|Ahead of print
|Molecular subtypes of Invasive breast carcinoma of no special type, their correlation with histopathological features, Ki 67 index and tumor budding: A retrospective comparative study
Neelima Radhakrishnan1, Anitha Mathews1, KR Rajeev2, P Sindhu Nair1, Rexeena Bhargavan3, Ammu Jayanthi Viswanathan4
1 Department of Pathology, Regional Cancer Centre, Trivandrum, Kerala, India
2 Department of Radiotherapy, Regional Cancer Centre, Trivandrum, Kerala, India
3 Department of Surgical Oncology, Regional Cancer Centre, Trivandrum, Kerala, India
4 Department of Cancer Epidemiology and Biostatistics, Regional Cancer Centre, Trivandrum, Kerala, India
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|Date of Submission||26-Jan-2021|
|Date of Decision||02-May-2021|
|Date of Acceptance||03-May-2021|
|Date of Web Publication||25-May-2022|
| Abstract|| |
Context: Tumor budding (TB), poorly differentiated clusters (PDCs), and Ki 67 index are proven adverse prognostic factors in breast carcinoma. Though the relation of Ki 67 index with molecular subtypes of breast carcinoma have been extensively studied, there is very limited information on the role of TB and PDCs. Aims: To grade TB, PDCs, and Ki 67 index and assess histological features and relationship of all these with molecular subtypes of invasive breast carcinoma of no special type. Methods and Material: Retrospective study of 148 cases from 1/1/2019 to 30/12/2019. Division of molecular groups – Luminal A, Luminal B, Her2 neu positive, and triple-negative breast carcinomas (TNBC), and Ki 67 index grades based on St Gallen criteria, intratumoral and peritumoral TB and PDC grades as per the International Tumor Budding Consensus Conference (ITBCC) criteria for colon and correlation between these and other histological features with the molecular subtypes were done. Statistical Analysis: Chi-square test, univariate and multivariate logistic regression models were used. Results: Significant correlation was seen between TB and lymphovascular emboli, Luminal B tumors with high-grade TB and PDCs, Her 2 neu positive and TNBC tumors with low-grade TB, circumscribed tumor margins, tumor necrosis, and Luminal B, Her 2 neu positive and TNBC tumors with larger tumor size and high nuclear grades. Conclusions: TB and PDCs are useful in the prognostication of Luminal A and B tumors when the Ki 67 index values are low/intermediate. Her 2 neu positive and TNBC tumors have a high nuclear grade with necrosis and no association with TB or PDCs.
Keywords: Invasive breast carcinoma of no special type (IBC NST), Ki 67 index, lymph node metastasis, lymphovascular emboli, molecular subtypes, poorly differentiated clusters (PDCs), tumor budding (TB)
|How to cite this URL:|
Radhakrishnan N, Mathews A, Rajeev K R, Nair P S, Bhargavan R, Viswanathan AJ. Molecular subtypes of Invasive breast carcinoma of no special type, their correlation with histopathological features, Ki 67 index and tumor budding: A retrospective comparative study. Indian J Pathol Microbiol [Epub ahead of print] [cited 2022 Sep 28]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=345900
| Introduction|| |
Carcinoma breast is known for its genetic and phenotypic variability. Despite marked research progress with the identification of molecular subtypes, new simple prognostic markers are needed that facilitate customized treatment. TB (clusters of one to ≤ four undifferentiated malignant cells) and PDCs (clusters of ≥ five cells without gland formation) are two new prognostic variables seen either within the tumor center (intratumoral) or at the tumor periphery (peritumoral).[1–3] High TB and PDC scores are associated with lymphovascular emboli, distant metastasis, and shorter cancer-specific survival., Our study aims to grade TB, PDCs, and Ki 67 index, evaluate morphological features, and find the association of these factors with molecular subtypes of invasive breast carcinoma of no special type (IBC NST.)
| Subjects and Methods|| |
Patient cohort: The cohort comprised 148 cases of IBC NSTs and mixed carcinomas during the period 1/1/2019 to 30/12/2019. Cases for which wide excision/mastectomy with lymph node clearance/sentinel node biopsy and estrogen receptor/progesterone receptor (ER/PR), Her 2 neu and Ki 67 index done were included. Cases with preoperative administration of chemo/radiotherapy were excluded. All the pure common special subtype carcinomas including mucinous, micropapillary, lobular, and new and rare subtype carcinomas were excluded.
Study Method: Clinicopathological data and hematoxylin-eosin (HE) and immunohistochemistry (IHC) slides of all the cases were retrieved from archives in the Department of Pathology after Institute review board approval. The data were entered based on the proforma approval. Tumors were divided into four molecular groups – Luminal A, Luminal B, Her2 neu positive, and TNBC – based on the St Gallen criteria and modified criteria by Maisonneuve.,[Table 1]
Tumors' grades were assigned based on the Nottingham grading system. Tumor size was given as T1, T2, and T3 (TNM staging). The number of metastatic nodes was divided into N0, N1, N2, and N3 (TNM staging). ER/PR status ([Figure 1]b & c- Monoclonal, Ventana, Prediluted) was scored based on Allred criteria. Her 2 neu status (monoclonal, ventana, prediluted) was divided into positive (score 3+), negative (score 0 or 1+), and equivocal (score2+) based on the American Society of Clinical Oncology (ASCO)/College of American Pathologists
|Figure 1: (a) Tumor buds highlighted by cytokeratin (arrows) (Pan CK x 200), (b) IBC NST with high tumor bud count positive for ER (arrows) (x 400), (c) PR (arrows) (x 400), (d) and intermediate Ki 67 index (x 400)|
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(CAP) guidelines. Equivocal Her 2 neu in IHC were later confirmed by FISH using the probe- ZytoLight SPEC ERBB2/CEN 17 dual-color probe kit (ZytoVision). The results were expressed as the ratio of Her2 signals as compared to CEP 17 signals (ASCO/CAP guidelines). Ki 67 index values ([Figure 1]d -Monoclonal, Dako, 1:50 dilution) were divided based on St Gallen criteria and modified criteria by Maisonneuve, [Table 1]. Lymphoplasmacytic infiltrate were broadly divided as low (absent/scanty/mild and patchy/focal band-like infiltrate) and high (florid infiltrate obscuring the tumor cells) based on Klintrup-Makinen criteria. Tumor borders were assigned as infiltrative/irregular and well-circumscribed, and tumor stroma as those with a dense sclerotic/desmoplastic stroma and those without/scanty stroma. PDCs were defined as five or more cells with no gland formation.
Assessment of tumor budding: Under 10× magnification, hot spot areas with maximum TB were selected after analyzing at least four to si HE slides of each case. Under 20× magnification, the intra and peritumoral buds (ITB and PTB) were counted and graded separately. The International Tumor Budding Consensus Conference (ITBCC) group had suggested reporting area with a conversion table to normalize bud counts to 0.785 mm2 for microscopes with different fields of vision. The normalization factor for our microscope was 1.210 for eyepiece field number 22. ITB and PTB were graded as 1 (0–4), 2 (5–9), and 3 (≥10) [Figure 2]a, [Figure 2]b & [Figure 2]c. The same method of counting and grading was applied to PDCs (intratumoral and peritumoral) also [Figure 2]d. In cases where the morphology was obscured by dense lymphoplasmacytic infiltrate, TB and PDCs were counted in cytokeratin IHC slides (monoclonal, Dako, 1:50) [Figure 1]a.
|Figure 2: IBC NST with (a) dense lymphoplasmacytic infiltrate and no tumor buds-grade 1, (b) Grade two tumor budding (arrows), (c) Grade three tumor budding (arrows) (H and E x 200), (d) Poorly differentiated carcinoma clusters (H and E x 400)|
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Statistics: Statistical analysis was done in SPSS (Statistical package for social sciences) software version 12.0. The clinicopathological data were entered in Microsoft excel; continuous variables were expressed as mean and standard deviation and categorical variables, as frequency and percentage. Chisquare test/Fisher's exact test was used for comparison of pathological features. A logistic regression model was used to estimate the risk. Odds ratio (OR) and 95% confidence interval (CI) of OR were calculated from univariate logistic regression. Adjusted OR was calculated by multivariate logistic regression. P value < 0.05 was taken as statistically significant.
| Results|| |
Relevant pathological findings are summarized in [Table 2], [Table 3], [Table 4], and [Table 5]. Of the total 148 cases, a significant number of cases belonged to the luminal A and B molecular groups (n = 129) with the maximum being luminal B tumors (n = 90). Lymph node metastasis was seen in only 53 (35%) cases, lymphovascular emboli in 101 cases (68%), and high Ki 67 index in 102 (68%) cases. Fluorescence in situ hybridization (FISH) was done for 13 cases with Her2 neu equivocal IHC findings of which 6 cases were Her2 neu positive and 7 cases negative. The total number of Her2 neu positive cases (by both IHC and FISH) was 26 (8 cases in Her 2neu positive group and 18 in Luminal B group).
|Table 2: The relationship between clinicopathological features and molecular subtypes of breast carcinoma|
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|Table 3: The relationship between histopathological features and tumor budding|
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|Table 4: The relationship between histopathological features, tumor budding, Ki 67 index, and molecular subgroups (n=148) (TNBC and Her 2 positive groups versus Luminal A and B)|
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|Table 5: The relationship between histopathological features, tumor budding, Ki 67 index for luminal A versus B groups (n=129)|
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A statistically significant association was seen for tumor size, tumor grade, high stromal lymphoplasmacytic infiltrate, necrosis, tumor margins, tumor stroma, nuclear grade, Ki 67 index, TB, and PDCs (Intra and peritumoral) with the molecular subtypes of breast carcinoma. Age, skin infiltration, lymph node metastasis, number of metastatic nodes per case, lymphovascular emboli, and perineural invasion had no significant association with the molecular subgroups [Table 2].
Tumors with smaller sizes ≤2 cm and 2–5 cm were predominantly seen in luminal A and B groups and tumor size >5 cm in Her 2 neu positive and TNBC groups. Tumor grade two, low nuclear grade, and low Ki 67 index were predominantly seen in luminal A tumors and high nuclear grade, high Ki 67 index, and tumor grade three mainly in luminal B, Her 2 neu positive, and TNBC tumors. Low stromal lymphoplasmacytic infiltrate, ill-defined tumor margins, abundant sclerosed/desmoplastic stroma were predominantly seen in luminal A and B tumors, whereas circumscribed margins and scanty stroma in Her 2 neu positive and TNBC tumors. Necrosis was seen in TNBC tumors compared to the other groups. TB had a statistically significant association with the molecular subgroups with grade three TB mainly seen in luminal A and B tumors and grade one TB in Her 2 neu positive and TNBC tumors. Peritumoral and intratumoral PDCs (grade three) were predominantly seen in luminal A and B tumors and grade one PDCs mainly in Her 2 neu positive and TNBC tumors.
On logistic regression analysis between tumor budding and histomorphological features, [Table 3] it was shown that ITB and PTB had a significant association (odds ratio > one) with lymph node metastasis, lymphovascular emboli, ER hormonal status (mainly luminal groups A and B), and PDCs (intra- and peritumoral) on univariate analysis. The number of metastatic nodes per case (N1), had a significant association with high TB (grades two and three). On multivariate analysis, the association between TB, PDCs, and lymphovascular emboli was independent of all the other confounding variables. The high amount of stromal lymphoplasmacytic infiltrate, well-circumscribed tumor borders, absence of perineural invasion, and less amount of fibrotic stroma had a low odds ratio (protective effect) with high-grade TB, which was also statistically significant. In tumors with these morphological features, TB grade was seen to be predominantly low. There was no statistically significant association between TB and Ki 67 index.
Univariate analysis [Table 4] done in the molecular groups showed that larger tumor size (> 5 cm) had a statistically significant association (i.e, high risk) with Her 2 neu positive, TNBC, and luminal B tumors. Similarly, circumscribed tumor margins, lack of a desmoplastic stroma, and presence of tumor necrosis were significantly associated (P-value < 0.05) with Her2 neu and TNBC tumors. Low-grade ITB and PTB had a statistically significant association with Her 2 neu positive and TNBC subgroups. Infiltrative tumor margins, sclerosed/desmoplastic tumor stroma, and lack of necrosis were mainly seen in luminal A and B tumors. High-grade (grades two and three) TB and PDCs (intra and peritumoral) had a higher risk of association with luminal A and B tumors and a protective odds ratio with Her2 neu positive and triple-negative tumors, which was statistically significant. On multivariate analysis, circumscribed tumor margins and the presence of tumor necrosis had a significant association with Her 2neu positive and TNBC tumors independent of other confounding variables. High stromal lymphoplasmacytic infiltrate had a high odds ratio for TNBC and Her 2 positive tumors but was not statistically significant. In the lymph node-negative tumors, ITB had a significant correlation with the molecular subgroups (P-value = 0.01), with grade one TB predominantly seen in luminal A, Her 2 neu positive , and TNBC tumors and grades two and three TB in luminal B tumors.
Between Luminal A and B groups [Table 5], it was seen that Luminal B tumors had a statistically significant risk of having a larger tumor size (2–5 cm and >5 cm), increased stromal lymphoplasmacytic infiltrate, circumscribed tumor margins, intermediate grade Ki 67 index, and tumor necrosis than the Luminal A tumors. The association with Ki 67 index was seen in both lymph node-positive as well as negative tumors on subgroup analysis. A low Ki 67 index was seen predominantly in Luminal A tumors (P-value < 0.00001) and intermediate to high Ki 67 index values in Luminal B tumors (both the lymph node-negative and positive groups).
Between luminal B tumors and other subgroups [Table 6], a significant association with tumor grade three, high nuclear grade, high-grade ITB, PTB, and PDCs were seen. The association with high nuclear grade and high-grade PDCs in luminal B tumors was seen to be independent of all the other confounding variables. Though the odds ratio for necrosis was high in luminal B tumors, no significant association was seen. The maximum number of metastatic nodes including the number of metastatic nodes (> 10) per case (N3) were predominantly seen in the luminal B group but had no statistically significant association. Our findings were almost concurrent with the meta-analytic study done by Lloyd et al.
|Table 6: The relationship between histopathological features, tumor budding, and Ki 67 index for luminal B versus other groups (n=148)|
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| Discussion|| |
Breast carcinomas always show a high heterogeneity at the histopathological, hormonal, and molecular levels leading to differences in tumor behavior and prognosis. Using complementary DNA microarrays with 8102 human genes, Perou et al. had defined four intrinsic molecular subtypes based on gene expression that corresponds with the molecular changes driving tumorigenesis, clinical behavior, and prognosis. But the gene expression profiling procedure is technically difficult and highly expensive, and its clinical applications are limited. Therefore, the consensus of the St. Gallen Conference defined four molecular subtypes of breast carcinoma – luminal A, luminal B, Her 2 neu positive, and TNBC – based on ER/PR/Her 2 neu status and Ki 67 index, which was a simple classification with better clinical implications.,
The luminal A tumors, which are indolent and endocrine responsive comprise about 35% of breast carcinoma cases in India. Luminal B tumors represent about only 8% of carcinoma cases. They are heterogeneously characterized by higher grade, low endocrine sensitivity, increased proliferation rate, and poorer prognosis.,, Tumors with HER2 gene amplification and/or protein overexpression, account for 11% of all breast cancers. They are aggressive in nature and show a good response to anti-HER2 targeted therapy., The TNBCs lack any specific targeted therapy and show a high risk of distant metastasis, unlike the other molecular subtypes. The TNBCs, though considered as a single entity based on IHC and molecular profiling, have marked heterogeneity with aggressive subtypes and show specific epidemiological, clinical, and prognostic features.
Luminal B tumor was the largest in number in our series unlike the other studies (n = 90) (60%). They had a significant association with a high nuclear grade, high-grade PDCs, and high-grade TB. In comparison with luminal A tumors, they were associated with larger tumor size, increased stromal lymphoplasmacytic infiltrate, high Ki 67 index, and circumscribed tumor margins, indicating aggressive behavior. The luminal A tumors also had an increased number of high-grade TB compared to the hormone-negative aggressive molecular groups. TB had a significant association with lymph node metastasis and lymphovascular emboli independent of all the other variables. Our study also showed that tumor size, degree of differentiation, or Ki 67 index have no evident influence on the detachment and dissociation of tumor buds., A definite correlation was seen between TB and ER-positive status. Tumor bud cells are proven to have an epithelial-mesenchymal transition (EMT) phenotype with vimentin positivity, beta-catenin expression, and E-cadherin loss., Estrogen causes EMT in breast cancer stem cells and is involved in tight junction disruption and increased cell motility, causing the budding of tumor cells. Hence, it can be concluded that the luminal A and B tumors being hormone-dependent will show distinct genetic alterations that can influence the tumor microenvironment and cellular features resulting in a high-grade TB.
Larger tumor size, circumscribed tumor margins, lack of a desmoplastic stroma, high Ki 67 index, high stromal lymphoplasmacytic infiltrate, and presence of tumor necrosis had a significant association with Her2 neu positive and TNBC tumors compared to the luminal tumors though the values were not statistically significant. It may be due to the low sample size of these subgroups in our study. The signaling pathways that contribute to the metastatic progression of these tumors are still not clearly understood. Few studies have shown that the androgen receptor (AR), a potential prognostic marker and therapeutic target for TNBC cases, was proven to be an important regulator of TB. AR expression in ER-negative tumors and TNBC was associated with a higher nuclear grade. Though TNBC is known to up-regulate many of the EMT-related proteins, they were associated with a low-grade TB as seen in our study. It is possible that EMT exists as a spectrum with respect to each molecular and histological phenotypes. In the TNBCs, EMT may result in an invasive stem cell type, which is molecularly similar to TB but morphologically closer to an immune cell. This can cause difficulties in the detection of TB under the current histological criteria.
Her 2 neu gene amplification is an early event in breast carcinoma with a significant association with cell migration and cell proliferation., Bartlett et al. had identified a significant inverse association between Her 2 gene amplification and ER status via ER/Her 2 mediated crosstalk. Her 2 activates ER in a low-estrogen microenvironment, and ER activates intracellular signaling activating Her 2 activity and down-regulates HER2 expression. This negative loop is neutralized by Her 2 overexpression. In ER-positive tumors, overexpression of Her 2 causes increased tumor grade and in ER-negative tumors, Her 2 overexpression is associated with increased lymph node metastasis. Proliferation in these tumors is linked to RAS/MAPK cascade and increased cell migration and lymph node metastasis linked to Akt/PI3 kinase activity. Thus, the mode of infiltration and metastatic behavior of these tumors are entirely different from that of the luminal subtypes based on the interaction between tumor cells, host response, and tumor microenvironment.
Chemotherapy plays an important role in the treatment of patients with advanced breast carcinoma and hormone receptor-negative disease. Nonetheless, there is a lack of complete consensus on the indications for giving chemotherapy to patients with luminal breast cancers. In these tumors, clinicopathological poor prognostic factors such as age <40 years, lymph node status, tumor size, presence of lymphovascular invasion, histological grade, high Ki 67 index, luminal B-Her2 neu positive tumors, hormone treatment resistance, distant metastasis, and visceral disease/life-threatening disease are all considered as indicators for chemotherapy. Tumor burden including tumor size >2 cm (T2 and T3) and positive lymph node status are the two factors significantly affecting relapse-free survival in the luminal tumors, but they are not predictive for a benefit of adjuvant chemotherapy., Chemotherapy usually brings Luminal A tumors longer relapse-free periods and significantly improves overall/disease-free survival in luminal B tumors irrelevant of Her 2 neu or PR status.,
Ki 67 index is a clinically validated prognostic factor in early Luminal A and B breast carcinomas. They are usually used in combination with other prognostic factors to decide upon chemotherapy. When the Ki 67 index values are low or intermediate, with the lack of metastatic nodes, lymphovascular emboli, or other poor prognostic factors the treatment decision becomes extremely difficult. The updated guidelines from the European Group on Tumor Markers have suggested multianalyte tests such as urokinase plasminogen activator (uPA)-PAI-1, Oncotype DX, MammaPrint, EndoPredict, Breast Cancer Index (BCI), and Prosigna (PAM50) to be used for determining prognosis and help decision-making for the administration of adjuvant chemotherapy to Luminal A and B patients with low/intermediate Ki 67 index values, lymph node-negative, and lymph node-positive (1 to 3 nodes) tumors. But these tests are highly expensive, not available in all centers, and need technical expertise. A significant proportion of luminal carcinomas may have an intermediate Oncotype DX score, which again adds to the clinical uncertainty. Stromelysin-3, which encodes matrix metalloproteinase (MMP)-11 is one of the signature genes of Oncotype Dx. Metastatic carcinoma cells with EMT features have increased secretion of MMP-11, indicating a relationship between TB and Oncotype Dx. Many studies have shown that high-grade TB will significantly shorten the overall survival and disease-free survival in luminal carcinomas. Thus, TB being hormone driven, MMP associated, and predominant in luminal tumors can help in such situations when the patient cannot afford molecular tests.
The effects of hormonal and chemotherapy in the budding of tumor cells, the influence of TB and PDCs in the development of treatment resistance, and detailed molecular biology of TB and PDCs are areas that need to be studied in detail. More prospective studies with increased patient cohort and survival details are essential to assess the influence of TB, PDCs, and Ki 67 index in the luminal tumors to develop newer treatment strategies like targeted drugs against the budding cells.
Study caveats: The role of TB, PDC, and Ki 67 index in cancer-specific survival was not assessed, as the study was retrospective. Our findings could not be generalized to the entire Indian population as the samples are from a tertiary referral center.
Conclusion: TB and PDCs can be easily incorporated as poor prognostic markers in luminal tumors to improve risk stratification when prognostic markers like Ki 67 index cannot provide sufficient information. They are no better substitutes for sophisticated predictive molecular tests like Oncotype Dx but can be used in resource-constrained settings like ours where all the patients cannot afford to do gene expression profiling. They have no role in the prognostication of Her 2 neu positive and TNBC tumors as the metastatic signaling pathways of these tumors are different.
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Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, Regional Cancer Centre, Medical College PO, Trivandrum - 11, Kerala
Source of Support: None, Conflict of Interest: None
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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