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A new pathological system for grading DCIS with improved prediction of local recurrence
A new pathological system for grading DCIS with improved prediction of local recurrence: results from the UKCCCR DCIS trial
S E Pinder1, C Duggan2, I O Ellis3, J Cuzick4,rolex perpetual oyster datejust fake, J F Forbes5, H Bishop6, I S Fentiman7 and W D George8 on behalf of the UK Coordinating Committee on Cancer Research (UKCCCR) Ductal Carcinoma In Situ (DCIS) Working PartyReceived 17 February 2010; Revised 30 April 2010; Accepted 5 May 2010Advance online publication 1 June 2010
Top of pageAbstractBackground: Method: Results: Conclusion: Materials and methods Results Discussion References Figures and TablesBackground: There is no consensus agreement regarding optimal management of locally excised ductal carcinoma in situ (DCIS) or features of greatest assistance in predicting disease behaviour. Cases in the UKCCCR DCIS trial have been histologically reviewed to determine the features of prognostic importance.
Method: A total of 72 of 1694 cases entered into the UKCCCR DCIS trial had full pathological review. In addition, we found little difference in ipsilateral recurrence rates between low and intermediate grade groups. Hazard ratios for low, intermediate, high and the new, very high, grade were 0.42, 0.33, 0.62 and 1.00, respectively, for ipsilateral in situ or invasive recurrence.
Mammographic breast screening facilitates the diagnosis of ductal carcinoma in situ (DCIS) (Anderson et al, 1991) and the apparent incidence has increased as a result (Baxter et al, 2004). Thus, DCIS comprised 21 of screen detected breast carcinoma in the United Kingdom in 2006 (NHS Breast Screening Programme. Annual Review, 2008). In the early 1990s, three large randomised clinical trials began recruiting with the aim of assessing the safety of breast conserving surgery (BCS) for DCIS and the requirement for subsequent radiotherapy (RT) in women having wide local excision (WLE) for DCIS. The NSABP B 17 (Fisher et al, 1998, 1999b) and EORTC 10853 trials (Julien et al, 2000; Bijker et al, 2001, 2006), as well as the UKCCCR DCIS trial (UK Coordinating Committee on Cancer Research Ductal Carcinoma in situ Working Party, 2003) recruited patients diagnosed with DCIS in the early 1990s and have already presented results comparing complete surgical excision with and without RT. Two of these trials (Fisher et al, 1999a; UK Coordinating Committee on Cancer Research Ductal Carcinoma in situ Working Party, 2003) also addressed the effect of the addition of tamoxifen to complete local excision in the management of DCIS.
The clinical management of patients with DCIS changed during the 1990s, but, despite the large reduction of local recurrence risk from RT after BCS for DCIS, only 57 of women have RT after BCS in the United Kingdom (Dodwell et al, 2007). There is a widespread belief that not all patients with DCIS require RT. However, the search for features that can assist in this clinical decision making process remains unresolved (Silverstein et al, 1996; Sakorafas and Farley, 2003).
Top of pageMaterials and methodsBackground: Method: Results: Conclusion: Materials and methods Results Discussion References Figures and TablesThe UKCCCR DCIS trial was a 2 2 factorial randomised clinical trial comparing complete WLE alone with WLE plus RT to the residual ipsilateral breast tissue. Two further arms consisted of WLE followed by tamoxifen and WLE plus RT and tamoxifen. The dose of tamoxifen was 20 daily taken for 5 years. Patients receiving RT were given supervoltage treatment with opposed tangential fields that included the breast and the axillary tail,fake datejust rolex. A dose of 50 in 25 fractions over 5 weeks was suggested. No boost was recommended.
Patients had unilateral or bilateral DCIS detected through the UK National Health Service Breast Screening Programme, which was considered suitable for BCS. The Australian Zealand Breast Cancer Trials Group also participated in the trial. Exclusion criteria included a diagnosis of atypical ductal hyperplasia, lobular carcinoma in situ or Paget's disease of the nipple. Patients gave witnessed, written or verbal consent for inclusion, and local ethics approval was obtained in all centres recruiting patients.
After randomisation and treatment, patients were followed up as per local protocol. Dates of relapse (ipsilateral or contralateral), diagnosis of new, non breast malignant disease and death (breast cancer related or not) were recorded.
Histological reviewRepresentative material was sought from the surgical excision. Slides were examined by a single breast pathologist (SEP) and a large number of histological features were recorded in a database (see Table 1). Any cases that on review showed histological features, which were not sufficient for the diagnosis of DCIS, or which showed an invasive focus, were reviewed and the diagnosis confirmed by a second pathologist (IOE). For some of these, criteria had to be specifically defined as, after literature and guideline review, it was found that no globally agreed definitions could be applied. All these features had to be present for classification of pure comedo disease in both the traditional sub type categorisation and for DCIS grade.
The original clinical protocol for the UKCCCR DCIS trial required complete excision of DCIS, but no margin width was defined. Review of completeness of excision and margin width is problematic within the auspices of a central pathology view. However, the evaluation of margin status and distance was determined on a case by case basis, taking into account the original histology report, number and orientation of specimens and the histological review, in which the distance (mm) to the nearest margin was measured on the histological sections received using the Vernier scale of the microscope. For the purposes of the present analysis, a distance of 1 or more from the nearest margin was defined as complete excision. Thus,fake rolex oyster datejust, if DCIS was stated to be 1 or more from the surgical margin (or completely excised) in the original report, and this was confirmed on review, excision was deemed complete. Excision was coded as uncertain, when multiple pieces of unorientated tissue were received by the original pathologist or excision was stated as uncertain in original report (and no subsequent surgical procedure undertaken) or there was a discrepancy between the review and original report that could not be explained taking all features into account.
For determination of size of DCIS, the larger of the measurements of maximal dimension from either the original report or review of histological sections was recorded. If there was DCIS in first and any subsequent re excision, or several pieces of tissue were excised bearing DCIS, the measurements were summed (recognising that this would be an approximation and would generally be an overestimate of total size). In some cases, size could not be assessed on review and was not recorded in the original histology report.
The presence and degree of associated chronic inflammation was recorded. This was typically immediately adjacent to the involved ducts spaces and some cases included nodular aggregates of lymphoid cells, with lymphoid follicle formation. In other cases, this was seen as a complete, targetoid, peri ductal population of lymphoid cells. This was assessed in a semi quantitative manner and scored as absent, mild, moderate or marked.
Top of pageResultsBackground: Method: Results: Conclusion: Materials and methods Results Discussion References Figures and TablesTreatment comparison analyses have been presented earlier (UK Coordinating Committee on Cancer Research Ductal Carcinoma in situ Working Party, 2003). Here, we present results from the histological review with the same follow up. Between May 1990 and August 1998, 1701 patients were entered into the trial. Seven were excluded because of protocol violations (earlier malignant disease,value of a rolex oyster perpetual datejust fake, treated by mastectomy, known to have invasive carcinoma) (n patients in total in the trial overall).
The number of slides submitted for pathological review varied (range 0 per case), with some laboratories submitting all slides, whereas others sent one representative slide or block (total number of sections 9649, mean 7.6, median 5 slides per case). On review, 33 patients were found to have earlier undiagnosed invasive carcinoma in the sections submitted (usually small and low grade) and were excluded from analysis. Twenty patients were not proven to have DCIS; in these cases, additional material was sought from the originating laboratory and reviewed, but no DCIS was identified in any of the material sent.
Sections were unavailable, or could not be retrieved, from 300 patients; these were not from any particular unit, coordinating centre or trial arm. the section submitted bore insufficient DCIS for a complete assessment). A total of 1224 (72.3 patients had full data from histological review available on DCIS size, histological grade presence and degree of comedo type necrosis, presence and degree of inflammation and excision status and were included in the present analyses (Table 1). Accurate review of the presence or absence of microinvasion was felt to be too error prone for meaningful analysis; some cases had the original sections submitted for review, but from other cases, new sections had been cut and submitted for re evaluation. Nevertheless, only 16 of the 1224 cases in this series had definite microinvasion and a further 42 had microinvasion in the original histology report. This feature was related to size of DCIS lesion, but not, perhaps surprisingly, to the grade of DCIS (data not shown).
Analysis for treatment arms was repeated, using the sub set of cases with full pathological data from this review, to confirm that the results were not significantly different from the whole group analysis presented earlier (UK Coordinating Committee on Cancer Research Ductal Carcinoma in situ Working Party, 2003).
One hundred and fifty four of the 1224 cases reviewed (12.6 developed recurrence of disease either DCIS or invasive carcinoma in the ipsilateral breast. Ninety nine (64 developed recurrent DCIS and 55 invasive disease, comparable with the results in analysis of the overall trial.
Univariate analyses and distribution of features of DCIS are shown in Table 1. The DCIS was found to be of high cytonuclear grade (National Pathology Co ordinating Group, 2005) in 74.6 of cases (n 18.4 were of intermediate grade and only 7.0 of cases (n were of low cytonuclear grade (n Breakdown by Van Nuys grade (Silverstein et al, 1995) showed that in addition to the 913 patients (as above) with high grade disease (74.6 212 had DCIS, which was non high grade but in which necrosis was present (17.3 and 99 patients had non high grade DCIS without necrosis (8.1 Comedo type necrosis, to a greater or lesser extent, was present in all, but 117 cases (90.4 in this series of screen detected DCIS.
All of the systems of grading of DCIS applied showed a significant association with recurrence of ipsilateral DCIS or invasive disease, as did the predominant growth pattern of the disease. Patients with a solid morphology as the main architectural pattern of DCIS had a 15.2 recurrence rate compared with 14.3 of those with micropapillary DCIS and only 7.3 of those with predominantly cribriform DCIS. The presence or absence of comedo type necrosis and the presence of associated chronic inflammation was also associated with increased risk of recurrence of DCIS or progression to invasive cancer in the ipsilateral breast (Table 1).
Intragrade analysis showed that the pure comedo type cases (n 39.5 fared particularly poorly. This novel classification system showed a strong relationship with development of ipsilateral recurrence (Table 2a), both overall and separately for DCIS and invasive disease (Figures 1, 2 and 3). This new classification system, retained significance across the range of sizes of disease (although numbers in the groups are by necessity smaller).
A new pathological system for grading DCIS with improved prediction of local recurrence: results from the UKCCCR DCIS trial
S E Pinder1, C Duggan2, I O Ellis3, J Cuzick4,rolex perpetual oyster datejust fake, J F Forbes5, H Bishop6, I S Fentiman7 and W D George8 on behalf of the UK Coordinating Committee on Cancer Research (UKCCCR) Ductal Carcinoma In Situ (DCIS) Working PartyReceived 17 February 2010; Revised 30 April 2010; Accepted 5 May 2010Advance online publication 1 June 2010
Top of pageAbstractBackground: Method: Results: Conclusion: Materials and methods Results Discussion References Figures and TablesBackground: There is no consensus agreement regarding optimal management of locally excised ductal carcinoma in situ (DCIS) or features of greatest assistance in predicting disease behaviour. Cases in the UKCCCR DCIS trial have been histologically reviewed to determine the features of prognostic importance.
Method: A total of 72 of 1694 cases entered into the UKCCCR DCIS trial had full pathological review. In addition, we found little difference in ipsilateral recurrence rates between low and intermediate grade groups. Hazard ratios for low, intermediate, high and the new, very high, grade were 0.42, 0.33, 0.62 and 1.00, respectively, for ipsilateral in situ or invasive recurrence.
Mammographic breast screening facilitates the diagnosis of ductal carcinoma in situ (DCIS) (Anderson et al, 1991) and the apparent incidence has increased as a result (Baxter et al, 2004). Thus, DCIS comprised 21 of screen detected breast carcinoma in the United Kingdom in 2006 (NHS Breast Screening Programme. Annual Review, 2008). In the early 1990s, three large randomised clinical trials began recruiting with the aim of assessing the safety of breast conserving surgery (BCS) for DCIS and the requirement for subsequent radiotherapy (RT) in women having wide local excision (WLE) for DCIS. The NSABP B 17 (Fisher et al, 1998, 1999b) and EORTC 10853 trials (Julien et al, 2000; Bijker et al, 2001, 2006), as well as the UKCCCR DCIS trial (UK Coordinating Committee on Cancer Research Ductal Carcinoma in situ Working Party, 2003) recruited patients diagnosed with DCIS in the early 1990s and have already presented results comparing complete surgical excision with and without RT. Two of these trials (Fisher et al, 1999a; UK Coordinating Committee on Cancer Research Ductal Carcinoma in situ Working Party, 2003) also addressed the effect of the addition of tamoxifen to complete local excision in the management of DCIS.
The clinical management of patients with DCIS changed during the 1990s, but, despite the large reduction of local recurrence risk from RT after BCS for DCIS, only 57 of women have RT after BCS in the United Kingdom (Dodwell et al, 2007). There is a widespread belief that not all patients with DCIS require RT. However, the search for features that can assist in this clinical decision making process remains unresolved (Silverstein et al, 1996; Sakorafas and Farley, 2003).
Top of pageMaterials and methodsBackground: Method: Results: Conclusion: Materials and methods Results Discussion References Figures and TablesThe UKCCCR DCIS trial was a 2 2 factorial randomised clinical trial comparing complete WLE alone with WLE plus RT to the residual ipsilateral breast tissue. Two further arms consisted of WLE followed by tamoxifen and WLE plus RT and tamoxifen. The dose of tamoxifen was 20 daily taken for 5 years. Patients receiving RT were given supervoltage treatment with opposed tangential fields that included the breast and the axillary tail,fake datejust rolex. A dose of 50 in 25 fractions over 5 weeks was suggested. No boost was recommended.
Patients had unilateral or bilateral DCIS detected through the UK National Health Service Breast Screening Programme, which was considered suitable for BCS. The Australian Zealand Breast Cancer Trials Group also participated in the trial. Exclusion criteria included a diagnosis of atypical ductal hyperplasia, lobular carcinoma in situ or Paget's disease of the nipple. Patients gave witnessed, written or verbal consent for inclusion, and local ethics approval was obtained in all centres recruiting patients.
After randomisation and treatment, patients were followed up as per local protocol. Dates of relapse (ipsilateral or contralateral), diagnosis of new, non breast malignant disease and death (breast cancer related or not) were recorded.
Histological reviewRepresentative material was sought from the surgical excision. Slides were examined by a single breast pathologist (SEP) and a large number of histological features were recorded in a database (see Table 1). Any cases that on review showed histological features, which were not sufficient for the diagnosis of DCIS, or which showed an invasive focus, were reviewed and the diagnosis confirmed by a second pathologist (IOE). For some of these, criteria had to be specifically defined as, after literature and guideline review, it was found that no globally agreed definitions could be applied. All these features had to be present for classification of pure comedo disease in both the traditional sub type categorisation and for DCIS grade.
The original clinical protocol for the UKCCCR DCIS trial required complete excision of DCIS, but no margin width was defined. Review of completeness of excision and margin width is problematic within the auspices of a central pathology view. However, the evaluation of margin status and distance was determined on a case by case basis, taking into account the original histology report, number and orientation of specimens and the histological review, in which the distance (mm) to the nearest margin was measured on the histological sections received using the Vernier scale of the microscope. For the purposes of the present analysis, a distance of 1 or more from the nearest margin was defined as complete excision. Thus,fake rolex oyster datejust, if DCIS was stated to be 1 or more from the surgical margin (or completely excised) in the original report, and this was confirmed on review, excision was deemed complete. Excision was coded as uncertain, when multiple pieces of unorientated tissue were received by the original pathologist or excision was stated as uncertain in original report (and no subsequent surgical procedure undertaken) or there was a discrepancy between the review and original report that could not be explained taking all features into account.
For determination of size of DCIS, the larger of the measurements of maximal dimension from either the original report or review of histological sections was recorded. If there was DCIS in first and any subsequent re excision, or several pieces of tissue were excised bearing DCIS, the measurements were summed (recognising that this would be an approximation and would generally be an overestimate of total size). In some cases, size could not be assessed on review and was not recorded in the original histology report.
The presence and degree of associated chronic inflammation was recorded. This was typically immediately adjacent to the involved ducts spaces and some cases included nodular aggregates of lymphoid cells, with lymphoid follicle formation. In other cases, this was seen as a complete, targetoid, peri ductal population of lymphoid cells. This was assessed in a semi quantitative manner and scored as absent, mild, moderate or marked.
Top of pageResultsBackground: Method: Results: Conclusion: Materials and methods Results Discussion References Figures and TablesTreatment comparison analyses have been presented earlier (UK Coordinating Committee on Cancer Research Ductal Carcinoma in situ Working Party, 2003). Here, we present results from the histological review with the same follow up. Between May 1990 and August 1998, 1701 patients were entered into the trial. Seven were excluded because of protocol violations (earlier malignant disease,value of a rolex oyster perpetual datejust fake, treated by mastectomy, known to have invasive carcinoma) (n patients in total in the trial overall).
The number of slides submitted for pathological review varied (range 0 per case), with some laboratories submitting all slides, whereas others sent one representative slide or block (total number of sections 9649, mean 7.6, median 5 slides per case). On review, 33 patients were found to have earlier undiagnosed invasive carcinoma in the sections submitted (usually small and low grade) and were excluded from analysis. Twenty patients were not proven to have DCIS; in these cases, additional material was sought from the originating laboratory and reviewed, but no DCIS was identified in any of the material sent.
Sections were unavailable, or could not be retrieved, from 300 patients; these were not from any particular unit, coordinating centre or trial arm. the section submitted bore insufficient DCIS for a complete assessment). A total of 1224 (72.3 patients had full data from histological review available on DCIS size, histological grade presence and degree of comedo type necrosis, presence and degree of inflammation and excision status and were included in the present analyses (Table 1). Accurate review of the presence or absence of microinvasion was felt to be too error prone for meaningful analysis; some cases had the original sections submitted for review, but from other cases, new sections had been cut and submitted for re evaluation. Nevertheless, only 16 of the 1224 cases in this series had definite microinvasion and a further 42 had microinvasion in the original histology report. This feature was related to size of DCIS lesion, but not, perhaps surprisingly, to the grade of DCIS (data not shown).
Analysis for treatment arms was repeated, using the sub set of cases with full pathological data from this review, to confirm that the results were not significantly different from the whole group analysis presented earlier (UK Coordinating Committee on Cancer Research Ductal Carcinoma in situ Working Party, 2003).
One hundred and fifty four of the 1224 cases reviewed (12.6 developed recurrence of disease either DCIS or invasive carcinoma in the ipsilateral breast. Ninety nine (64 developed recurrent DCIS and 55 invasive disease, comparable with the results in analysis of the overall trial.
Univariate analyses and distribution of features of DCIS are shown in Table 1. The DCIS was found to be of high cytonuclear grade (National Pathology Co ordinating Group, 2005) in 74.6 of cases (n 18.4 were of intermediate grade and only 7.0 of cases (n were of low cytonuclear grade (n Breakdown by Van Nuys grade (Silverstein et al, 1995) showed that in addition to the 913 patients (as above) with high grade disease (74.6 212 had DCIS, which was non high grade but in which necrosis was present (17.3 and 99 patients had non high grade DCIS without necrosis (8.1 Comedo type necrosis, to a greater or lesser extent, was present in all, but 117 cases (90.4 in this series of screen detected DCIS.
All of the systems of grading of DCIS applied showed a significant association with recurrence of ipsilateral DCIS or invasive disease, as did the predominant growth pattern of the disease. Patients with a solid morphology as the main architectural pattern of DCIS had a 15.2 recurrence rate compared with 14.3 of those with micropapillary DCIS and only 7.3 of those with predominantly cribriform DCIS. The presence or absence of comedo type necrosis and the presence of associated chronic inflammation was also associated with increased risk of recurrence of DCIS or progression to invasive cancer in the ipsilateral breast (Table 1).
Intragrade analysis showed that the pure comedo type cases (n 39.5 fared particularly poorly. This novel classification system showed a strong relationship with development of ipsilateral recurrence (Table 2a), both overall and separately for DCIS and invasive disease (Figures 1, 2 and 3). This new classification system, retained significance across the range of sizes of disease (although numbers in the groups are by necessity smaller).
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