Publications by authors named "Tibor Tot"

74 Publications

Granulomatous mastitis caused by Rickettsia species.

Virchows Arch 2021 Apr 13. Epub 2021 Apr 13.

Pathology & Cytology Dalarna, Region Dalarna, Falun, Sweden.

Granulomatous mastitis is a rare inflammatory disease of varying etiology. Tuberculosis and cystic neutrophilic granulomatous mastitis caused by Corynebacterium are the best-established infectious examples. Despite the increasing incidence of Rickettsia-related diseases worldwide, granulomatous inflammation of breast parenchyma caused by Rickettsia has not yet been reported. We present a unique case of bilateral granulomatous mastitis documented with mammography, magnetic resonance imaging and core-needle biopsy. The rickettsial etiology of the disease was proved with specific immunohistochemistry and confirmed with DNA extraction, PCR and serology. The lesions completely resolved after a full-course tetracycline treatment. This case report widens the knowledge about the possible clinical manifestations of Rickettsia infection and adds a new bacterium to the list of etiological factors causing granulomatous mastitis.
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http://dx.doi.org/10.1007/s00428-021-03098-2DOI Listing
April 2021

The clinical value of detecting microcalcifications on a mammogram.

Semin Cancer Biol 2021 Jul 14;72:165-174. Epub 2019 Nov 14.

Center for Clinical Research Dalarna, Falun, Sweden.

Many breast lesions are associated with microcalcifications that are detectable by mammography. In most cases, radiologists are able to distinguish calcifications usually associated with benign diseases from those associated with malignancy. In addition to their value in the early detection of breast carcinoma and accurate radiological diagnosis, the presence of microcalcifications often affects the extent of surgical intervention. Certain types of microcalcifications are associated with negative genetic and molecular characteristics of the tumor and unfavorable prognosis. Microcalcifications localized in the larger ducts (duct-centric, casting-type microcalcifications) represent an independent negative prognostic marker compared to lesions containing other types of microcalcifications and to non-calcified lesions. In this review, we summarize the theoretical and methodological background for understanding the clinical impact and discuss the diagnostic and prognostic value of microcalcifications detected in the breast by mammography.
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http://dx.doi.org/10.1016/j.semcancer.2019.10.024DOI Listing
July 2021

The subgross morphology of breast carcinomas: a single-institution series of 2033 consecutive cases documented in large-format histology slides.

Virchows Arch 2020 Mar 13;476(3):373-381. Epub 2019 Aug 13.

Pathology & Cytology Dalarna, County Hospital Falun, Falun, Sweden.

A large-format histology technique represents the most convenient method for documenting and assessing the subgross morphological prognostic parameters of breast cancer (i.e., the distribution of the tumor's invasive and in situ components, disease extent, and tumor size), especially when used in conjunction with systematic radiological-pathological correlation. Here we report a consecutive series of 2033 breast carcinomas operated on in Dalarna, Sweden, with a particular focus on these subgross parameters. We separately analyzed the distributions of the in situ and invasive components of the tumors and then combined these into an aggregate pattern when both components were present. We found that 40% of breast carcinomas had a simple (unifocal) subgross morphology, while 60% had a complex morphology presenting with multifocal or diffuse components. Extensive tumors (occupying a total volume of breast tissue with the greatest dimension being ≥ 40 mm) were more common in complex cases, occurring in 66% of multifocal cases and 88% of diffuse cases, compared with only 5% of unifocal cases. Compared with luminal A-like tumors, HER2-expressing tumors exhibited a significantly larger extent. Triple-negative and basal-like carcinomas tended to have a larger tumor size (based on the largest dimension of the largest invasive focus). In this report, we discuss the prognostic impact of these parameters and the necessity of their correct assessment in the diagnostic routine.
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http://dx.doi.org/10.1007/s00428-019-02641-6DOI Listing
March 2020

Imaging Biomarkers as Predictors for Breast Cancer Death.

J Oncol 2019 10;2019:2087983. Epub 2019 Apr 10.

National Taiwan University, Taipei, Taiwan.

Background: To differentiate the risk of breast cancer death in a longitudinal cohort using imaging biomarkers of tumor extent and biology, specifically, the mammographic appearance, basal phenotype, histologic tumor distribution, and conventional tumor attributes.

Methods: Using a prospective cohort study design, 498 invasive breast cancer patients diagnosed between 1996 and 1998 were used as the test cohort to assess the independent effects of the imaging biomarkers and other predictors on the risk of breast cancer death. External validation was performed with a cohort of 848 patients diagnosed between 2006 and 2010.

Results: Mammographic tumor appearance was an independent predictor of risk of breast cancer death (P=0.0003) when conventional tumor attributes and treatment modalities were controlled. The casting type calcifications and architectural distortion were associated with 3.13-fold and 3.19-fold risks of breast cancer death, respectively. The basal phenotype independently conferred a 2.68-fold risk compared with nonbasal phenotype. The observed deaths did not differ significantly from expected deaths in the validation cohort. The application of imaging biomarkers together with other predictors classified twelve categories of risk for breast cancer death.

Conclusion: Combining imaging biomarkers such as the mammographic appearance of the tumor with the histopathologic distribution and basal phenotype, accurately predicted long-term risk of breast cancer death. The information may be relevant for determining the need for molecular testing, planning treatment, and determining the most appropriate clinical surveillance schedule for breast cancer patients.
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http://dx.doi.org/10.1155/2019/2087983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481030PMC
April 2019

Internodal HER2 heterogeneity of axillary lymph node metastases in breast cancer patients.

Bosn J Basic Med Sci 2019 Aug 20;19(3):242-248. Epub 2019 Aug 20.

Department of Clinical Pathology, University Clinical Centre of the Republic of Srpska, Banja Luka, Bosnia and Herzegovina.

Determination of human epidermal growth factor receptor 2 (HER2) status is important for adequate treatment of breast cancer (BC) patients. The novel HER2 gene protein assay (GPA) is particularly convenient, as it allows the simultaneous assessment of HER2 protein expression and gene amplification at individual cell level. Here we investigated the frequency of internodal HER2 heterogeneity in axillary lymph node macrometastases of BC patients and compared HER2 status between primary breast tumor and its metastases. We included a total of 41 female patients operated between 2014 and 2015 for primary BC with axillary lymph node macrometastases. Representative paraffin blocks of metastatic lymph nodes were sectioned and the slides were stained using the GPA in 38 BC cases. GPA results were assessed according to the ASCO/CAP 2013 criteria. We analyzed 12586 individual tumor cells, 120 cells per section of each metastatic lymph node. HER2 status differed between the primary tumor and its metastases in 5/38 cases (13.2%). In patients with at least two metastatic nodes, the HER2 status of lymph node metastases was only slightly different in 4/23 cases (17.4%). Our results indicate rare but substantial differences in HER2 status between primary breast tumor and its axillary lymph node metastases that may direct the choice and outcomes of targeted therapy in BC patients. The impact of the rare and subtle internodal HER2 heterogeneity evidenced in this study remains uncertain. Determining the HER2 status of lymph node metastases in BC seems to be rational, but assessing a limited number of metastatic nodes may be sufficient.
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http://dx.doi.org/10.17305/bjbms.2019.3970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716091PMC
August 2019

The sick lobe hypothesis, field cancerisation and the new era of precision breast surgery.

Gland Surg 2018 Dec;7(6):611-618

Department of Pathology & Head, Pathology and Cytology Dalarna, County Hospital Falun, Falun, Sweden.

Understanding the ductal anatomy of the breast provides insights into tumorigenesis, which in turn offers guidance on therapeutic decisions. In this regard, the sick lobe hypothesis, which states that cancer arises from genetically unstable cells through mutations acquired in utero, forms the basis of malignant transformation. These 'at risk' cells line the mammary ductal-lobular system of a single 'sick' lobe and when exposed to noxious events in the surrounding microenvironment, further genetic changes occur which completes conversion to malignancy, in certain defined patterns. This review explores how anatomy, pathology and genomics can merge, not only to guide optimum surgery, but also to provide a more comprehensive portal for precision medicine.
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http://dx.doi.org/10.21037/gs.2018.09.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323249PMC
December 2018

Eccrine ductal and acrosyringeal metaplasia in breast carcinomas: report of eight cases.

Authors:
Tibor Tot

Virchows Arch 2019 Mar 22;474(3):383-387. Epub 2018 Nov 22.

Pathology & Cytology Dalarna, County hospital Falun, Falun, Sweden.

Eccrine ductal and acrosyringeal metaplasia was described in 2006 as the presence of tumor structures that resemble the epithelium of the eccrine skin ducts and their opening within the epidermis, the acrosyringeum. Here, we report the clinical, morphological, and phenotypic characteristics of eight breast carcinomas that we collected over the past years showing this metaplasia. Unlike squamous metaplasia, acrosyringeal and eccrine ductal metaplasia are luminated structures comprising cells with eosinophilic cytoplasm that are easily detectable in routine histological slides. These lesions invariably appeared in triple-negative carcinomas, but the cases differed in their clinical, radiological, and histological manifestations. Correct interpretation of these changes may facilitate identification of some metaplastic carcinomas.
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http://dx.doi.org/10.1007/s00428-018-2488-9DOI Listing
March 2019

Equivocal (HER2 IHC 2+) breast carcinomas: gene-protein assay testing reveals association between genetic heterogeneity, individual cell amplification status and potential treatment benefits.

Histopathology 2019 Jan 11;74(2):300-310. Epub 2018 Nov 11.

Pathology and Cytology, County Hospital Falun, Falun, Sweden.

Aims: Genetic heterogeneity can pose a challenge to identifying eligible cases for targeted therapy in the human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 2+ breast carcinoma group. In this study, we characterised this subset of tumours according to clinicopathological parameters.

Methods And Results: We assessed 1000 tumour cells per case and recorded the number of HER2 and chromosome enumeration probe 17 (CEP17) copies using gene-protein assay slides. HER2 status was determined based on ASCO/CAP 2013 guidelines. Tumours with 5-50% of cancer cells with amplification were considered to be heterogeneous, whereas those with >50% were considered to be non-heterogeneous. In a study cohort of 110 HER2 IHC 2+ carcinomas, 93 (84.5%) were non-amplified, 12 (10.9%) were amplified and five (4.5%) were ISH-equivocal. All the HER2-amplified and two of ISH-equivocal cases (12.7%) corresponded to non-heterogeneous tumours, with highly significant differences evident in the average HER2/CEP17 ratio (P = 0.0002) and the proportion of cells with HER2 >6 copies (P < 0.0001) compared with heterogeneous lesions. NST grade 3 and HER2-amplified carcinomas average HER2/CEP17 ratio correlated with an increased number of cells with HER2/CEP17 ≥2.0 (P < 0.014). Triple-negative CEP17 polysomic carcinomas showed increased metastatic capacity (P = 0.003) compared with other tumour types.

Conclusion: Non-heterogeneous HER2 IHC 2+ tumours tend to be HER2-amplified. Adding the percentage of cells with HER2 >6 copies to the average HER2/CEP17 ratio may facilitate assessment of amplification status in ISH-equivocal cases. The proportion of cells with HER2/CEP17 ≥2.0 contributes information concerning the actual average HER2/CEP17 ratio, depending on tumour type.
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http://dx.doi.org/10.1111/his.13733DOI Listing
January 2019

Metastasis of breast cancer prior to invasion.

Authors:
Tibor Tot

Breast Cancer Res Treat 2018 Jul 19;170(1):197. Epub 2018 Feb 19.

Pathology & Cytology Dalarna, Uppsala University, Falun, Sweden.

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http://dx.doi.org/10.1007/s10549-018-4721-2DOI Listing
July 2018

LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer.

Int J Oncol 2018 Apr 9;52(4):1189-1197. Epub 2018 Feb 9.

Oncology Research Laboratory, Department of Radiation Sciences, Umeå University, SE-90187 Umeå, Sweden.

Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are characterized by genomic rearrangements and point mutations in the proto-oncogene RET. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a suppressor of various receptor tyrosine kinases, including RET. LRIG1 expression levels are associated with patient survival in many cancer types. In the present study, we investigated whether the oncogenic RET mutants RET2A (C634R) and RET2B (M918T) were regulated by LRIG1, and the possible effects of LRIG1 expression in thyroid cancer were investigated in three different clinical cohorts and in a RET2B-driven mouse model of MTC. LRIG1 was shown to physically interact with both RET2A and RET2B and to restrict their ligand-independent activation. LRIG1 mRNA levels were downregulated in PTC and MTC compared to normal thyroid gland tissue. There was no apparent association between LRIG1 RNA or protein expression levels and patient survival in the studied cohorts. The transgenic RET2B mice developed pre-cancerous medullary thyroid lesions at a high frequency (36%); however, no overt cancers were observed. There was no significant difference in the incidence of pre-cancerous lesions between Lrig1 wild-type and Lrig1-deficient RET2B mice. In conclusion, the findings that LRIG1 is a negative regulator of RET2A and RET2B and is also downregulated in PTC and MTC may suggest that LRIG1 functions as a thyroid tumor suppressor.
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http://dx.doi.org/10.3892/ijo.2018.4273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843404PMC
April 2018

The new TNM-based staging of breast cancer.

Virchows Arch 2018 May 27;472(5):697-703. Epub 2018 Jan 27.

Pathology and Cytology Dalarna, Falun County Hospital, 79182, Falun, Sweden.

This review describes the changes that have been implemented in the Tumor-Node-Metastasis (TNM)-based staging of breast cancers by the new, 8th editions of the relevant Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) publications. After giving a background for TNM being the common language of cancer staging and related activities like cancer treatment and registration, it summarizes not only the changes but reviews some highlights important for pathologists, and lists and comments on the differences between the publications and diagnostic practices based on them. A section is dedicated to the prognostic stages of breast carcinomas introduced in the AJCC Cancer Staging Manual, but not mentioned in the UICC TNM classification of malignant tumors. A few issues that are not appropriately covered by TNM according to the authors' view (e.g., multifocal tumors, larger lymph node metastases identified by molecular methods, the heterogeneous prognosis of M1-defined stage IV disease) close the review with the final thoughts raising the vision of a potential loss of the common staging language.
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http://dx.doi.org/10.1007/s00428-018-2301-9DOI Listing
May 2018

Integrating anatomy, radiology, pathology, and surgery: An alternative approach in resecting multifocal and multicentric breast carcinoma.

Breast J 2017 Nov 22;23(6):663-669. Epub 2017 Aug 22.

Department of Pathology and Clinical Cytology, County Hospital Falun, Falun, Sweden.

The sick lobe hypothesis provides the basis for a lobar approach in radiology, pathology, and surgical treatment of breast cancer. This approach aims to remove the tumor together with the surrounding field of genetic aberrations. Detailed preoperative lobar imaging that properly maps the disease and assesses its extent guides the parenchymal resection. Integration of our knowledge of breast anatomy and pathology with the results of preoperative radiological mapping is critical in assessing the eligibility of patients with multifocal and/or multicentric breast cancer for breast conservation treatment. Through an appropriately selected incision, a multisegment resection of the diseased lobe(s) is performed, which leaves the residual parenchyma in a formation that allows dovetailing of one part into the other, like the way pieces of a jigsaw puzzle fit together. Detailed pathologic analysis of the surgical specimen provides valuable feedback to the radiologist, establishes the completeness of surgical intervention, and generates predictive information for therapeutic decisions. Our approach is a step in continuous search for ideal tailored therapy to avoid under or over-treatment of breast cancer patients.
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http://dx.doi.org/10.1111/tbj.12891DOI Listing
November 2017

Ductal Breast Carcinoma In Situ: Mammographic Features and Its Relation to Prognosis and Tumour Biology in a Population Based Cohort.

Int J Breast Cancer 2017 14;2017:4351319. Epub 2017 Feb 14.

Department of Surgical Sciences, Uppsala University, Uppsala Academic Hospital, Uppsala, Sweden.

Casting-type calcifications and a histopathological picture with cancer-filled duct-like structures have been presented as breast cancer with neoductgenesis. We correlated mammographic features and histopathological neoductgenesis with prognosis in a DCIS cohort with long follow-up. Mammographic features were classified into seven groups according to Tabár. Histopathological neoductgenesis was defined by concentration of ducts, lymphocyte infiltration, and periductal fibrosis. Endpoints were ipsilateral (IBE) in situ and invasive events. Casting-type calcifications and neoductgenesis were both related to high nuclear grade, ER- and PR-negativity, and HER2 overexpression but not to each other. Casting-type calcifications and neoductgenesis were both related to a nonsignificant lower risk of invasive IBE, HR 0.38 (0.13-1.08) and 0.82 (0.29-2.27), respectively, and the HR of an in situ IBE was 0.90 (0.41-1.95) and 1.60 (0.75-3.39), respectively. Casting-type calcifications could not be related to a worse prognosis in DCIS. We cannot explain why a more aggressive phenotype of DCIS did not correspond to a worse prognosis. Further studies on how the progression from in situ to invasive carcinoma is driven are needed.
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http://dx.doi.org/10.1155/2017/4351319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329681PMC
February 2017

Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis.

J Clin Oncol 2017 Apr 28;35(10):1119-1127. Epub 2016 Dec 28.

Iris D. Nagtegaal, Nikki Knijn, and Niek Hugen, Radboud University Medical Center, Nijmegen, the Netherlands; Helen C. Marshall and Philip Quirke, Leeds University, Leeds, United Kingdom; Kenichi Sugihara, Tokyo Medical and Dental University, Tokyo; Hideki Ueno, National Defence Medical College, Tokorozawa, Japan; and Tibor Tot, Falu Lasarett, Falun, Sweden.

Purpose Colorectal cancer (CRC) treatment is largely determined by tumor stage. Despite improvements made in the treatment of various types of metastatic disease, staging has not been refined. The role of tumor deposits (TDs) in staging remains debated. We have assessed the relation of TDs with metastatic pattern to evaluate whether TDs might add significant new information to staging. Methods We performed a systematic literature search that was focused on the role of TDs in CRC. Studies with neoadjuvant-treated patients were excluded. Data on stage, histologic factors, and outcome were extracted. Data from four large cohorts were analyzed for the relevance of the presence of TDs, lymph node metastases (LNMs), and extramural vascular invasion (EMVI) on the pattern of metastases and outcomes. Results Of 10,106 included patients with CRC, 22% presented with TDs. TDs are invariably associated with poor outcome. Presence of TDs was associated with presence of LNMs and EMVI. In a pairwise comparison, effects of TD were stronger than those of both LNMs and EMVI. In the logistic regression model, TDs in combination with LNMs is the strongest predictor for liver (odds ratio [OR], 5.5), lung (OR, 4.3) and peritoneal metastases (OR, 7.0). Presence of EMVI adds information for liver and lung metastases, but not for peritoneal metastases. Conclusion We have shown that TDs are not equal to LNMs or EMVI with respect to biology and outcome. We lose valuable prognostic information by allocating TDs into nodal category N1c and only considering TDs in the absence of LNMs. Therefore, we propose that the number of TDs should be added to the number of LNMs to derive a final N stage.
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http://dx.doi.org/10.1200/JCO.2016.68.9091DOI Listing
April 2017

The lobar approach to breast ultrasound imaging and surgery.

J Med Ultrason (2001) 2015 Jul 2;42(3):331-9. Epub 2015 Apr 2.

Department of Clinical Pathology and Cytology, Central Hospital Falun, 79182, Falun, Sweden.

Breast cancer is a lobar disease in the sense that, at the earliest stages, the cancer is structurally confined to a single sick lobe. The subgross morphology of breast carcinoma is often complex, as multiple invasive foci are frequently present and the ductal system often contains an extensive in situ component. Adequate preoperative visualization of all of the malignant structures within the affected breast and preoperative mapping of the lesions in relation to the surrounding normal structures are essential for successful image-guided breast surgery and therefore are key factors in assuring adequate local control of the disease. We advocate use of the lobar approach in ultrasound imaging (ducto-radial echography) and breast-conserving surgery based on the lobar anatomy of the breast, the sick lobe theory, our extensive clinical experience with the approach, and favorable long-term patient outcomes. Despite abundant evidence demonstrating the advantages of the lobar approach, the number of breast centers using it in practice is still limited. In this review, we aim to call attention to the advantages of the lobar approach from the theoretical, imaging, and surgical points of view.
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http://dx.doi.org/10.1007/s10396-015-0625-5DOI Listing
July 2015

Diffuse invasive breast carcinoma of no special type.

Authors:
Tibor Tot

Virchows Arch 2016 Feb 31;468(2):199-206. Epub 2015 Oct 31.

Department of Pathology, Laboratory Medicine Dalarna, County Hospital Falun, Falun, Sweden.

Diffuse invasive breast carcinomas are rare tumors associated with unfavorable prognostic parameters. This growth pattern is often related to invasive lobular cancer (ILC). Diffuse ductal breast carcinoma of no special type (NST) is largely under-recognized in the literature. We identified 70 diffuse invasive breast carcinomas in a consecutive series of 1249 invasive tumors. Based on morphology and E-cadherin expression, 15/70 were NST and 55/70 were ILC. Subgroups differed in mammographic appearance, as more NST tumors than ILCs formed stellate masses (53 vs. 18 %, p = 0.000436) while ILCs displayed more architectural distortion. NST tumors were significantly more often radiologically extensive than ILCs (80 vs. 38 %, p = 0.0042987). Subgroups did not differ significantly in disease extent on histology, lymph node status, progesterone receptor status, and molecular phenotype, with a difference of borderline statistical significance in estrogen receptor status (87 vs. 100 %, p = 0.0434783). Significantly more NST tumors were HER2 positive (27 vs. 4 %, p = 0.0050463) and showed high Ki67 proliferation index (60 vs. 25 %, p = 0.0121808). The most striking differences occurred in the histology grade of the in situ (high grade in 53 vs. 4 %) and invasive (high grade in 27 vs. 2 %) tumor components and in the distribution of the in situ component (diffuse in 73 vs. 11 %). We conclude that diffuse invasive breast carcinomas of NST comprise a small subgroup of breast carcinomas. Most of these cancers are non-high grade and of luminal phenotype, but extensive and lymph node positive with worse prognostic parameters than diffuse ILC.
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http://dx.doi.org/10.1007/s00428-015-1873-xDOI Listing
February 2016

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer.

Genome Res 2015 Oct;25(10):1521-35

Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.
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http://dx.doi.org/10.1101/gr.187823.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579338PMC
October 2015

Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content.

Histopathology 2016 Feb 12;68(3):411-21. Epub 2015 Aug 12.

Department of Pathology and Clinical Cytology, Central Hospital Falun, Falun, Sweden.

Aims: To determine the volume of tumoral and normal breast tissue containing sufficient DNA (>2 μg/sample) for genetic platforms and biobanking, with a focus on multifocality, tumoral heterogeneity, and factors that critically influence sample acceptability.

Methods And Results: We examined 57 breast surgical specimens with multifocal (46/57) and unifocal (11/57) cancers. Punch biopsies were obtained from tissue slices under multimodal radiological guidance, and the colour-coded sampling sites were identified in large-format histology slides. The study comprised 415 DNA isolations from tumour (n = 105) and normal (n = 283) tissue, including skin (n = 27) samples. A single 2-mm core from invasive tumour contained sufficient DNA in 91.4% (96/105) of cases, depending on tumour type (3.8-108.2 μg/sample), number and size of additional foci in multifocal cases (P = 0.001), tumour consistency, and degree of necrosis. Three biopsies obtained with a 4-mm device were required from normal breast tissue, at least 10 mm from the tumour. Cold ischaemia for up to 82 min did not influence the yield of DNA.

Conclusions: Radiological disease mapping is useful for guiding optimal specimen slicing and for targeting breast lesions. A single 2-mm core from tumour and multiple 4-mm cores from normal breast tissue yield adequate DNA in the majority of samples.
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http://dx.doi.org/10.1111/his.12758DOI Listing
February 2016

Early (<10 mm) HER2-Positive Invasive Breast Carcinomas are Associated with Extensive Diffuse High-Grade DCIS: Implications for Preoperative Mapping, Extent of Surgical Intervention, and Disease-Free Survival.

Authors:
Tibor Tot

Ann Surg Oncol 2015 Aug 13;22(8):2532-9. Epub 2015 Jan 13.

Department of Pathology and Clinical Cytology, Central Hospital Falun, Falun, Sweden,

Background: The few publications on <10-mm invasive breast carcinomas have reported worse outcomes for women with human epidermal growth factor receptor 2 (HER2)-positive cancer compared with HER2-negative cases and indicated that the high risk of recurrence in HER2-positive cases is related to the high grade, hormone receptor negativity, and high proliferation index of the invasive tumor component.

Methods: We studied the subgross morphology of such tumors in a consecutive series of 203 cases documented in large-format histology slides and worked up with detailed radiological-pathological correlation.

Results: The invasive component was associated with a diffuse in situ component in 78 % of the HER2-positive and 26 % of HER2-negative tumors <10 mm in size (odds ratio [OR], 11.3936; P < .0001). The in situ component was of high grade in 75 % of HER2-positive and 9 % of HER2-negative cases (OR, 29.6000; P < .0001). Significant associations were also found between the HER2 positivity of the invasive component and diffuse combined lesion distribution (P > .0001), invasive tumor grade 3 (P = .0004), presence of vascular invasion (P = .0026), extensive disease (P = .0170), "not special" (ductal) histological tumor type (P = .0302), estrogen receptor negativity (OR, 7.8846; P < .0001), and high Ki67 proliferation index (OR, 5.0000; P = .0007). The HER2-positive tumors tended to be multifocal (OR, 2.000) and lymph node-positive (OR, 3.0147), but the tendency was not statistically significant.

Conclusions: The vast majority of <10-mm HER2-positive breast carcinomas exhibited a high-grade, diffuse, and extensive in situ component, which may explain the high risk of recurrence among these tumors.
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http://dx.doi.org/10.1245/s10434-015-4367-9DOI Listing
August 2015

Breast cancer with neoductgenesis: histopathological criteria and its correlation with mammographic and tumour features.

Int J Breast Cancer 2014 8;2014:581706. Epub 2014 Oct 8.

Department of Surgical Sciences, Uppsala University, 751 85 Uppsala, Sweden ; Department of Surgery, Uppsala Academic Hospital, 751 85 Uppsala, Sweden.

Introduction. Breast cancer with mammographic casting type calcifications, high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction, lymphocyte infiltration, and tenascin-C (TN-C) overexpression has been proposed to represent a more aggressive form of breast cancer and has been denominated as breast cancer with neoductgenesis. We developed histopathological criteria for neoductgenesis in order to study reproducibility and correlation with other tumour markers. Methods. 74 cases of grades 2 and 3 DCIS, with or without an invasive component, were selected. A combined score of the degree(s) of concentration of ducts, lymphocyte infiltration, and periductal fibrosis was used to classify cases as showing neoductgenesis, or not. Diagnostic reproducibility, correlation with tumour markers, and mammographic features were studied. Results. Twenty-three of 74 cases were diagnosed with neoductgenesis. The kappa value between pathologists showed moderate reproducibility (0.50) (95% CI; 0.41-0.60). Neoductgenesis correlated significantly with malignant type microcalcifications and TN-C expression (P = 0.008 and 0.04) and with ER, PR, and HER2 status (P < 0.00001 for all three markers). Conclusions. We developed histological criteria for breast cancer with neoductgenesis. Neoductgenesis, by our applied histopathological definition was related to more aggressive tumour biology and malignant mammographic calcifications.
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http://dx.doi.org/10.1155/2014/581706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220584PMC
November 2014

Tumor marker score for prognostication of early-stage squamous cell cervical cancer.

Anticancer Res 2014 Feb;34(2):887-92

Center for Clinical Research, Nissers vag 3, 79182 Falun, Sweden. and Associate Professor Tibor Tot, Department of Pathology and Clinical Cytology, Falun Hospital, 79182 Falun, Sweden. E-mail:

Background/aim: Histopathological and clinical scores to predict prognosis in cervical cancer have been of limited value. In the present study a tumor marker expression score was evaluated for prognostication in early-stage cervical cancer.

Materials And Methods: The entire study population included 128 women with invasive squamous cell cervical cancer followed-up for at least 10 years.

Results: Expression of 12 tumor markers (epidermal growth factor receptor (EGFR), Ki-67, c-MYC, p53, p27, E-cadherin, CD44, vascular endothelial growth factor receptor (VEGF), cyclooxygenase-2 (COX2), CD4, and leucine-rich immunoglobulin-like repeats-1 (LRIG1) and LRIG2, considered relevant for cervical cancer prognostication was evaluated by immunohistochemistry. Expression of five markers, LRIG1, LRIG2, p53, COX2 and c-MYC were useful to make a prognostication score, ranging from 0 to 5. Score 0-1 correlated to less than 5% 10-year mortality, while the mortality rate of those with score 4-5 approached 70%; those with score 2 formed an intermediate group. Using different models, a high sensitivity, specificity, positive predictive value and negative predictive value was attained.

Conclusion: Tumor marker scoring could be an adjunct to histopathological and clinical parameters in prognostication of early-stage cervical cancer.
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February 2014

Molecular phenotype of the foci in multifocal invasive breast carcinomas: intertumoral heterogeneity is related to shorter survival and may influence the choice of therapy.

Cancer 2014 Jan 11;120(1):26-34. Epub 2013 Oct 11.

Central Hospital Falun, Department of Pathology and Clinical Cytology, Falun, Sweden.

Background: Multiple synchronous, ipsilateral, invasive foci of breast carcinomas are frequent and are associated with a poorer prognosis. Few studies have investigated the prognostic and therapeutic implications of heterogeneity of such foci.

Methods: The authors reviewed the tumor type, grade, and size of all invasive foci in a series of 110 multifocal breast carcinomas documented on large-format slides. Molecular phenotype was determined by immunohistochemistry in tissue microarray blocks using 3 classification systems. The survival of patients who had tumors with microscopic (tumor type and/or grade) heterogeneity and of those who had tumors with phenotypic heterogeneity was compared with the survival of patients who had multifocal homogeneous tumors using Kaplan-Meier curves. The hazard ratio of dying from breast cancer was also calculated.

Results: Intertumoral heterogeneity in tumor type and grade was detected in 16 of 110 tumors (14.6%) and in 6 of 110 tumors (5.5%), respectively. The molecular phenotype of invasive tumor foci within the same breast differed in 10% to 12.7% of patients (11-14 of 110 tumors), depending on the classification system used. Patients who had phenotypically heterogeneous, multifocal cancers had a greater risk of dying from disease (HR=2.879; 95%CI=1.084-7.649; P = .034) and had significantly shorter survival (P = .016). Phenotypic differences were most common in patients who had tumors that were homogeneous in terms of tumor type (11 of 18 tumors) and histology grade (14 of 18 tumors). Phenotyping additional tumor foci had the potential to influence the therapeutic decisions in up to 8 patients.

Conclusions: Phenotyping more than 1 invasive focus of multifocal breast carcinomas only if the individual foci deviate microscopically appears to be insufficient, because phenotypic intertumoral heterogeneity may be observed in microscopically identical foci and has potential prognostic and therapeutic consequences.
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http://dx.doi.org/10.1002/cncr.28375DOI Listing
January 2014

Large-format histology in diagnosing breast carcinoma.

Int J Breast Cancer 2012 27;2012:618796. Epub 2012 Dec 27.

Department of Pathology and Clinical Cytology, Central Hospital, Uppsala University, 791 82 Falun, Sweden.

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http://dx.doi.org/10.1155/2012/618796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544254PMC
January 2013

Multifocal breast cancer documented in large-format histology sections: long-term follow-up results by molecular phenotypes.

Cancer 2013 Mar 27;119(6):1132-9. Epub 2012 Dec 27.

Department of Pathology and Clinical Cytology, Falun Central Hospital, Falun, Sweden.

Background: The prognostic significance of molecular phenotype in breast cancer is well established in the literature. Recent studies have demonstrated that subgross lesion distribution (unifocal, multifocal, and diffuse) and disease extent also carry prognostic significance in this disease. However, the correlation of molecular phenotypes with subgross parameters has not yet been investigated in detail.

Methods: In total, 444 consecutive invasive breast cancers that were documented in large-format histology slides and worked up with detailed radiologic-pathologic correlation were sampled into tissue microarray blocks and stained immunohistochemically to delineate the molecular subtypes.

Results: Diffuse or multifocal distribution of the invasive component of breast carcinomas in this series was associated with a 4.14-fold respectively 2.75-fold risk of cancer-related death compared with unifocal tumors irrespective of molecular phenotype. Patients who had human epidermal growth factor receptor 2 (HER2)-positive cancers; estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) cancers; or basal-like cancers had a 2.18-fold, 2.33-fold, and 4.07-fold risk of dying of disease, respectively, compared with patients who had luminal A carcinomas. Unifocal luminal A, HER2-positive, and basal-like cancers were associated with significantly better long-term survival outcomes than their multifocal or diffuse counterparts; luminal B and triple-negative tumors also had the same tendency. In multivariate analysis, patient age, tumor size category, lymph node status, lesion distribution, and molecular phenotypes remained significant.

Conclusions: Multifocality and diffuse distribution of the invasive component were associated with significantly poorer survival in women with breast carcinomas compared with unifocal disease in patients with luminal A, HER2 type, and basal-like cancers. Molecular classification of breast cancer is a powerful tool but gains in power when combined with conventional and subgross morphologic parameters.
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http://dx.doi.org/10.1002/cncr.27877DOI Listing
March 2013

The role of large-format histopathology in assessing subgross morphological prognostic parameters: a single institution report of 1000 consecutive breast cancer cases.

Authors:
Tibor Tot

Int J Breast Cancer 2012 21;2012:395415. Epub 2012 Oct 21.

Department of Pathology and Clinical Cytology, Central Hospital Falun, 791 82, Falun, Sweden.

Breast cancer subgross morphological parameters (disease extent, lesion distribution, and tumor size) provide significant prognostic information and guide therapeutic decisions. Modern multimodality radiological imaging can determine these parameters with increasing accuracy in most patients. Large-format histopathology preserves the spatial relationship of the tumor components and their relationship to the resection margins and has clear advantages over traditional routine pathology techniques. We report a series of 1000 consecutive breast cancer cases worked up with large-format histology with detailed radiological-pathological correlation. We confirmed that breast carcinomas often exhibit complex subgross morphology in both early and advanced stages. Half of the cases were extensive tumors and occupied a tissue space ≥40 mm in its largest dimension. Because both in situ and invasive tumor components may exhibit unifocal, multifocal, and diffuse lesion distribution, 17 different breast cancer growth patterns can be observed. Combining in situ and invasive tumor components, most cases fall into three aggregate growth patterns: unifocal (36%), multifocal (35%), and diffuse (28%). Large-format histology categories of tumor size and disease extent were concordant with radiological measurements in approximately 80% of the cases. Noncalcified, low-grade in situ foci, and invasive tumor foci <5 mm were the most frequent causes of discrepant findings.
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http://dx.doi.org/10.1155/2012/395415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485542PMC
November 2012

Comparison of the subgross distribution of the lesions in invasive ductal and lobular carcinomas of the breast: a large-format histology study.

Int J Breast Cancer 2012 14;2012:436141. Epub 2012 Oct 14.

Department of Pathology and Clinical Cytology, Central Hospital Falun, 79182 Falun, Sweden.

To compare the lesion distribution and the extent of the disease in ductal and lobular carcinomas of the breast, we studied 586 ductal and 133 lobular consecutive cancers. All cases were documented on large-format histology slides. The invasive component of ductal carcinomas was unifocal in 63.3% (371/586), multifocal in 35.5% (208/586), and diffuse in 1.2% (7/586) of the cases. The corresponding figures in the lobular group were 27.8% (37/133), 45.9% (61/586), and 26.3% (35/133), respectively. When the distribution of the in situ and invasive component in the same tumors was combined to give an aggregate pattern, the ductal carcinomas were unifocal in 41.6% (244/586), multifocal in 31.6% (185/586), and diffuse in 26.8% (157/586) of the cases. The corresponding figures in the lobular category were 15.0% (20/133), 54.2% (72/133), and 30.8% (41/133), respectively. Ductal cancers were extensive in 45.7% (268/586), lobular in 65.4% (87/133) of the cases. All these differences were statistically highly significant (P < 0.0001). While the histological tumor type itself (ductal versus lobular) did not influence the lymph node status, multifocal and diffuse distribution of the lesions were associated with significantly increased risk of lymph node metastases in both ductal and lobular cancers.
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http://dx.doi.org/10.1155/2012/436141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477712PMC
October 2012

Immunohistochemical verification of ductal differentiation in prostate cancer.

APMIS 2012 Jun 12;120(6):510-8. Epub 2012 Jan 12.

Department of Pathology and Clinical Cytology, Central Hospital, Falun, Sweden.

Recent studies have shown that patients with prostate carcinomas exhibiting ductal differentiation have an unfavourable prognosis compared with those with purely acinar adenocarcinomas. We studied the expression of nine immunohistochemical markers to evaluate their value in delineating carcinomas with and without ductal differentiation. Thirteen tumours showing cellular characteristics and growth patterns typical of ductal differentiation were identified among 110 analysed prostatectomy specimens. The levels of cytoplasmic expression of chromogranine A (69% vs 19%, p = 0.0003) and nuclear expression of p53 (76% vs 12%, p < 0.0001) as well as nuclear expression of Ki-67 (69% vs 26%, p = 0.0047) in the tumour cells, were found to be statistically significantly different in the two tumour categories. Assessment of chromogranine A, p53 and Ki-67 in prostate carcinoma may serve as useful adjunctive diagnostic tools for delineating more aggressive prostate cancer cases exhibiting ductal differentiation.
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http://dx.doi.org/10.1111/j.1600-0463.2011.02862.xDOI Listing
June 2012

Improved differentiation between ductal and acinar prostate cancer using three-dimensional histology and biomarkers.

Scand J Urol Nephrol 2012 Aug 23;46(4):258-66. Epub 2012 Apr 23.

Department of Pathology and Clinical Cytology, Central Hospital, Falun, Sweden.

Objective: The aim of the study was to refine the methodology for discriminating the ductal (DAP) and acinar adenocarcinomas (AAP) of the prostate and confirm that prostate carcinoma of ductal origin is a more aggressive subtype.

Material And Methods: A retrospective analysis of 110 consecutive radical prostatectomy cases operated on between 2000 and 2006 and worked up using large-format "two-dimensional" (2D; 4 μm thick) and "three-dimensional" (3D; 1500 μm thick) histology sections was carried out, with an average follow-up of 5.1 years. The same material was also analysed for selected biomarkers in tissue microarray blocks. The most discriminatory biomarkers were then tested on preoperative core biopsy specimens from 24 of these patients.

Results: 3D histology classified 97/110 (88%) cases of AAP and 13/110 (12%) DAP, which was then confirmed in 2D specimens. The DAP cases had a significantly greater frequency of pT3a and more advanced cancers, > 20 mm tumour focus, high-grade prostatic intraepithelial neoplasia, Gleason score ≥ 7, positive margin, extracapsular extension, vascular invasion, seminal vesicle infiltration, biochemical/local recurrence, regional lymph-node metastases and distant metastases. Three biomarkers in combination (chromogranin A, epidermal growth factor receptor and p53] distinguished DAP from AAP with an accuracy of 94% (area under the curve 0.94, 95% confidence interval 0.88-0.99). The same high accuracy was achieved using these three biomarkers on the preoperative specimens.

Conclusions: Both 3D histology and the three selected biomarkers can help in accurately distinguishing DAP from AAP. The clear-cut distinction of two forms of prostate cancers by the approach advocated in this paper would allow AAP patients to undergo less radical treatment and would segregate DAP patients into a subset requiring more effective treatment regimens.
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http://dx.doi.org/10.3109/00365599.2012.675586DOI Listing
August 2012

Axillary lymph node status in unifocal, multifocal, and diffuse breast carcinomas: differences are related to macrometastatic disease.

Authors:
Tibor Tot

Ann Surg Oncol 2012 Oct 3;19(11):3395-401. Epub 2012 Apr 3.

Department of Pathology and Clinical Cytology, Central Hospital Falun, Falun, Sweden.

Background: Multifocality in breast carcinoma is associated with an increased propensity to metastasis. However, it is not clear whether this propensity manifests in the form of macrometastases or as presumably less-significant low-volume metastatic disease.

Methods: A total of 948 cases of invasive breast carcinoma documented in large-format histology sections and assessed with detailed radiologic-pathologic correlation were categorized as unifocal, multifocal, or diffuse on the basis of the subgross distribution of the invasive component. Rates of macrometastases (>2 mm), micrometastases (0.2-2 mm), and isolated tumor cells (<0.2 mm) in these categories were compared. The influence of tumor size and histology grade on lymph node positivity rates was also tested.

Results: Macrometastases were present in 20.4% (112 of 550) of unifocal, 48.3% (172 of 356) of multifocal, and 61.9% (26 of 42) of diffuse cases (P < 0.0001). Among the macrometastatic cases, more than three nodes were involved in 18.9% (21 of 112) of unifocal, 35.5% (61 of 172) of multifocal, and 50.0% (13 of 26) of diffuse cases. The rates of micrometastases (5.1, 5.1, and 2.4% unifocal, multifocal, and diffuse, respectively) and isolated tumor cells (4.5, 3.7, and 2.4% unifocal, multifocal, and diffuse, respectively) were low and similar in all examined categories. The relative risk (RR) of having macrometastatic disease was approximately doubled (RR 2.3726, P < 0.0001) in multifocal and tripled (RR 3.0562, P < 0.0001) in diffuse compared to unifocal cases. The findings were similar for all size categories, tumor grade categories, and sentinel lymph nodes, as well as all examined lymph nodes.

Conclusions: The significantly increased lymph node positivity rates in multifocal and diffuse invasive breast carcinomas results from large-volume macrometastatic disease.
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http://dx.doi.org/10.1245/s10434-012-2346-yDOI Listing
October 2012