| Abstract|| |
Background: Triple negative breast carcinoma (TNBC) and basal-like breast carcinoma (BLBC) are subtypes of breast carcinoma (BCa) that are associated with poor survival. Aims: To study the prevalence, clinicopathological profile and survival of TNBC among a Sri Lankan patient cohort and to determine the proportion and predictive histological features of BLBC among TNBCs. Study Setting and Design: A cohort of 221 women undergoing primary surgery for BCa at a tertiary-care center in Sri Lanka was studied. Materials and Methods: Clinicopathological and follow-up information were collected by patient interviews and review of slides and clinical records. Estrogen, progesterone, HER2 receptors, and basal markers (CK5/6, CK14, EGFR, 34βE12) were evaluated immunohistochemically. Statistical Analysis: Data was analyzed with Chi-square test, multinomial logistic regression, and Cox regression using SPSS20.0. Results: Fifty-three (24%) tumors were triple-negative (95%CI = 18.37%–29.63%). On multivariate analysis, young age (P = 0.002), high Nottingham grade (P = 0.005), moderate to severe tumor necrosis (P = 0.004), absent ductal carcinoma in situ (DCIS) (P = 0.04), reduced vascular density at tumor edge (P = 0.016) and distinct cell margins (P = 0.047) predicted TNBC over luminal subgroups, whereas reduced vascular density (P = 0.004) and low TNM stage (P = 0.011) distinguished TNBC and HER2. BLBC accounted for 45.28% (95%CI 32.66%–58.55%-24/53) of TNBC. The presence of extensive necrosis in TNBC correlated significantly with BLBC (P = 0.03). The survival among the TNBC subgroup did not differ significantly from other subgroups. Conclusion: Twenty four percent were TNBCs by immunohistochemical analysis, comparable to studies in the Indian subcontinent, however higher than the West. TNBC status correlated with younger age, high tumor grade, necrosis, absent DCIS, reduced vascular density at tumor edge, and distinct cell margins. The presence of moderate to extensive necrosis in TNBC was predictive of BLBC.
Keywords: Basal like breast carcinoma, breast carcinoma, clinicopathological features, prevalence, triple negative breast carcinoma
|How to cite this article:|
Wijesinghe HD, Fernando J, Senarath U, Wijesinghe GK, S. Lokuhetty MD. A clinicopathological study of triple-negative breast carcinoma in a patient cohort from a tertiary care center in Sri Lanka. Indian J Pathol Microbiol 2020;63:388-96
|How to cite this URL:|
Wijesinghe HD, Fernando J, Senarath U, Wijesinghe GK, S. Lokuhetty MD. A clinicopathological study of triple-negative breast carcinoma in a patient cohort from a tertiary care center in Sri Lanka. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Sep 21];63:388-96. Available from: http://www.ijpmonline.org/text.asp?2020/63/3/388/291683
| Introduction|| |
Triple-negative breast carcinoma (TNBC) is a subtype of breast carcinoma (BCa) that has been shown to be associated with a poor prognosis. The reported prevalence of TNBC varies according to ethnicity ranging from 10%–13% in studies conducted in the United Kingdom and United States of America with a higher prevalence reported among South Asian women (18.6%–46%).,,,,, Studies have shown TNBC to have worse breast cancer-specific short-term survival and to be associated with distinct clinicopathological features including younger age, postmenopausal status, larger tumor size, aggressive morphological features, necrosis, and lymph node metastasis.,,,,
Basal-like breast carcinoma (BLBC) is a subtype of BCa characterized by expression of genes usually found in basal/myoepithelial cells of the normal breast. Although BLBC is mostly triple negative by immunohistochemical analysis (IHC), it is not synonymous with TNBC. Not all BLBC are triple negative and not all TNBCs show a basal phenotype. However, of the TNBCs, those that express basal markers form a clinically distinct subtype that have been shown to be associated with a poorer prognosis and different chemotherapeutic response in comparison to non-basal subtypes.
Although gene expression profiling remains the gold standard for identification of the basal subtype, IHC is a more feasible method in clinical settings.,, with the expression of basal cytokeratins (CK5/6, CK14, CK17, 34βE12) and EGFR in TNBC reported to range within 56%–84% depending on the immunohistochemical panel used.,
Our objective was to study the prevalence, clinicopathological profile, and survival of triple-negative breast carcinoma (TNBC) among a Sri Lankan patient cohort and to determine the proportion of basal-like breast carcinoma (BLBC) among TNBC and its predictive histological features. Ethical approvals were obtained from the Ethical Review Committees of the Faculty of Medicine, University of Colombo and the National Hospital of Sri Lanka.
| Materials and Methods|| |
A cohort of 221 women who underwent primary surgery for breast carcinoma at a tertiary-care center in Sri Lanka from June 2012–December 2014 was studied.
Patients who had undergone neoadjuvant chemotherapy, cases with suboptimal tumor preservation involving ≥80% of the tumor and microinvasive carcinoma or ductal carcinoma in situ (DCIS) alone, were excluded.
Clinical data (ethnicity, age, parity, breast feeding history, menopausal status, family history of breast carcinoma, use of oral contraceptives and hormone therapy, clinical symptoms and duration of symptoms, height, weight, and the type of surgery) was collected through patient interviews and clinical records. Body mass index (BMI) was calculated.
Standard laboratory protocols were applied for specimen dissection. Tumor size and lymph node status were recorded. TNM stage was determined.
Hematoxylin and eosin stained slides were evaluated. Histological type was categorized based on 4th series WHO classification of breast tumors. The Modified Bloom and Richardson (Nottingham) grade of the tumor was determined.
Necrosis, DCIS, calcification, and lymphovascular invasion were categorized as present or absent. Necrosis when present was quantified as focal, <50% (moderate), or >50% (extensive) of the tumor. Tumor margins were assessed qualitatively and categorized as pushing or infiltrative. The degree of lymphoid infiltrate and desmoplasia/hyalinization at the tumor host interface and within the tumor were analyzed semiquantitatively and categorized as absent, mild, moderate, and extensive. The vascular density at the tumor host interface was assessed in the area of highest vascular density and categorized according to the number of vessels per medium power field (×10 objective, field diameter 2.0 mm) (<5 vessels/medium power field and ≥5 vessels/medium power field). Tumors with cells having well-defined cell membranes, in which individual cells could be identified separately on microscopy, were classified as having distinct cell margins.
IHC of estrogen, progesterone, and human epidermal growth factor receptor 2 (ER, PR, and HER2) receptors were performed on paraffin-embedded tissue. Additional basal markers CK5/6, EGFR, 34βE12, and CK14 that were assessed in tumors found to be triple negative. Relevant control slides were included with each staining batch. The antibodies, dilution, methods, and interpretation of immunohistochemistry are shown in [Table 1]. HER2 2+ tumors were further analyzed with fluorescent in situ hybridization (FISH) using an FDA approved FISH assay (PATHVYSION) and interpreted according to the modified ASO CAP guidelines of 2013.
|Table 1: Immunohistochemical protocols and scoring for ER, PR, and HER2 and basal markers|
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The tumors were broadly categorized into luminal, HER2, and triple-negative groups based on ER, PR, and HER2 status. Tumors that were ER/PR positive and HER2 positive or negative were classified as luminal. Tumors that were ER/PR negative and HER2 positive were classified as HER2 and tumors that were negative for all 3 markers were classified as TNBC. Further classification of the luminal subgroup into luminal A and B was not attempted as the proliferative index by Ki67 was not available for all cases. The triple-negative tumors were subdivided into two groups based on the expression of basal markers, i.e., non-basal triple negative (basal markers negative) and basal triple negative (basal markers positive).
A combination of positivity for CK5/6 and/or EGFR (Specificity of 100% and a sensitivity of 76%) and/or a combination of positivity for 34βE12 and EGFR (Specificity of 95% and sensitivity of 88%) or positivity for 34βE12 and CK14 (Specificity 89% with sensitivity of 80%) to recognize the basal phenotype were used as the minimal criteria for identifying the basal phenotype [Figure 1].,, This combination of panels was used to increase the sensitivity while maintaining a high specificity.
|Figure 1: A basal-like breast carcinoma showing positive expression of basal markers: (a) Cytoplasmic positivity for CK5/6 (Light microscope CK5/6 400×), (b) Cytoplasmic positivity for 34β E12 (Light microscope 34β E12 400×), (c) Cytoplasmic positivity for CK14 (Light microscope CK14 400×), (d) Cell membrane positivity for EGFR (Light microscope EGFR 400×)|
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All patients were treated and managed according to standard protocols,, with combinations of targeted hormonal therapy (in luminal subgroup), trastuzumab (in HER2 positive tumors), radiotherapy, and chemotherapy. Overall survival (OS) and disease-free survival (DFS) (over 1 ½ to 4 years after surgery) were determined from patient interviews and review of clinic records.
Proportions and 95% confidence intervals were calculated to estimate prevalence. The relationship between clinicopathological parameters and the phenotype (as determined by IHC/FISH) were analyzed using univariate (Chi-square test) and multivariate (multinomial logistic regression) analysis. Cox regression analysis was used to analyze survival. SPSS (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.) was used for analysis.
| Results|| |
The age of women with breast carcinoma ranged from 29 to 86 years (mean age 56.25 years, s = 11.06). The majority (95.9%;212/221) presented with a self-detected breast lump and had an invasive carcinoma of no special type (197/221;89.5%). Other special types included lobular (10/221), mucinous (6/221), metaplastic (5/221), medullary-like (5/221), micro papillary (1/221), adenoid cystic (1/221), and carcinoma with neuroendocrine features (1/221).
Fifty-three tumors were triple negative. The estimated prevalence of TNBC was 23.98% (95% CI = 18.35%–29.61%). The non-triple negative cases comprised luminal, 62.90% (95% CI = 56.53%–69.27%;139/221) and HER2, 13.12% (95% CI = 8.67%–17.57%;29/221).
Twenty-four carcinomas of basal phenotype were identified out of 53 cases of TNBC accounting for 45.28% (95% CI 32.66%–58.55%.) of the TNBCs. Immunohistochemical protocols and scoring adopted for basal markers and their reactivity in TNBC are shown in [Table 1] and [Table 2]. Criteria used to categorize TNBC as basal and non-basal, and the results of basal markers in the 24 cases categorized as basal are given in [Table 3] and [Table 4]. Of the BLBC identified among TNBC, most were invasive carcinomas of no special type. Among special types, metaplastic (n = 2/5), medullary-like (n = 5/5), and adenoid cystic carcinomas (n = 1/1) expressed basal phenotype.
|Table 2: Immunohistochemical reactivity of basal markers in the 53 cases of TNBC|
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|Table 3: Criteria used to categorize the 53 cases of TNBC as basal TNBC and non-basal TNBC|
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|Table 4: Results of basal markers in the 24 cases categorized as basal TNBC|
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The clinical and pathological features of triple negative, luminal and HER2 subtypes of breast carcinoma are summarized in [Table 5]. One-way ANOVA showed a statistically significant difference in age among the three subtypes (P = 0.008) with post hoc Scheffe test showing that patients with TNBC (mean age 52.70 years, s = 12.08) were significantly younger than patients with luminal type (mean age 57.99, s = 10.39) (P = 0.012).
|Table 5: Univariate analysis of clinicopathological parameters of Luminal, HER2, and TNBC subgroups|
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On Chi-square analysis, patients with TNBC were more likely to be premenopausal (P = 0.026) than those with a luminal subtype. There was no significant difference among the three subgroups with regard to other clinical parameters studied.
Chi-square analysis with z test for column proportions showed that HER2 subtype was more likely to be of TNM stage III in comparison to luminal and TNBC subtypes (P = 0.014).
Both TNBC and HER2 subtypes correlated with a higher Nottingham grade (P < 0.001) including higher nuclear grade (P < 0.001), increased mitoses (P < 0.001), and absence of tubule formation (P = 0.001) and presence of distinct cell margins (P = 0.008) [Figure 2]a. Necrosis of moderate to extensive extent (P < 0.001) [Figure 2]b, absent DCIS (P = 0.001), pushing margins (P < 0.001) [Figure 2]c, and absent/mild central desmoplasia/hyalinization (P < 0.001) distinguished TNBC from both luminal and HER2 subtypes. Moderate to severe lymphoid infiltrate at tumor edge (P = 0.005) [Figure 2]d was useful to distinguish TNBC from luminal subtype but not from HER2 subtype. Of the three subgroups, HER2 tumors were more likely to show calcification (P = 0.044) and increased vascular density at tumor host interface (P = 0.008) [Table 5]. There was no statistically significant difference between the three groups with respect tumor stage, presence of nodal metastasis, lymphovascular invasion, desmoplasia at the periphery, and lymphoid infiltrate within the tumor.
|Figure 2: Histopathological features predictive of triple-negative breast carcinoma: (a) Nottingham grade-3 tumors with high nuclear and architectural grades and increased mitoses (Light microscope—Hematoxylin and eosin 400×), (b) Moderate to extensive tumor necrosis (Light microscope—Hematoxylin and eosin 100×), (c) Pushing tumor margins (Light microscope–Hematoxylin and eosin 100×), (d) Lymphoid infiltrate at tumor margin (Light microscope–Hematoxylin and eosin 100×)|
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On multivariate analysis with multinomial logistic regression age (P = 0.004), TNM stage (P = 0.021), Nottingham grade (P < 0.001), tumor necrosis (P = 0.011), vascular density at the tumor margin (P = 0.003) and cell margins (P = 0.037) were found to be statistically significant in distinguishing between the three tumor subtypes. Young age (P = 0.002), high tumor grade (P = 0.005), increased tumor necrosis (P = 0.004), absent DCIS (P = 0.04), reduced vascular density (P = 0.016), and distinct cell margins (P = 0.047) predicted TNBC over luminal subgroup, whereas reduced vascular density (P = 0.004) and low TNM stage (P = 0.011) predicted TNBC over HER2 [Table 6].
|Table 6: Multivariate analysis of clinicopathological parameters of luminal and HER2 vs TNBC by multinomial logistic regression|
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On Chi-square analysis of the clinical and pathological characteristics of basal and non-basal TNBCs, only the presence of moderate to extensive necrosis correlated significantly with the occurrence of BLBC (P = 0.03) [Table 7] and [Figure 2]b.
|Table 7: Clinicopathological profile of characteristics of basal vs non-basal TNBC|
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The mean follow-up duration was 26.77 months (s = 8.99 months, range; 0.5 months to 44 months) in 179 cases (81%). There was a total of 17 deaths, with 4 patients surviving with local recurrences and 12 surviving with metastases. On Cox regression analysis, HER2 and TNBC subtypes had worse OS (HR 1.670, 95% CI = 0.452–6.171, HR = 1.207, 95% CI = 0.404–3.602, respectively) compared to the luminal subtype. This pattern persisted when adjusted for age. When adjusted for TNM stage, TNBC had the worst OS (HR 1.533, 95% CI = 0.496–4.737) followed by HER2 (HR 1.231, 95% CI = 0.319–4.746). However, none of these differences reached statistical significance.
HER2 subtype had the worst DFS followed by TNBC subtype; this pattern also persisted when adjusted for age and TNM stage. DFS of HER2 subtype was significantly worse than luminal subtype (HR 2.624, 95% CI = 1.066–6.456), but not TNBC. The difference in DFS between TNBC and luminal subtypes was not significant (HR 1.247, 95% CI = 0.564-2.756).
| Discussion|| |
TNBC accounted for 23.98% of BCa among this Sri Lankan breast carcinoma patient cohort from a tertiary care center. This prevalence is higher than most populations studied in the West and East Asia.,,, Post neoadjuvant chemotherapy cases were excluded; therefore, it is likely that the true prevalence of TNBC in Sri Lanka is higher. Technical errors resulting in false-negative staining for ER/PR and HER2 may also contribute to the higher prevalence of TNBC. However, all tumors included in the study were subjected to IHC twice, at the National immunohistochemistry laboratory (for treatment purposes) and then at the immunohistochemistry laboratory of the University of Colombo (for this research). The results were comparable, thus minimizing this possibility. Suboptimally preserved tumors which could have resulted in false-negative testing leading to a higher TNBC prevalence are not included in the study. A Sri Lankan study from 2007 found that 28.23% of tumors were negative for ER/PR and HER2, while a more recent Sri Lankan study by Wathuge andRatnatunga reports an even higher predisposition for TNBC, affecting 36% of the study population. A meta-analysis in India reported a prevalence of TNBC of 31%. A Pakistan study reported a prevalence of 19%. Similarly in studies in the west, prevalence of TNBC was highest (17.2%) among blacks in the USA, a slightly higher prevalence was reported among women of South Asian (10.4%), Hispanic (10%), Chinese (8.8%), and Japanese (8.2%) origin in comparison to non-Hispanic white women (8.0%).
The expression of basal cytokeratins and EGFR in TNBC has been reported to range within 56–84% depending on immunohistochemical panel used., Studies conducted in India have shown a wide variation in the prevalence of BLBC ranging from 30%–82.3% of TNBCs., In this study, BLBC accounted for 45.3% of the TNBCs. It is known that some luminal and HER2 subgroups also express BLBC phenotype. These two subgroups were not tested for BLBC phenotype in this study.
TNBC has been shown to be associated with younger age., Although TNBC is now considered a heterogeneous disease based on molecular profiling in this study too, TNBC status was associated with younger age, reaching statistical significance on both multivariate and univariate analysis. Univariate analysis showed an association with premenopausal status, in comparison to the luminal subgroup, but this difference was not present on multivariate analysis, possibly because of the confounding effect of age on menopausal status.
Studies have also shown TNBC to be associated with larger, high grade, poorly differentiated, high stage tumors., In this study, there was no significant difference between the three subtypes with respect to tumor size, lymph node metastasis, tumor stage, or lymphovascular invasion. Under representation of higher TNM stage tumors that underwent post neoadjuvant therapy in the study population may have had an impact on these results. However, on both univariate and multivariate analysis HER2 tumors were of a higher TNM stage than the other two subgroups. Advanced TNM stage of the HER2 subgroup may have been a contributory factor to the worse OS and DFS observed, since when corrected for TNM stage, TNBC showed a worse OS than HER2.
TNBC was associated with high Nottingham grade, high nuclear grade, increased mitotic count ≥15/10 hpf (field diameter 0.50 mm), absence of tubule formation, distinct cell margins [Figure 2]a, and moderate to extensive lymphoid infiltrate at the tumor host margin [Figure 2]d. These factors were useful to distinguish TNBC from tumors of luminal subtype but not HER2 subtype, with Nottingham grade and distinct cell margins being significant on both univariate and multivariate analysis.
The presence of moderate to severe necrosis [Figure 2]b, pushing tumor margins [Figure 2]c, absent DCIS, and absent/mild central desmoplasia/hyalinization distinguished TNBC from both HER2 and luminal subtypes. Of these, the presence of moderate to severe necrosis and absent DCIS was useful to distinguish TNBC and luminal subtypes on both univariate and multivariate analysis. These findings are similar to studies which have described central necrotic zones, pushing borders, and heavy lymphoid infiltrate in association with TNBC,,, whereas non-TNBCs have been shown to have more fibrosis with areas of hyalinization.
The presence of a tumor with high Nottingham grade and distinct cell borders was indicative of a HER2 or TNBC subtypes. In such a tumor, the presence of moderate to extensive necrosis and absence of DCIS was predictive of TNBC subtype, whereas higher TNM stage and increased vascular density at tumor host interface was predictive of HER2 subtype.
Some studies have shown BLBC identified by immunohistochemical markers to be associated with young age and higher grade tumors. Other studies have shown that most cardinal morphological features do not differ between non-basal and basal type triple-negative carcinomas. In this study, only the presence of moderate to extensive tumor necrosis showed a significant correlation with BLBC, in comparison to non-basal TNBC. The small numbers of BLBC (24 cases) encountered among TNBC may have contributed to this result.
Studies have shown that TNBC have a worse short-term survival compared to the luminal subtype, similar to the trend observed in this study.,, The current study showed an increased risk of death or recurrence/metastasis among women with HER2 and TNBC tumors over a period of 1½–4 years. However, only the difference in DFS, among HER2 and luminal subgroups was statistically significant. Limited sample size, the short duration of follow-up (over 1 ½ to 4 years after surgery), and exclusion of post neoadjuvant cases may have contributed to this. All but two patients with HER2 positive tumors had received trastuzumab indicating that the short-term prognosis of HER2 tumors was poor despite treatment. The two patients not receiving trastuzumab were disease-free at follow-up.
| Conclusion|| |
In conclusion, TNBC comprised 23.98% in this limited sample. The percentage of TNBC is higher than observed in the West and East Asia, supporting an increased prevalence of TNBC among South Asian populations. The basal subtype accounted for 45.8% of the triple-negative breast carcinomas that were studied.
The current study develops further on the previous studies conducted in Sri Lanka by analyzing in greater depth the clinicopathological features associated with TNBC and BLBC., Triple-negative status correlated with younger age, higher Nottingham grade, moderate to severe tumor necrosis, absent DCIS, and distinct cell margins on both univariate and multivariate analysis. These findings are similar to other studies conducted worldwide. The basal phenotype showed significant correlation with moderate to extensive tumor necrosis in comparison to the other triple-negative breast carcinomas. Therefore, in a tumor with the above described clinicopathological features of TNBC, the presence of moderate to extensive necrosis should raise the possibility of a basal-like TNBC.
TNBC and HER2 subtypes, who have received treatment as per standard protocols showed a trend of reduced short-term OS and DFS in comparison to the luminal subtype, however only reduced DFS for HER2 in comparison to luminal was statistically significant.
We wish to acknowledge the contribution of Dr. Ridma Padmakumara, Dr Samalai Kangasabapathy, and Dr. Thuvarakan Poobalasingam who assisted in data acquisition and entry.
Financial support and sponsorship
This study was funded by the National Research Council of Sri Lanka Grant No 11:51 and the Kumi and Heram Bilmoria Trust Fund.
Conflicts of interest
There are no conflicts of interest.
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Harshima D Wijesinghe
Senior Lecturer and Consultant Histopathologist, Department of Pathology, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo 8
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]