P Heikkila

Helsinki University Central Hospital, Helsinki, Southern Finland Province, Finland

Are you P Heikkila?

Claim your profile

Publications (11)23.77 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: As macrophages are some of the first cells to encounter metastatic tumor cells in sentinel lymph nodes (SLN) and natural killer (NK) cells are critical to the cytotoxicity of abnormal cells, we sought to determine if these cell populations were altered in the presence of nodal metastasis. We used immunohistochemistry to assess the SLN of 47 patients with breast cancer (36 with nodal metastasis and 11 without nodal metastasis) and 10 control lymph nodes. We assessed metastatic areas and nonmetastatic areas separately for CD163, a marker of macrophages, and ANK-1, a marker for precursors of activated NK cells. Positively stained cells were manually counted in multiple high-power fields and averaged. Groups were compared with the Kruskal-Wallis test. Spearman rank order test was used for correlations. There was a lower frequency of CD163(+) macrophages in the SLN of patients with breast cancer (median, 11.0 %; range, 4.1-20.4 %) than controls (median, 16.5 %; range, 8.9-19.6 %; p = 0.002). There were no differences in the expression of ANK between patients with cancer (median, 1.4 %; range, 0.23-6.3 %) and controls (median, 1.5 %; range, 0.60-5.4 %; p = 0.5). In patients with nodal metastasis, the accumulation of CD163(+) cells in the sinuses correlated negatively with CD8(+) tumor-infiltrating lymphocytes (r (2) = 0.23; p = 0.001). These results suggest that the reduction of CD163(+) macrophages in the sinuses of the SLN is associated with nodal metastasis and may have a role in regional immunity.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 11/2012; · 2.68 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Although axillary lymph node dissection (ALND) has been the standard intervention in breast cancer patients with sentinel lymph node (SLN) metastasis, only a small proportion of patients benefit from this operation, because most do not harbor additional metastases in the axilla. Several predictive tools have been constructed to identify patients with low risk of non-SLN metastasis who could be candidates for the omission of ALND. In the present work, predictive nomograms were used to predict a high (>50 %) risk of non-SLN metastasis in order to identify patients who would most probably benefit from further axillary treatment. Data of 1000 breast cancer patients with SLN metastasis and completion ALND from 5 institutions were tested in 4 nomograms. A subset of 313 patients with micrometastatic SLNs were also tested in 3 different nomograms devised for the micrometastatic population (the high risk cut-off being 20 %). Patients with a high predicted risk of non-SLN metastasis had higher rates of metastasis in the non-SLNs than patients with low predicted risk. The positive predictive values of the nomograms ranged from 44 % to 64 % with relevant inter-institutional variability. The nomograms for micrometastatic SLNs performed much better in identifying patients with low risk of non-SLN involvement than in high-risk-patients; for the latter, the positive predictive values ranged from 13 % to 20 %. The nomograms show inter-institutional differences in their predictive values and behave differently in different settings. They are worse in identifying high risk patients than low-risk ones, creating a need for new predictive models to identify high-risk patients.
    Pathology & Oncology Research 07/2012; · 1.56 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Sentinel lymph node (SN) biopsy offers the possibility of selective axillary treatment for breast cancer patients, but there are only limited means for the selective treatment of SN-positive patients. Eight predictive models assessing the risk of non-SN involvement in patients with SN metastasis were tested in a multi-institutional setting. Data of 200 consecutive patients with metastatic SNs and axillary lymph node dissection from each of the 5 participating centres were entered into the selected non-SN metastasis predictive tools. There were significant differences between centres in the distribution of most parameters used in the predictive models, including tumour size, type, grade, oestrogen receptor positivity, rate of lymphovascular invasion, proportion of micrometastatic cases and the presence of extracapsular extension of SN metastasis. There were also significant differences in the proportion of cases classified as having low risk of non-SN metastasis. Despite these differences, there were practically no such differences in the sensitivities, specificities and false reassurance rates of the predictive tools. Each predictive tool used in clinical practice for patient and physician decision on further axillary treatment of SN-positive patients may require individual institutional validation; such validation may reveal different predictive tools to be the best in different institutions.
    Surgical Oncology 12/2011; 21(2):59-65. · 2.14 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The regional immune systems of patients with breast cancer are immunosuppressed. Dendritic cells are professional antigen-presenting cells and present cancer-associated antigens to the adaptive immune system in sentinel lymph nodes. Dendritic cells may promote, or inhibit, an adaptive immune response to specific antigens. Our aim was to assess whether dendritic cells were associated with nodal metastasis in patients with breast cancer. Sentinel lymph nodes of 47 patients with breast cancer with varying degrees of nodal disease and ten controls were evaluated using immunohistochemistry for the accumulation of dendritic cells in general (CD1a(+)), mature dendritic cells (CD208(+)), and plasmacytoid dendritic cells (CD123(+)). Cytotoxic T cell and regulatory T cell accumulation were also evaluated. Sentinel lymph nodes with macrometastases demonstrated fewer mature dendritic cells than sentinel lymph nodes without metastasis (p = 0.028), but not controls. There were fewer mature dendritic cells to cytotoxic T cells in sentinel lymph nodes with metastasis than those without (p = 0.033). Also, there were more regulatory T cells to mature dendritic cells in sentinel lymph nodes with metastasis than those without (p = 0.02). In conclusion, our study suggests that sentinel lymph nodes with metastasis have arrest of maturation of dendritic cells, fewer mature dendritic cell interactions with cytotoxic T cells, and more regulatory T cells than sentinel lymph nodes without metastasis in patients with breast cancer. These findings extend our understanding of regional immunosuppression and suggest that most regional immunosuppressive changes are associated with nodal metastasis in breast cancer.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 09/2011; 459(4):391-8. · 2.68 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: There is evidence that the immune systems of patients with breast cancer are dysfunctional. Regulatory T cells (Tregs), and IDO, an immunosuppressive enzyme, are associated with more advanced disease in some cancers and may promote immunologic tolerance to tumors. Our aim was to assess whether expression of Foxp3, a marker of Tregs, and IDO were linked with nodal metastasis in breast cancer patients. Inhibitors of IDO are available and could potentially demonstrate utility in breast cancer if IDO drives progression of disease. Sentinel lymph nodes (SLN) of 47 breast cancer patients with varying degrees of nodal disease and 10 controls were evaluated for expression of Foxp3 and IDO using immunohistochemistry. Positively stained cells were quantified and their distribution within the SLN noted. The proportion of Foxp3+ cells was higher in SLN of cancer patients than controls (19% v. 10%, p < 0.001). Specifically, there were more Foxp3+ cells in SLN with metastasis than tumor-free SLN (20% v. 14%, p = 0.02). The proportion IDO+ cell in SLN of cancer patients was not statistically different than controls (4.0% v. 1.6%, p = 0.08). In order to demonstrate the combined immunosuppressive effect of Foxp3 and IDO, we categorized each SLN as positive or negative for Foxp3 and IDO. The Foxp3+/IDO+ group almost exclusively consisted of cancer patients with node positive disease. In conclusion, our study shows that Foxp3+ cells are associated with more advanced disease in breast cancer, a finding that is proving to be true in many other cancers. As IDO has been found to promote differentiation of Tregs, IDO may become a suitable target to abrogate the development of T-cell tolerance and to promote an effective immune response to breast cancer. Our results about the combined expression of IDO and Foxp3 in metastastic SLN support this assumption.
    BMC Cancer 07/2009; 9:231. · 3.33 Impact Factor
  • Ejc Supplements - EJC SUPPL. 01/2008; 6(7):154-154.
  • Ejc Supplements - EJC SUPPL. 01/2008; 6(7):80-80.
  • [show abstract] [hide abstract]
    ABSTRACT: To assess the variability of oestrogen receptor (ER) testing using immunocytochemistry, centrally stained and unstained slides from breast cancers were circulated to the members of the European Working Group for Breast Screening Pathology, who were asked to report on both slides. The results showed that there was almost complete concordance among readers (kappa=0.95) in ER-negative tumours on the stained slide and excellent concordance among readers (kappa=0.82) on the slides stained in each individual laboratory. Tumours showing strong positivity were reasonably well assessed (kappa=0.57 and 0.4, respectively), but there was less concordance in tumours with moderate and low levels of ER, especially when these were heterogeneous in their staining. Because of the variation, the Working Group recommends that laboratories performing these stains should take part in a external quality assurance scheme for immunocytochemistry, should include a tumour with low ER levels as a weak positive control and should audit the percentage positive tumours in their laboratory against the accepted norms annually. The Quick score method of receptor assessment may also have too many categories for good concordance, and grouping of these into fewer categories may remove some of the variation among laboratories.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 09/2004; 445(2):119-28. · 2.68 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.
    Journal of Clinical Pathology 07/2004; 57(7):695-701. · 2.44 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Controversies and inconsistencies regarding the pathological work-up of sentinel lymph nodes (SNs) led the European Working Group for Breast Screening Pathology (EWGBSP) to review published data and current evidence that can promote the formulation of European guidelines for the pathological work-up of SNs. After an evaluation of the accuracy of SN biopsy as a staging procedure, the yields of different sectioning methods and the immunohistochemical detection of metastatic cells are reviewed. Currently published data do not allow the significance of micrometastases or isolated tumour cells to be established, but it is suggested that approximately 18% of the cases may be associated with further nodal (non-SN) metastases, i.e. approximately 2% of all patients initially staged by SN biopsy. The methods for the intraoperative and molecular assessment of SNs are also surveyed.
    European Journal of Cancer 09/2003; 39(12):1654-67. · 5.06 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: In premature infants with necrotizing enterocolitis (NEC) the gastrointestinal mucosal barrier is immature, but little is known about the immune response of immature bowel. The aim of this study was to evaluate the intestinal mucosal immune response in experimental NEC. In general anaesthesia, NEC was induced in six newborn piglets by injection of bovine casein into terminal ileum. Six controls received an equal amount of saline. Four hours later, samples were taken from the macroscopically most affected part of the treated loop and from the macroscopically healthy untreated intestine. Monoclonal antibodies to porcine CD1, CD2, CD4, CD8, CD45 and IgM were used for immunohistochemical staining. Casein-treated bowel showed typical macro- and microscopic findings of NEC. No changes were found in the saline-treated bowel. In both groups the bowel outside the treatment sector was normal. In casein-treated animals, treated samples showed significant decrease in density of CD4+ cells when compared with saline-treated controls. Similar trend was found in CD2+ and CD8+ cells but without statistical significance. Macroscopically healthy proximal untreated samples showed significant decrease in densities of CD2+, CD4+ and CD8+ lymphocytes in casein-treated group when compared with control samples. In casein-treated animals the density of CD45+ cells in the non-injected bowel was also decreased, but this did not reach statistical significance. Densities of CD1+ and IgM+ cells did not differ between casein-treated and saline-treated groups. A significant T-cell decrease was found in the present NEC model. Surprisingly, this was most prominent in the macroscopically healthy bowel outside the casein injection segment. The reason for T-cell decrease remains unclear, but bovine casein is known to contain peptide fractions that can modulate immune function. These findings may have implications in the design of neonatal milk formulas.
    Pediatric Surgery International 08/2003; 19(5):326-30. · 1.22 Impact Factor