovação em Saúde (i3s), Universidade do Porto, Porto, Portugal.

Axillary lymph node metastases represent the most powerful breast cancer prognostic factor, dictating disease staging and clinical therapeutic decisions. Nonetheless, breast cancer patients with positive lymph nodes still exhibit a heterogeneous behavior regarding disease progression. Stem-like subpopulations of cancer cells show high migratory and metastatic capacity, thus we hypothesize that breast cancer stem cell markers evaluation in metastasized lymph nodes could provide a more accurate prediction of patient's prognosis. Therefore, the expression profile of P-cadherin, CD44, and CD49f, which have been already associated to stem cell properties in breast cancer, has been evaluated by immunohistochemistry in a series of 135 primary tumors and matched axillary lymph node metastases from 135 breast cancer patients. Taking in consideration the expression of the stem cell markers only in axillary nodes, P-cadherin was the only biomarker significantly associated with poor disease-free and overall patient's survival. Moreover, although a concordant expression between primary tumors and matched lymph nodes has been found in the majority of the cases, a small but significant percentage displayed divergent expression (18.2-26.2%). Remarkably, although CD44 and CD49f changes between primary tumors and lymph node metastasis did not impact survival, the cases that were positive for P-cadherin in lymph node metastases being negative in the primary tumor, presented the worst disease-free and overall survival of the whole series. Accordingly, negative cases for this marker in the lymph nodes with positive expression in the matched breast carcinoma demonstrated a better prognosis, which overlapped with tumors that were negative in both sites. P-cadherin and CD49f gain of expression was mainly found in triple-negative carcinomas. Our results indicate for the first time that the evaluation of P-cadherin expression in lymph node metastases is an important predictor of disease outcome, being a putative valuable marker for axillary-based breast cancer decisions in the clinical practice.
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http://dx.doi.org/10.1038/modpathol.2016.232DOI Listing
May 2017

Positive margins prediction in breast cancer conservative surgery: Assessment of a preoperative web-based nomogram.

Breast 2016 Aug 18;28:167-73. Epub 2016 Jun 18.

Medical Faculty of Porto University, Alameda Prof. Hernâni Monteiro, Porto 4200 - 319, Portugal; Breast Center, São João University Hospital, Alameda Prof. Hernâni Monteiro, Porto 4200 - 319, Portugal.

Margin status of the surgical specimen has been shown to be a prognostic and risk factor for local recurrence in breast cancer surgery. It has been studied as a topic of intervention to diminish reoperation rates and reduce the probability of local recurrence in breast conservative surgery (BCS). This study aims to validate the Dutch BreastConservation! nomogram, created by Pleijhus et al., which predicts preoperative probability of positive margins in BCS. Patients with diagnosis of breast cancer stages cT1-2, who underwent BCS at the Breast Center of São João University Hospital (BC-CHSJ) in 2013-2014, were included. Association and correlation were evaluated for clinical, radiological, pathological and surgical variables. Multivariable logistic regression and ROC curves were used to assess nomogram parameters and discrimination. In our series of 253 patients, no associations were found between margin status and other studied variables (such as age or family history of breast cancer), except for weight (p-value = 0.045) and volume (p-value = 0.012) of the surgical specimen. Regarding the nomogram, a statistically significant association was shown between cN1 status and positive margins (p-value = 0.014). No differences were registered between the scores of patients with positive versus negative margins. Discrimination analysis showed an AUC of 0.474 for the basic and 0.508 for the expanded models. We cannot assume its external validation or its applicability to our cohort. Further studies are needed to determine the validity of this nomogram and achieve a broader view of currently available tools.
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http://dx.doi.org/10.1016/j.breast.2016.05.009DOI Listing
August 2016

Anal HR-HPV prevalence assessed with the cobas HPV Test in an HIV-infected population of men who have sex with men.

Porto Biomed J 2016 Mar-Apr;1(1):29-31. Epub 2016 Mar 1.

Serviço de Anatomia Patológica, São João Hospital Center, Porto, Portugal.

Background: Anal squamous cell cancer is an HPV associated disease, highly prevalent in HIV-infected men who have sex with men (MSM). We evaluate the prevalence of HPV infection in an HIV-positive MSM population attending our hospital. Cytological results are correlated with an HR-HPV genotype.

Methods: From February 2013 to July 2014, 95 anal Thin Prep cytologies and 17 histological specimens were evaluated in 89 HIV-infected MSM. HPV detection (cobas HPV Test) was done in 78 patients. Patients with a positive cytological result were biopsied according to the recommendations of the European Society for Medical Oncology Clinical Practical Guidelines. The STATVIEW statistical computer program was used.

Results: The mean age was 37 years. Cytological results: 40% - NILM, 17.9% - ASCUS, 24.2% - LSIL, 4.2% - HSIL and 1.1% - AGC. The overall prevalence of HR-HPV was of 80.8%. In 76.9% of the cases, infection occurred with multiple HR-HPV genotypes. The "other" HR-HPV pattern was the most prevalent HR-HPV genotype. Considering age, HPV-16 prevalence was 50.0% and 28.6% in patients under and over 30 years, respectively. A histological specimen was obtained from 17 patients and 82.4% of them had AIN.

Conclusion: 1 - HIV-infected MSM is a highly HR-HPV genotype infected population; 2 - The multiple infection pattern was the most prevalent; 3 - "Other", an HPV subtype was the most prevalent pattern; 4 - The prevalence of HPV infection and multiplicity of infection was directly related to the severity of the cytological abnormalities and age; 5 - HPV-16 prevalence was more prevalent in patients under 30 years.
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http://dx.doi.org/10.1016/j.pbj.2016.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806940PMC
March 2016

Morphological features and mucin expression profile of breast carcinomas with signet-ring cell differentiation.

Pathol Res Pract 2015 Aug 27;211(8):588-95. Epub 2015 May 27.

Department of Pathology, Centro Hospitalar São João, Porto, Portugal; IPATIMUP, Institute of Molecular Pathology and Immunology, Porto, Portugal.

Signet-ring cells are relatively common in breast cancers but are frequently overlooked. Although previously defined as a subtype of mucin producing carcinomas, breast carcinomas with signet-ring cell (SRC) differentiation nowadays are not considered a distinct entity. The objective of the present study was to characterize the morphological features and mucin expression profile of breast carcinomas with SRC differentiation. All breast carcinomas diagnosed at Centro Hospitalar S. Joao between 1996 and 2006 in which the pathology report mentioned the presence of SRCs (n=11) and four mucinous carcinomas were included in the study. The frequency of SRCs and immunohistochemistry expression of MUC1/MUC2/MUC5AC/MUC6 were evaluated. We confirmed that SRC differentiation can occur in different histological types, including ductal, lobular, mucinous and metaplastic carcinomas. The proportion of SRCs was highly variable (range: 8-70%). Tumors encompassed SRCs of intracytoplasmic lumina and goblet-cell type. A higher percentage of SRCs was associated with lymphovascular invasion (p=0.047). All tumors expressed cytoplasmic and membranous MUC1. Secretory mucins were more frequent in mucinous carcinomas and in carcinomas with extensive SRC differentiation. We conclude that besides the usefulness of mucin immunodetection for the differential diagnosis of carcinomas with SRC differentiation of breast origin, it is important to report SRC differentiation regardless of histological type because of its intrinsic prognostic value.
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http://dx.doi.org/10.1016/j.prp.2015.05.003DOI Listing
August 2015

Genotypes and prevalence of HPV single and multiple concurrent infections in women with HSIL.

Diagn Cytopathol 2014 Nov 13;42(11):919-23. Epub 2014 Mar 13.

IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Portugal; Department of Pathology, Centro Hospitalar de São João, Porto, Portugal.

The contribution of human papillomavirus (HPV) types to the carcinogenesis of cervical cancer has been established for a long time. However, the role of phylogenetically related and rare variants remains uncertain, as well as the influence of concurrent multiple HPV genotypes infection. We aimed at studying the prevalence of several HPV genotypes infecting women with single versus concurrent multiple HPV genotypes infection with a HSIL diagnosis in a cervical cytology. We conducted a cross-sectional study using Thin-Prep(®) liquid-based cervical cytology specimens with the diagnosis of high-grade squamous intraepithelial lesion (HSIL), in which HPV genotype was sequentially tested. Genotypes were determined with a PapilloCheck(®) system, a DNA-Chip for the type-specific identification of 18 high-risk and six low-risk types of HPV. Of the total study population, 176 cases had a diagnosis of HSIL and positive HPV genotyping result, being HPV16 the most prevalent genotype (48.86%; 95%CI: 41.58-56.19) followed by HPV31 (14.20%; 95%CI: 9.75-20.18). Concurrent multiple HPV genotypes were detected in 36.93% (95%CI: 30.15-44.27) of the patients. The prevalence of the 10 most common HPV genotypes detected varied significantly according to the presence of single vs. concurrent multiple HPV genotypes (P = 0.022). Moreover, women with concurrent multiple HPV genotypes were on average 3.53 (95%CI: 0.43-6.64) years younger than women with single genotype infection. Our results suggest that women with multiple genotype HPV infection differ in terms of age and distribution of the most prevalent HPV genotypes. Additionally, we provide further evidence of the predominance of HPV16 in HSIL lesions of the uterine cervix.
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http://dx.doi.org/10.1002/dc.23143DOI Listing
November 2014

Distribution pattern of the Ki67 labelling index in breast cancer and its implications for choosing cut-off values.

Breast 2014 Jun 7;23(3):259-63. Epub 2014 Mar 7.

Department of Pathology, University College Hospital, London, United Kingdom.

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.
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http://dx.doi.org/10.1016/j.breast.2014.02.003DOI Listing
June 2014

Improved malignancy prediction by B3 breast lesions subclassification.

Ann Diagn Pathol 2013 Oct 15;17(5):434-6. Epub 2013 Jun 15.

IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal; Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; Department of Pathology, Centro Hospitalar de São João, 4200-319 Porto, Portugal. Electronic address:

Core-needle biopsy (CNB) of breast lesions can be classified into 5 categories according to lesion type and associated risk of malignancy. B3 category (lesion of uncertain malignant potential) constitutes a challenging problem in clinical decision, with most ending in excisional biopsy. Therefore, the aim of this study was to establish the incidence of malignancy on excision biopsy of B3 lesions and assess if subclassification (in B3a and B3b categories) according to the presence of atypia in otherwise B3 lesions better predicts malignancy on excision. Forty-eight cases with diagnosis of B3 lesion on CNB and matched surgical excision specimen were included to evaluate the positive predictive value (PPV) and odds for malignancy in CNB. All cases were further subclassified into B3a and B3b categories. B3 category lesions had an overall PPV for malignancy of 12.5% and significant low odds of malignancy of 0.14. When subclassified, B3b (lesions with atypia) demonstrated a higher PPV for malignancy (36.36%) with a nonsignificant odds. Inversely, B3a (lesions without atypia) demonstrated a PPV for malignancy of only 5.41% and a significant low odds of malignancy of only 0.06. The described low rate of malignancy in some of B3 lesions additionally reinforces the practice of avoiding surgical excision in selected patients and provides data that additionally support B3 lesion subclassification according to the presence of atypia. Subclassification of B3 category can further refine the current classification of associated risk of malignancy with possible implications in clinical management.
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http://dx.doi.org/10.1016/j.anndiagpath.2013.05.003DOI Listing
October 2013

Ghost tumor: an inflammatory pseudotumor of the liver.

Gastroenterol Hepatol (N Y) 2012 Sep;8(9):630-3

Department of Gastroenterology, Alto Ave Hospital Center, Guimarães, Portugal.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594965PMC
September 2012

P-cadherin as prognostic factor for loco-regional relapse in breast cancer.

Acta Med Port 2012 Mar-Apr;25(2):97-105. Epub 2012 Jun 25.

Faculdade de Medicina da Universidade do Porto / Centro Hospitalar S. João, Porto, Portugal.

Background: Breast cancer is the most frequent malignant tumor and the leading cause of cancer death in women in Portugal. Due to its relation to an increase in distant metastasis and subsequent death, loco-regional relapse is one major concern in breast cancer women. Several classic prognostic factors as tumour size, nodal stage, histological grade, HER2 status and hormonal receptors have been identified as the most important factors for determining loco-regional relapse, disease free and overall survival. However, there is heterogeneity in prognosis and tumor behaviour in patients with identical disease staging and a similar pattern of expression of known molecular markers, hence the need to discover new prognostic factors. One of the possibilities is P-cadherin, already described by researchers as a possible independent marker of prognosis in breast cancer. The aim of this work was to study in a retrospective series of patients the correlation of P-cadherin expression with loco-regional recurrence in breast cancer women.

Material And Methods: We analyzed the clinical records of 1432 consecutive patients with breast cancer and treated in a University Hospital over a 10 year period. Patients with loco-regional relapse (n=101) without prior or simultaneous distant disease were selected as case group. Control group consisted of patients with more than 10 years follow-up and without disease progression. For both groups demographic, clinical, pathological and molecular markers were analyzed. Tissue micro-arrays were constructed to study P-cadherin expression from 86 tumors with available paraffin embedded blocks.

Results: Mean time to recurrence was 41 months and mean survival time after recurrence was 33 months, with a 5-year survival rate of 55%. Tumour size, nodal status and histological grade were identified as independent markers of prognosis. P-cadherin was associated with higher histological grades and hormone negative tumours. P-cadherin was identified as an independent prognostic marker for disease free survival, but not for overall survival.

Conclusion: P-cadherin was related to other known factors of worse prognosis and had an independent relation to disease-free survival. P-cadherin might constitute a novel therapeutic target, but its real biological value is yet to be determined. Doubt persists whether it is an independent marker of tumour behaviour or only a surrogate marker of a set of clinical and molecular features related with worse prognosis.
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April 2013

Cardiac metastasis from epidermoid esophageal cancer mimicking anterior myocardial infarction.

Rev Port Cardiol 2012 Feb 3;31(2):163-6. Epub 2012 Jan 3.

Cardiology Department, Hospital São João, Porto, Portugal.

Cardiac metastases are more common than primary tumors. Several types of malignant tumors have been reported to metastasize to the heart, mainly lung cancer, but in the setting of esophageal cancer, myocardial metastasis is comparatively rare. We report a case of a cardiac metastasis from esophageal squamous cell carcinoma detected 9 months after surgically curative esophagectomy, which presented mimicking acute myocardial infarction. The use of different imaging modalities was fundamental to a correct diagnosis considering the challenging presentation.
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http://dx.doi.org/10.1016/j.repc.2011.12.011DOI Listing
February 2012

High-Grade Breast Epithelioid Angiosarcoma Secondary to Radiotherapy Metastasizing to the Contralateral Lymph Node: Unusual Presentation and Potential Pitfall.

Breast Care (Basel) 2011 14;6(3):227-229. Epub 2011 Jun 14.

Department of Pathology, Hospital de S. João, Porto, Portugal.

BACKGROUND: Breast angiosarcoma is a rare disease occurring as primary tumour or secondary to lymphoedema or radiotherapy. The more frequent use of breast-conserving therapy and radiotherapy for breast carcinoma explains the increasing diagnosis of these tumours. CASE REPORT: We report a case of a breast epithelioid angiosarcoma which metastasized to the contralateral axillary lymph node, occurring 4 years after breast-conserving therapy with axillary lymph node dissection and radiotherapy. The patient presented skin lesions and an axillary lump (clinically diagnosed as carcinoma relapse and lymph node metastasis). Fine-needle cytology on both lesions and a core needle biopsy of the axillary lump were carried out. Differential diagnosis included carcinoma, malignant melanoma, and angiosarcoma. Immunohistochemistry confirmed the diagnosis of angiosarcoma. CONCLUSIONS: Breast angiosarcoma is a challenge - clinically, radiologically and pathologically - and requires a high index of suspicion in susceptible patients.
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http://dx.doi.org/10.1159/000329323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132971PMC
June 2011

Nottingham Prognostic Index in triple-negative breast cancer: a reliable prognostic tool?

BMC Cancer 2011 Jul 15;11:299. Epub 2011 Jul 15.

Institute of Molecular Pathology and Immunology of Porto University, Porto, Portugal.

Background: A breast cancer prognostic tool should ideally be applicable to all types of invasive breast lesions. A number of studies have shown histopathological grade to be an independent prognostic factor in breast cancer, adding prognostic power to nodal stage and tumour size. The Nottingham Prognostic Index has been shown to accurately predict patient outcome in stratified groups with a follow-up period of 15 years after primary diagnosis of breast cancer. Clinically, breast tumours that lack the expression of Oestrogen Receptor, Progesterone Receptor and Human Epidermal growth factor Receptor 2 (HER2) are identified as presenting a "triple-negative" phenotype or as triple-negative breast cancers. These poor outcome tumours represent an easily recognisable prognostic group of breast cancer with aggressive behaviour that currently lack the benefit of available systemic therapy. There are conflicting results on the prevalence of lymph node metastasis at the time of diagnosis in triple-negative breast cancer patients but it is currently accepted that triple-negative breast cancer does not metastasize to axillary nodes and bones as frequently as the non-triple-negative carcinomas, favouring instead, a preferentially haematogenous spread. Hypothetically, this particular tumour dissemination pattern would impair the reliability of using Nottingham Prognostic Index as a tool for triple-negative breast cancer prognostication.

Methods: The present study tested the effectiveness of the Nottingham Prognostic Index in stratifying breast cancer patients of different subtypes with special emphasis in a triple-negative breast cancer patient subset versus non- triple-negative breast cancer.

Results: We demonstrated that besides the fact that TNBC disseminate to axillary lymph nodes as frequently as luminal or HER2 tumours, we also showed that TNBC are larger in size compared with other subtypes and almost all grade 3. Additionally, survival curves demonstrated that these prognostic factors are equally important to stratify different survival outcomes in non-TNBC as in TNBC. We also showed that the NPI retains the ability to stratify and predict survival of TNBC patients.

Conclusion: The importance of this study relies on the need of prognostication improvements on TNBC, showing, at a clinical standpoint, that Nottingham Prognostic Index is as a truthful prognostic tool in TNBC.
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http://dx.doi.org/10.1186/1471-2407-11-299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151231PMC
July 2011

Distinction of isolated tumour cells and micrometastasis in lymph nodes of breast cancer patients according to the new Tumour Node Metastasis (TNM) definitions.

Eur J Cancer 2011 Apr 16;47(6):887-94. Epub 2010 Dec 16.

Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary.

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.
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http://dx.doi.org/10.1016/j.ejca.2010.11.011DOI Listing
April 2011

PIKing the right isoform: the emergent role of the p110beta subunit in breast cancer.

Virchows Arch 2010 Mar 4;456(3):235-43. Epub 2010 Feb 4.

IPATIMUP: Institute of Molecular Pathology and Immunology of the University of Porto, University of Porto, Rua Dr Roberto Frias s/n, 4200-465, Porto, Portugal.

Class IA phosphoinositide-3'-kinases (PI3Ks) regulate many cellular processes. Despite a clear implication of PI3K in cancer, the involvement of each of its isoforms namely p110alpha and p110beta in the development of breast cancer remains elusive. Until recently, the spotlight was given to the alpha subunit; however, the p110beta isoform has now emerged as an interesting target as well. In order to determine the importance of both these subunits in breast cancer, we aimed to study the expression of p110alpha and p110beta in a series of invasive breast carcinomas. We constructed tissue microarrays from 315 invasive breast carcinomas and performed immunohistochemistry for p110alpha and beta, correlating the expression patterns with clinicopathological parameters. Furthermore, overall survival was analysed through Kaplan-Meier survival curves and Cox regression. We found that p110 subunits are expressed in 23.8% of invasive breast carcinomas, of which 11.8% express p110alpha and 15.2% p110beta. The p110alpha positive tumours correlated with hormone receptor (HR) expression, and were not associated with overall survival. The membrane expression of p110beta was associated with worse prognosis. This was due to its link to HER2-overexpression, lower age of onset, higher grade, lymph node involvement, distant metastasis and was inversely associated with HR status. Furthermore, p110beta expression was associated with worse overall survival. Importantly our results indicate a role for the beta subunit in the development/progression of HER2-overexpressing tumours, highlighting possible therapeutic associations between HER2 and p110beta inhibitors.
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http://dx.doi.org/10.1007/s00428-010-0881-0DOI Listing
March 2010

Nodal-stage classification in invasive lobular breast carcinoma: influence of different interpretations of the pTNM classification.

J Clin Oncol 2010 Feb 19;28(6):999-1004. Epub 2010 Jan 19.

University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands.

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.
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http://dx.doi.org/10.1200/JCO.2009.22.0723DOI Listing
February 2010

Validation of clinical prediction rules for a low probability of nonsentinel and extensive lymph node involvement in breast cancer patients.

Am J Surg 2007 Sep;194(3):288-93

Department of Surgical Pathology, Bács-Kiskun County Teaching Hospital, Nyiri út 38, H-6000 Kecskemét, Hungary.

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 < or = 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.
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http://dx.doi.org/10.1016/j.amjsurg.2007.02.014DOI Listing
September 2007

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

Eur J Cancer 2007 Jun 24;43(9):1407-14. Epub 2007 May 24.

Department of Pathology, Bács-Kiskun County Teaching Hospital, Nyiri út 38, H-6000 Kecskemét, Hungary.

This study aimed at identifying factors related to sentinel lymph node (SLN) involvement in patients with tubular, cribriform, mucinous or papillary breast carcinoma and those related to non-SLN metastases if an SLN was positive. Multivariate analyses involved logistic and stepwise regressions. The SLNs harboured metastases in 85 of 572 cases, 78 of whom underwent axillary dissection; 19 presented non-SLN positive disease. Lack of lymphovascular invasion, a tumour size < or = 10 mm and a single SLN removed were the factors predicting an SLN metastasis rate <10%, and patients with these features could be candidates for no surgical axillary staging. A positive SLN proportion of < or = 50% and no lymphovascular invasion were associated with a <10% rate of non-SLN invasion; patients with a positive SLN and these features could be candidates for the omission of completion axillary dissection. The opposite presentation of these factors would mandate SLN biopsy and axillary dissection, respectively.
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http://dx.doi.org/10.1016/j.ejca.2007.04.004DOI Listing
June 2007

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

Pathol Oncol Res 2007 27;13(1):5-14. Epub 2007 Mar 27.

Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, H-6000, Hungary.

Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early breast cancer, but controversy exists regarding its universal use and consequences in small tumors. 2929 cases of breast carcinomas not larger than 15 mm and staged with SLN biopsy with or without axillary dissection were collected from the authors' institutions. The pathology of the SLNs included multilevel hematoxylin and eosin (HE) staining. Cytokeratin immunohistochemistry (IHC) was commonly used for cases negative with HE staining. Variables influencing SLN involvement and non-SLN involvement were studied with logistic regression. Factors that influenced SLN involvement included tumor size, multifocality, grade and age. Small tumors up to 4 mm (including in situ and microinvasive carcinomas) seem to have SLN involvement in less than 10%. Non-SLN metastases were associated with tumor grade, the ratio of involved SLNs and SLN involvement type. Isolated tumor cells were not likely to be associated with further nodal load, whereas micrometastases had some subsets with low risk of non-SLN involvement and subsets with higher proportion of further nodal spread. In situ and microinvasive carcinomas have a very low risk of SLN involvement, therefore, these tumors might not need SLN biopsy for staging, and this may be the approach used for very small invasive carcinomas. If an SLN is involved, isolated tumor cells are rarely if ever associated with non-SLN metastases, and subsets of micrometastatic SLN involvement may be approached similarly. With macrometastases the risk of non-SLN involvement increases, and further axillary treatment should be generally indicated.
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http://dx.doi.org/10.1007/BF02893435DOI Listing
July 2007
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