Falun, Sweden
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Lindquist D.,Center for Clinical Research Dalarna | Lindquist D.,Karolinska Institutet | Lindquist D.,Umeå University | Ahrlund-Richter A.,Karolinska Institutet | And 3 more authors.
Anticancer Research | Year: 2012

Background: Patients with tonsillar and base of tongue cancer, which are human papillomavirus (HPV) positive, have a better clinical outcome than those with HPV-negative tumors. The identification of additional predictive markers for response to therapy could still be of great use. Materials and Methods: Tumor markers CD44, p16, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), E-cadherin, cyclooxygenase-2 (COX 2), Ki-67, and p27 were analyzed by immunochemistry, and HPV status was tested by polymerase chain reaction (PCR) in tumors from 73 patients and correlated to survival. Results: High intensity CD44 staining (p=0.006) and high EGFR expression (p=0.026) were indicators of poor prognosis, while high p16 expression (p=0.021) and younger age (p=0.002) were positive prognostic markers for disease-specific survival. Furthermore, staining of CD44 (p=0.026) and age (p=0.002) were shown to be strong prognostic markers in multivariate analysis, which should be evaluated further for possible use in clinical practice.

Lindquist D.,Umeå University | Nasman A.,Karolinska Institutet | Tarjan M.,Central Hospital Falun | Henriksson R.,Umeå University | And 3 more authors.
British Journal of Cancer | Year: 2014

Background:The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer has increased rapidly during the past decades. HPV is typically associated with a favourable outcome; however, a need exists for new and more effective prognostic and predictive markers for this disease. Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a tumour suppressor protein that belongs to the LRIG family. LRIG1 expression has prognostic significance in various human cancers, including cervical cancer, where HPV is a key aetiological agent.Methods:The prognostic value of LRIG1 and LRIG2 immunoreactivity was investigated in tumour specimens from a Swedish cohort of patients with tonsillar and base of tongue oropharyngeal cancers, including 278 patients.Results:LRIG1 immunoreactivity correlated with disease-free survival and overall survival in univariate and multivariate analyses. Notably, patients with HPV-positive tumours with high LRIG1 staining intensity or a high percentage of LRIG1-positive cells showed a very good prognosis. Furthermore, LRIG1 expression correlated with HPV status, whereas LRIG2 expression inversely correlated with HPV status.Conclusions:Taken together, the results suggest that LRIG1 immunoreactivity could be a clinically important prognostic marker in HPV-associated oropharyngeal cancer. © 2014 Cancer Research UK.

Aims : This study was designed to evaluate the prognostic significance of focal chromogranin A (cgA) expression in prostate cancer in a series of cases with autopsy-verified cause of death. Methods and Results : Seventy seven autopsy-verified cases of prostate cancer were identified, 41 cases with metastatic disease and 36 with nonmetastatic disease at autopsy. Immunohistochemical analysis for cgA was performed in 40 cases on the archived diagnostic biopsies taken during the patients' lifetime. After exclusion of a single case of carcinoid tumor, 14 of the 18 (78%) metastatic and none of the 21 (0%) nonmetastatic tumors showed focal neuroendocrine differentiation (NED). The Gleason score and focal cgA expression further increased the accuracy of the prediction of the outcome, as all the cases with focal NED associated with high Gleason score had metastatic disease in contrast to cases without cgA-expression and low Gleason score, all of which were non-metastatic. Conclusions : Focal NED seems to be a powerful negative prognostic parameter in prostate adenocarcinomas. The outcome of the disease in prostate cancer can be accurately predicted based on focal NED of the tumor cells either alone or in combination with Gleason score.

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 lowvolume 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. © Society of Surgical Oncology 2012.

Pekar G.,Central Hospital Falun | Gere M.,Central Hospital Falun | Tarjan M.,Central Hospital Falun | Hellberg D.,Uppsala University | Tot T.,Central Hospital Falun
Cancer | Year: 2014

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. Cancer 2014;120:26-34. © 2013 American Cancer Society. In a series of 110 multifocal breast carcinomas, the tumor type, grade, size, and molecular phenotype of all invasive foci are evaluated. Significant proportions of tumors reveal intertumoral heterogeneity; patients with phenotypically heterogeneous, multifocal cancers have a greater risk of dying from disease and a significantly shorter survival; and the phenotypic differences are most common among women with tumors that are homogeneous in terms of tumor type and histology grade. © 2013 American Cancer Society.

Tot T.,Central Hospital Falun
Seminars in Diagnostic Pathology | Year: 2010

Assessing the distribution of the in situ and invasive components of breast carcinomas and the extent of the disease represent an integrated part of our diagnostic routine. In this article, we summarize findings from 792 consecutive breast carcinoma cases, each documented in large-format histology slides. Selected cases were also analyzed in thick, large sections. Of these, 35.0% (42/120) of the purely in situ carcinomas were diffuse and occupied mostly larger ducts, whereas 37.5% (45/120) were multifocal and involved several distant terminal ductal-lobular units (TDLUs). The proportion of unifocal in situ cases involving a single TDLU or several neighboring TDLUs was 27.5% (33/120). Forty-one percent (136/332) of early (<15 mm) invasive carcinomas and 40.0% (136/340) of larger invasive tumors contained only a single invasive focus, with or without an in situ component within it. The remaining tumors were nonunifocal because of multiple invasive or multiple in situ foci or both. The proportion of extensive nonunifocal cases within purely in situ, early invasive, and more advanced invasive cases were 45.0% (54/120), 42.5% (141/332), and 42.4% (144/340), respectively. The results are discussed in the context of recent molecular genetic findings and the sick lobe theory. Elements that are congruent with the classical views of Professor Azzopardi expressed over 3 decades ago will be pointed out. Breast carcinoma seems to develop within a field of genetic alterations, often at multiple sites, and a considerable proportion of the cases comprise extensive lesions occupying a tissue space ≥40 mm in all tumor size categories. © 2010 Elsevier Inc.

Early breast carcinoma, defined as purely in situ cancer and invasive carcinomas < 15 mm, represents the most frequent category of breast carcinomas in diagnostic routine in a regularly screened population. These tumors are usually detected with mammography screening and are preoperatively characterized with radiological imaging. The role of pathology in preoperative settings is to help understand the subgross morphology and to confirm malignancy in biopsy material. Postoperatively, the pathologist needs to verify the size of the cancer (defined as the largest dimension of the largest invasive focus), the extent of the disease (defined as the area or the volume of the breast tissue containing all the malignant foci), the distribution of the in situ and invasive lesions (as unifocal, multifocal, or diffuse), and intratumoral and intertumoral heterogeneity (in addition to determining margin status, histologic tumor type, hormone receptor status, and other parameters). Despite their small size, early breast carcinomas often exhibit complex morphology as they are multifocal/diffuse in about 60% and extensive (occupying an area ≥ 4 cm) in 40% of the cases. Routine use of large-format histopathology technique is a prerequisite for detailed correlation of the radiologic and histopathologic findings and for the correct assessment of these parameters. Breast pathologists must be aware of the advantages and disadvantages of the different imaging modalities and have detailed information about the radiological findings before work-up of the operative specimen. Multidisciplinary preoperative and postoperative tumor board meetings are essential in guiding the pathologists and in confirming the radiological findings. Interdisciplinary diagnosis is inevitably becoming the new gold standard in the diagnosis and management of early breast carcinomas. © 2010 Springer-Verlag.

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. © 2015, Society of Surgical Oncology.

Tot T.,Central Hospital Falun
Clinical Breast Cancer | Year: 2011

Background: I examined the relationship between the recently established prognostic parameter, molecular tumor phenotype and tumor size, lesion distribution (unifocal, multifocal, diffuse growth), and lymph node status. Materials and Methods: I analyzed 660 consecutive invasive breast carcinomas documented in large-format histology sections. Immunohistochemistry was used to phenotype the tumors on the basis of estrogen and progesterone receptor expression, HER2 (human epithelial growth factor receptor 2) overexpression, and expression of basal markers. Results: The proportion of luminal A tumors (84.8% vs. 71.6%; P <.0001) and basal-like tumors (5.0% vs. 14.8%; P <.0001) were significantly different in early (<15 mm) and more advanced invasive breast carcinomas, whereas the proportion of luminal B and HER2 type tumors (4.2% vs. 7.8%, and 5.7% vs. 4.8%, respectively) were not. All the phenotypes had similar percentages of multifocal tumors, whereas most diffuse invasive carcinomas were luminal A type. Early luminal A carcinomas had significantly fewer lymph node metastases (LNM) than more advanced carcinomas but luminal B and HER2 type tumors showed no such difference. This difference was evident (15.4% vs. 42.4%) but statistically not significant in the basal-like category. Multifocal tumors of all phenotypes had significantly higher frequencies of LNM compared with unifocal tumors. Conclusion: Multifocality of the invasive component represents a negative prognostic parameter associated with significantly increased LNM in all phenotype, whereas larger tumor size was such a parameter only in the luminal A category. HER2 overexpression occurs early in the natural history of tumors and is associated with high LNM rates. © 2011 Published by Elsevier Inc.

Tot T.,Central Hospital Falun | Pekar G.,Central Hospital Falun
Annals of Surgical Oncology | Year: 2011

Background: Basal-like breast carcinomas often are regarded for circumscribed solitary lesions having unfavorable prognosis. On the other hand, a considerable proportion of breast carcinomas is multifocal and has increased metastatic potential. In this study, we analyzed the subgross distribution of the lesions in a series of basal-like carcinomas, compared it with that in nonbasal-like tumors and studied the frequency of vascular invasion and lymph node metastasis in relation to focality of the lesions. Methods: A total of 511 consecutive cases documented in large-format histologic sections were studied. Tumors expressing at least one of the basal (myoepithelial) markers (CK5/6, CK14, EGFR) in at least one of the invasive tumor foci were categorized as basal-like tumors. Triple-negative (ER/PR/HER-2-negative) basal-like carcinomas also were analyzed. The distribution of lesions and the frequency of vascular invasion and lymph node metastasis were analyzed. The study was approved by the Regional Ethical Committee Uppsala-Örebro. Results: In 44% of cases, the invasive component was multifocal or diffuse. Combining the in situ and invasive tumor components resulted in 61% of cases with multifocal/diffuse distribution. The only statistically significant difference observed was that basal-like tumors lacked in situ components more often (21% vs. 9%; P = 0.0075). No significant differences could be demonstrated regarding vascular invasion and lymph node status. Lymph node metastasis appeared significantly more frequently in multifocal cases in both tumor categories. Conclusions: Basal-like breast carcinomas are as frequently multifocal as their non-basal-like counterparts; multifocality is associated with increased risk for vascular invasion and lymph node metastasis in both tumor categories. © 2010 Society of Surgical Oncology.

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