| Abstract|| |
Background: Breast carcinoma (BCa) is the commonest malignancy among women worldwide and in Sri Lanka. Several prognostic indices are described for BCa. Aims: To assess clinicopathological features and prognostic indices derived from routine clinical, histopathological and immunohistochemical (IHC) data, in a cohort of patients undergoing primary surgery for BCa and to determine their prognostic impact on short-term disease free survival. Setting and Design: This is a bidirectional cohort study of 208 women undergoing primary surgery for BCa at the National Hospital of Sri Lanka, from 2012-2014, excluding post-neoadjuvant chemotherapy cases. Material and Methods: Clinical details, tumor size and nodal status were obtained from histopathology reports. Histopathology and estrogen/progesterone receptor and HER2 status were reviewed. Molecular subtype based on IHC was determined. Nodal ratio (number of positive nodes/total number retrieved) and Nottingham prognostic index were calculated. Follow up information was obtained by patient interviews and record review. Statistical Analysis: Data was analyzed by univariate and multivariate Cox regression using SPSS19.0. Results: Mean follow-up duration was 27.16 months (0.5-52 months, s = 9.35 months). 174 (82.9%) remained disease free with 19 (9%) deaths. Thirteen (6.2%) survived with metastasis and 4 (1.9%) with recurrences. On univariate Cox regression, tumor, nodal and TNM stages, nodal ratio and lymphovascular invasion (LVI) were predictive of disease free survival (DFS) (P = 0.001, P = 0.021, P = 0.022, P = 0.002, P = 0.018). On multivariate analysis TNM stage and LVI were predictive of DFS. Conclusion: TNM stage and LVI were the most important predictors of short-term disease free survival in this study population, confirming that early detection of BCa at a lower stage has a significant impact on short-term outcomes.
Keywords: Breast carcinoma, prognostic indices, short-term survival, Sri Lanka
|How to cite this article:|
Wijesinghe HD, Thuvarakan P, Samarasekera A, S. Lokuhetty MD. Prognostic indices predictive of short-term disease-free survival of breast carcinoma patients receiving primary surgical treatment in Sri Lanka. Indian J Pathol Microbiol 2018;61:505-9
|How to cite this URL:|
Wijesinghe HD, Thuvarakan P, Samarasekera A, S. Lokuhetty MD. Prognostic indices predictive of short-term disease-free survival of breast carcinoma patients receiving primary surgical treatment in Sri Lanka. Indian J Pathol Microbiol [serial online] 2018 [cited 2018 Dec 15];61:505-9. Available from: http://www.ijpmonline.org/text.asp?2018/61/4/505/242973
| Introduction|| |
Breast carcinoma (BCa) is the most common malignancy among women worldwide and in Sri Lanka., Several prognostic indices predictive of recurrence and survival in BCa have been described. Established parameters impacting prognosis and treatment of patients with BCa include tumor size, histological grade, lymph node stage, expression of estrogen receptor (ER), progesterone receptor (PR), overexpression of human epidermal growth factor receptor 2 (HER2), and the proliferation index determined by Ki-67.,,,, Incorporation of genetic information, determined by gene expression profiling, is also becoming the standard of care for patients with BCa.,,,
Tumor node metastasis (TNM) stage, Nottingham Prognostic Index (NPI), and Nottingham grade are other traditional prognostic indicators of BCa. Nodal ratio (number of lymph nodes containing metastasis/number of lymph nodes sampled) has been considered by some as a significant prognostic index.
The objective of this study was to assess clinicopathological features and prognostic indices derived from routinely available clinical, histopathological, and immunohistochemical data, in a cohort of patients receiving primary surgical treatment for BCa in Sri Lanka and to determine the prognostic impact of these indices on short-term disease-free survival (DFS).
| Materials and Methods|| |
This was a bidirectional cohort study of 208 women undergoing primary surgery (both mastectomy and wide local excision of breast lump) for BCa at the National Hospital of Sri Lanka (NHSL) during 2012–2014. Patients receiving neoadjuvant chemotherapy were excluded, in view of the impact of chemotherapy on the pathological variables that were to be assessed. All patients were treated according to the standard treatment protocols. Ethical approval was obtained from the Ethics Review Committees of the Faculty of Medicine, University of Colombo and the NHSL.
The clinical information collected retrospectively from records included age, menstrual status, clinical symptoms, duration of symptoms, and type of surgery. Pathological details obtained included tumor size and the lymph node status in cases with axillary node sampling/dissection. Relevant histology and immunohistochemistry slides for ER, PR, and HER2 of these cases were reviewed independent of the previous diagnosis. Follow-up information was obtained by patient interviews and record review.
The histopathological features studied included histological type, nuclear grade, tubule formation, mitotic score, associated ductal carcinoma in situ (DCIS), necrosis, lymphovascular invasion, lymphoid infiltrate within tumor and at tumor-host interface, and central fibrosis. Standard guidelines, were used to assess histological characteristics where available (e.g. histological type, nuclear grade, tubule formation, and mitotic score) and to determine the Nottingham grade. Necrosis and lymphoid infiltrate within tumor and at tumor–host interface were assessed semi-quantitatively. Central fibrosis and DCIS were categorized as present or absent.
Allred scoring system was used to determine ER/PR positivity. HER2 status was determined according to the American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update 2013.
The Nottingham grade, NPI, and TNM stage were determined in all cases. The nodal ratio was calculated based on the number of tumor-positive lymph nodes/number of lymph nodes sampled, in cases with axillary node dissection. Data was analyzed with SPSS (IBM Corp. Released 2010. IBM SPSS Statistics for Windows, Version 19.0. Armonk, NY:IBM Corp).
| Results|| |
The mean age of the study population was 56.39 years (29–87, s = 11.38). The majority (198/208, 95.2%) presented with a self-detected breast lump. The mean duration of the breast lump at surgery was 5.93 months (s = 3.27) with 16.8% (32/190) having a lump of over 6-month duration. The majority had invasive carcinomas of no special type (164/208, 79.3%). Eighteen cases (8.7%) showed severe autolysis precluding histological typing and grading. There were six cases of lobular carcinoma and five each of metaplastic carcinoma and DCIS with no invasive cancer. There were four cases of microinvasive carcinoma. The majority of assessable invasive carcinomas were of Nottingham Grade III (76/181-42%). The axilla was assessed in 186 (89.4%) patients (sentinel lymph node sampling-23 and lymph node clearance-163). The number of lymph nodes retrieved ranged from 1 to 50 with a mean of 14.06 (s = 8.395). Nodal metastases were present in 41.9% (78/186). With the exception of two cases in which patients had refused neoadjuvant chemotherapy, all cases were of tumor stage T3 or less. Most cases were of TNM stage 11 (130/208-62.5%). The mean and median duration of follow-up was 27.16 months (0.5–52 months, s = 9.35 months) and 27 months, respectively. 174 (82.9%) patients remained disease free. There were 19 (9%) deaths. Thirteen were (6.2%) surviving with metastasis and 4 (1.9%) had developed recurrences [Table 1].
Kaplan–Meier curves showed that tumor stage (P < 0.001), nodal stage (P = 0.009), TNM stage (P = 0.015), nodal ratio (P = 0.001), and lymphovascular invasion (P = 0.013) were predictive of DFS [Figure 1].
On Cox regression analysis, tumor stage (P < 0.001), nodal stage (P = 0.021), TNM stage (P = 0.022), nodal ratio (P = 0.002), and lymphovascular invasion (P = 0.018) were predictive of short-term DFS. There was a significant difference in DFS between patients with T3/T4 disease (who had not received neoadjuvant therapy and were included in the study), in comparison to those with T1. Patients with N3 stage had significantly worse DFS than those with N0 (P = 0.003) and N1 (P = 0.017) disease, and patients with TNM stage III disease showed worse DFS in comparison to stage I (P = 0.024) and stage II (P = 0.020) disease. A nodal ratio ≥0.5 was associated with worse DFS than a nodal ratio of 0 (P = 0.001) or <0.5 (P = 0.005) [Table 2].
|Table 2: Univariate Cox regression of prognostic factors affecting disease-free survival|
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Age, duration of breast lump at presentation, menstrual status, type of surgery, histological features assessed (histological type, nuclear grade, tubule formation, mitotic score, Nottingham grade, associated DCIS, necrosis, lymphoid infiltrate, and central fibrosis), NPI, hormonal and HER2 status, and molecular subtype (luminal, HER2, and triple negative) determined by immunohistochemistry were not significantly associated with DFS. However, there was a trend of younger age, lower grade, lower NPI, and luminal subtype being associated with improved survival on univariate Cox regression.
Multivariate analysis using a model incorporating age, tumor grade, lymphovascular invasion, TNM stage, and molecular subtype determined by immunohistochemistry showed that the absence of lymphovascular invasion (P = 0.040) and lower TNM stage (P = 0.049) was predictive of DFS [Table 3].
|Table 3: Multivariate Cox regression analysis of factors affecting disease-free survival|
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| Discussion|| |
The DFS in this study population that was followed up for a mean duration of 27 months was 82.7%. In comparison, studies in India on patients with early BCa report a five-year DFS ranging from 76% to 85.6%.,,, Studies conducted in Pakistan have reported 5-year DFS rates of 65% for nonmetastatic BCa and 10-year DFS rate of 70% for early BCa. The short duration of follow-up and loss of follow-up were limitations in this study. Overall survival rates are not discussed due to these limitations. In addition, patients with more advanced BCas requiring neoadjuvant therapy and patients with distant metastases were excluded from this study population, which may have contributed to an overestimate of the survival.
Many prognostic indices, both novel and traditional have been described for BCa. Traditional prognostic indicators of BCa include TNM stage, NPI, and Nottingham grade. Prognostic indices developed recently include NPI Plus (NPI+), which incorporates molecular data to the NPI and nodal ratio (number of lymph nodes containing metastasis/number of lymph nodes sampled). In addition to the variables included in the NPI, other routinely assessed clinicopathological variables such as histological grade, lymphovascular invasion, fibrosis, lymphocytic infiltrate, ER/HER 2 status, and molecular subtype have also been shown to have prognostic implications.,
This study looked at the impact of traditional prognostic indices of tumor size, lymph node status, TNM stage, Nottingham grade, and NPI, and more novel prognostic indices such as nodal ratio and molecular subtype defined by immunohistochemistry and individual clinicopathological variables on short-term DFS.
In this study population, T stage, N stage, TNM stage, nodal ratio, and lymphovascular invasion were shown to have an impact on short-term DFS with TNM stage and lymphovascular invasion showing a significant association on multivariate analysis.
Studies conducted in India have also shown stage, and lymphovascular invasion to be predictive of 5-year survival. In addition, factors such as age, menstrual status and ER, PR, and HER2 status have been shown to have an impact on survival in some Indian studies., These did not show a significant association with survival in this study. In the present study, the luminal subtype (defined by immunohistochemistry) showed a trend toward better survival, although it did not reach statistical significance.
Patients who had received neoadjuvant treatment were excluded from the study due to the impact of the treatment on the pathological variables that were assessed. Therefore, patients with more locally advanced and metastatic disease have been excluded from this study. This may have contributed to the fact that, although Nottingham grade, NPI, and molecular subtype showed a trend of being predictive of survival, they did not reach statistical significance.
| Conclusion|| |
The study showed good DFS rates in this cohort of Sri Lankan BCa patients. TNM stage and lymphovascular invasion were the most important predictors of survival in this study population. Stage at presentation is a modifiable factor and early detection of BCa at a lower stage would have a significant impact on short-term outcomes. Considering that there is currently no nationwide breast cancer screening program in Sri Lanka and that the majority of patients presented with a self-detected breast lump, training and educating women about breast awareness, and self-examination could serve as an important screening intervention for early detection.
Financial support and sponsorship
This study received financial support from the National Research Council of Sri Lanka Grant NRC 11:51 and the Kumi and Heram Bilmoria Trust Fund.
Conflicts of interest
There are no conflicts of interest.
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Harshima Disvini Wijesinghe
Department of Pathology, Faculty of Medicine, University of Colombo, Colombo
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]