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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 5  |  Page : 1024-1030

Impact of focality on prognostication of early and operable breast carcinomas of no special type


1 Department of Pathology, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India
2 Department of Medical Oncology, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India

Date of Web Publication4-Oct-2019

Correspondence Address:
Preithy Uthamalingam
Department of Pathology, Kovai Medical Center and Hospital, Coimbatore - 641 014, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_804_17

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 > Abstract 


Background and Objectives: Multifocal/multicentric (MF/MC) breast carcinomas are not uncommon and its prognostic significance debated. We attempted to analyze the association of focality and prognostic factors in operated pT1 and pT2 breast carcinomas of no special type (NST).
Materials and Methods: Retrospectively identified pathologically proven 124 unifocal (UF) and 49 MF/MC pT1 and pT2 breast carcinomas of NST over the past three years were compared in terms of clinical and pathological factors.
Results: The patients with MF/MC NST tumors were more likely to undergo radical surgery (P = 0.028). The tumors showed higher incidence of lymphovascular invasion (P = 0.024), perineural invasion (P = 0.046), ductal carcinoma in situ component (P < 0.001), higher number of positive axillary lymph nodes (P < 0.001), and higher anatomical staging (P = 0.048) when compared to the UF counterparts. Morphological intertumoral heterogeneity was noted in MF/MC tumors in 16 of 49 cases (32.65%).
Conclusion: Most published studies on MF breast cancers have included all histological types and varying definitions. We included only pathologically defined stages and a single histological type to ensure “purity” of the groups. Higher anatomic staging and morphological interlesional heterogeneity suggest that early MF/MC tumors represent multiple primaries with a different biology. Careful consideration of features of each focus needs to be considered when deciding appropriate adjuvant therapy and for accurately prognosticating these patients. Immunohistochemical and morphological (grade) heterogeneity between the different foci may pose problems with “prognostic stage grouping” these tumors according to the American Joint Committee on Cancer staging system (8th edition).

Keywords: American Joint Committee on Cancer, breast carcinoma, multifocal/multicentric, no special type, prognostic stage groups


How to cite this article:
Uthamalingam P, Rangarajan B, Sekar P, Mehta S. Impact of focality on prognostication of early and operable breast carcinomas of no special type. J Can Res Ther 2019;15:1024-30

How to cite this URL:
Uthamalingam P, Rangarajan B, Sekar P, Mehta S. Impact of focality on prognostication of early and operable breast carcinomas of no special type. J Can Res Ther [serial online] 2019 [cited 2019 Oct 20];15:1024-30. Available from: http://www.cancerjournal.net/text.asp?2019/15/5/1024/244235




 > Introduction Top


Multifocal/multicentric (MF/MC) breast carcinomas are not uncommon in clinical practice and have been a subject of ongoing debate in the medical literature in terms of definition, diagnosis, prognostication, and treatment, especially surgical, for these group of patients.[1] Tumor burden (T status) and nodal involvement (N status) are independent prognostic factors of breast carcinoma, constituting two of three parameters used in “anatomic” staging according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (Union for International Cancer Control) tumor (T)-node (N)-metastasis (M) classification.[2] Tumor biology which plays a significant role in prognostication of patients with breast cancer is complex and includes hormone receptor status, HER2/neu status, proliferation indices, various gene expression profile signatures and is reflected in part by histology.[3],[4],[5] Some of these factors are incorporated in the “prognostic” staging of breast carcinomas in the 8th edition of AJCC manual for staging of cancers.[6] Vast majority of breast carcinomas are invasive carcinoma of no special type (NST) while up to 25% is constituted by “special types” with distinct clinicopathological profiles.[4],[5] Almost all studies regarding MF/MC breast carcinomas have lumped the histological types together for analysis,[7],[8],[9],[10],[11],[12] thereby considering only tumor burden/anatomical aspect as the factor influencing prognosis in this group of patients. We attempted to analyze the association of focality and prognostic factors with respect to histology in early and operable breast carcinomas, with focus on invasive carcinoma of NST.


 > Materials and Methods Top


After obtaining the approval of the institutional review board, we retrospectively identified all operated patients diagnosed with invasive breast cancers between January 2014 and December 2016. The cases were classified as unifocal (UF) and MF/MC. MF tumor was defined as two or more separate invasive tumors in the same quadrant of the breast, while MC was defined as two or more separate invasive tumors in more than one quadrant of the same breast. Only grossly apparent foci with definite benign breast tissue in between the foci were considered. The MF and MC tumors were considered together for further analysis. Determinations were made by pathological review only; clinical and radiographic data were not considered. Only cases with at least the dominant focus showing pure invasive carcinoma, NST were included. Cases with even a minor component of a different histological type in the dominant or the only focus (in UF tumors) were excluded. All the tumors were staged according to the staging manual of AJCC, 7th edition.[2] Accordingly, the MF/MC tumors were staged according to the size and histology of the largest tumor focus. The NST tumors were histologically graded using Scarff–Bloom–Richardson grading system. Immunohistochemical analysis (IHC) for estrogen receptor (ER), progesterone receptor (PR), HER2/neu, and subsequent fluorescence in situ hybridization analysis for cases with equivocal HER2/neu positivity on IHC were performed on the largest focus only in case of MF tumors.

Inclusion criteria

All operated cases of pT1–pT2 invasive breast carcinomas, pure NST (in the dominant focus in case of MF tumors) with adequate axillary dissection (at least 10 lymph nodes examined) were included in this study.[13]

Exclusion criteria

Patients with metastatic disease at diagnosis and those treated with neoadjuvant chemotherapy were excluded. We also excluded patients with unknown pathological tumor size or nodal status available. Patients who had only ductal carcinoma in situ disease, only microscopic MF disease and any other histological tumor type in the largest focus were excluded.

The histology of the secondary foci was noted and documented regarding any heterogeneity if present. The background breast pathology was also noted down. Proliferative breast disease was defined as usual ductal hyperplasia which was moderate or more, atypical ductal hyperplasia, sclerosing adenosis, radial scar, and papillomatosis.[14]

Statistical methods

The statistical analysis was done using SPSS 20, (IBM, Armonk, NY, United States of America). The MF and MC tumors were analyzed as a group (MF/MC). Categorical and numerical variables were compared using Chi-square test and Student's t-tests, respectively. P < 0.05 was considered statistically significant.


 > Results Top


A total of 205 cases of operated early breast carcinomas (T1–T2) were considered in the study after initial exclusions. Of these, 147 (71.70%) were classified as UF disease and 58 (28.29%) were MF (n = 33)/MC tumors (n = 25). Distribution of cases according to the histological type is given in [Table 1]. The 124 cases of UF NST tumors were considered as the control group.
Table 1: Histological types of unifocal and multifocal T1/T2 breast carcinomas

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Clinical features

All patients were diagnosed on symptomatic presentation to the breast clinic. They were diagnosed to have breast carcinoma radiologically and then confirmed pathologically by core biopsies or fine-needle aspiration before definitive excision was performed. The age of the patients was not statistically different between patients with UF and MF NST tumors. Modified radical (MR) mastectomies were more common in the MF tumors than the UF counterparts (P = 0.028) [Table 2]. The distribution of laterality and quadrants of the breast involved by the dominant focus were not statistically different, although the cases with MF/MC tumors tended to involve the central quadrant (42.8% vs. 14.51%) with the largest or the smaller foci.
Table 2: Clinicopathological features of unifocal and multifocal/multicentric breast carcinomas

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Microscopic features

A comparison of UF/NST and MF/NST breast carcinomas is given in [Table 3]. The MF/MC NST type tumors exhibited significantly higher incidence lymphovascular invasion (LVI) (P = 0.024) and perineural invasion (PNI) (P = 0.046) when compared to UF counterparts. Mitotic rates were higher in the MF/MC tumors. Although the difference did not reach statistical significance, a definite trend was observed (P = 0.054). Associated DCIS component was also higher in the MF/MC group (P < 0.001). The higher number of positive axillary lymph nodes (P < 0.001) and higher incidence of level three axillary lymph nodal involvement (P < 0.001) in the MF/MC NST tumors subsequently lead to higher nodal stage (P < 0.001) and overall anatomical staging (P = 0.048) when compared to the UF counterparts. The MF/MC NST tumors also exhibited extracapsular spread more frequently in the involved axillary lymph nodes (P = 0.041). In spite of the higher nodal stage, the Nottingham Prognostic Index (NPI) did not differ significantly across the groups (P = 0.069).
Table 3: Comparison of microscopic features of unifocal and multifocal/multicentric breast carcinomas of no special type

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Among the NST tumors, the distribution of different Grades (1, 2, and 3) and the receptor expression and HER2 status did not differ across the UF and MF/MC groups when only the largest focus was considered for diagnosis. However, morphological intertumoral heterogeneity was noted in MF/MC tumors between the different foci in 32.65% (16 of 49 cases) of the tumors. Three of the 16 tumors showed differences in the grade of NST when compared to the largest focus (one showed higher grade and two lower grade tumors). Rest of the 13 tumors showed divergent differentiation in the form of mucinous (n = 2), solid papillary (n = 6), focal micropapillary (n = 2), and carcinoma with medullary features in the secondary focus (n = 3). Of these 16 tumors, 14 were MC tumors while 4 were MF. The background breast pathology did not differ significantly across the groups.

We further performed a subset analysis of pT1 and pT2 tumors across the two groups. The difference between UF (n = 30) and MF/MC (n = 11) pT1 NST tumors, in terms of LVI, PNI, nodal involvement, “N” stage, and overall anatomical staging disappeared. However, associated DCIS remained significantly higher in the MF/MC group (P = 0.023). Interestingly, the MF/MC pT1 tumors were more frequently ER (P = 0.008) and PR (P = 0.008) negative and were HER2/neu overexpressing (P = 0.028). This difference in hormone receptor status and HER2/neu overexpression was not observed in pT2 tumors, however, the differences in LVI (P = 0.013), PNI (P = 0.043), nodal “N” status (P = 0.001), and overall anatomic stage (P = 0.009) were significant.

Finally, we excluded a proportion of cases with intertumoral heterogeneity in MF/MC NST tumors, where at least one of the secondary foci was that of a solid papillary carcinoma without invasion (6 cases in the pT(m)2 group). The differences in terms of nodal involvement (P < 0.001), “N” status (P < 0.001), final anatomical (P < 0.001), and PNI (P = 0.023) gained more significance. In addition, the NPI became significantly higher (P < 0.001) when compared to the UF/NST counterparts.


 > Discussion Top


MF and MC tumors have traditionally been defined as tumors present in the same and different quadrants of the breast, respectively. Definitions used in different studies vary widely. Subsequently, incidence reported in the literature ranges from 6% to 75%.[15] Due to lack of defined anatomical borders of in the breast, our definition of MF/MC tumors remains arbitrary. Moreover, the sensitivity and specificity for the additional foci detected by conventional and MR mammography is not well established.[16] Hence, in this study, we included cases with multiple grossly visible lesions separated by benign breast tissue to be considered as MF/MC tumors. Our study reports an incidence of around 30 percent for MF/MC invasive breast carcinomas in the T1/T2 subset. This higher incidence of detected multifocality and subsequently higher numbers of MR mastectomies (MRMs) in the MF/MC group can also be attributed in part to the high sensitivity of MR mammogram done at out center.[16]

Epidemiologically, many of the previous studies have observed that patients with MF/MC carcinomas are younger and premenopausal.[7],[8],[9],[10],[11],[12] However, this observation was not seen in our study which can be attributed to the fact that the patients included in our study had the same histological type (NST) of tumor in contrast to most other studies. Previous studies have also shown that patients with MF/MC breast tumors are more likely to undergo radical surgery rather than breast conservation.[7],[8],[9],[10],[11],[12] This is reflected in our series too.[15]

Like the previous studies,[7],[8],[9],[10],[11],[12] we also observed a remarkably higher incidence of axillary lymph nodal metastasis in patient with MF/MC breast tumors when compared to the UF counterparts. For a given “T” stage, the number of axillary lymph nodes involved was significantly higher leading to higher overall anatomical stage (38.77% of MF/MC NST carcinomas were N2/N3, while only 13.7% of UF tumors were of the similar nodal stage in T1/T2 group). LVI, PNI, and extracapsular spread in the lymph nodes were also observed more frequently in MF/MC tumors.

In the T1 subset, the MF/MC NST tumors were more likely to be negative for ER and PR indicating aggressive tumor biology in these early tumors. This difference in hormonal receptor status was not observed in the T2 subset, however, the metastasizing capacity to the nodes appear to have increased in the MF/MC group. Whether this observation is because of the increasing tumor burden or inherent aggressiveness of the tumor is debatable. However, several studies attempting to quantify tumor burden using aggregate diameters of the invasive foci and tumor surface area have concluded that the aggressiveness of MF/MC breast carcinomas cannot be attributed just to the increased tumor bulk alone.[10],[17],[18]

This increased incidence of bad prognostic factors have not been consistently reflective of the survival outcomes in the patients with MF/MC breast carcinomas in the various published studies and meta-analysis in the literature.[7],[8],[9],[10],[11],[12],[17],[18] Contradictory results regarding disease-free survival, overall survival, and locoregional recurrences have been documented by different studies. Multifocality has not been found to be an independent prognostic marker in multivariate analyses.[8],[9],[10],[11] Major factors contributing to this observation is the heterogeneity in the study design, starting from the definitions, mode of diagnosis, and stage and type of the tumors included for comparison. All the large studies did not differentiate subgroups based on tumor histology, though the incidence of lobular differentiation was significantly higher in the MF/MC group. Many studies also included advanced “T” stages (T3 and above).[7],[8],[9],[10],[11],[12] Overall, we are of the opinion that these studies might have oversimplified the concept of multifocality and possibly underestimated the relevance of the histology, as the “special” subtypes constitute up to 40%[10] of the cases included in the same group for analysis. Since widely different tumor biologies with different prognostic profiles (e.g., NST carcinomas, lobular, papillary, and other special types) were considered in the same group, the survival outcomes did not reach significance when compared with stage-matched UF counterparts.[19] Moreover, in locally advanced breast cancers, the significance of multifocality in contributing to the overall prognosis may be lost when compared to the early and operable breast carcinomas, where the intent of treatment may be different. [Table 4] summarizes the findings of a few major studies in the past decade.
Table 4: Survival analysis of recent large retrospective studies on multifocal/multicentric breast carcinomas

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The origin and nature of the multiple ipsilateral breast carcinomas have been a subject of much debate in the past decades.[15] Two schools of thought exist, one being the notion that the multiple foci of tumor represent intramammary spread of a UF tumor through the ductal system or by metastatic deposits thorough lymphovascular emboli. This theory assumes an implied monoclonality of the lesions. Argument for monoclonality has been put forth based on histological, immunohistochemical,[20],[21] and genetic methods.[22] Involvement of the nipple, areola, and large lactiferous ducts by in situ carcinoma and increased incidence of lymphovascular emboli in patients with MF/MC carcinomas supported the notion of intraductal and lymphovascular intramammary spread of tumor, respectively.[21] Immunohistochemical features analyzed included ER, PR, HER2/neu, and Ki67.[20],[21] Genetic similarities based on cytogenetics and comparative genomic hybridization suggested clonal “relatedness” of the ipsilateral multiple synchronous tumors, while the bilateral breast tumors were clonally unrelated.[22]

The second theory is that of multiple synchronous primaries arising from different duct–lobular units, implying multiple synchronous primaries. The differences in immunohistochemical profiles of the different lesions in MF/MC breast carcinomas was being noted in the earlier studies by Dawson et al.[21] More recent studies have highlighted the immunohistochemical dissimilarities between different tumor foci in MF/MC breast carcinomas.[23],[24],[25],[26],[27] Although the differences in features were apparent in all the studies in cases with foci showing different histology, differences in tumor foci with similar morphology, especially in invasive carcinomas of NST were not consistent. Buggi et al. and Boros et al. found up to 12% discordance in ER, PR, and HER/2neu status in the different foci which would have led to different adjuvant therapy, histological similarities notwithstanding.[23],[24] Histological grade of the tumor was also found to be a poor predictor of HER/2neu status.[28] Recent studies using next-generation sequencing techniques allowing for deep genomic sequencing have started uncovering the genomic heterogeneity of the multiple ipsilateral primary tumors.[29] Desmedt et al. have shown that up to one-third of the patients with lesions presenting the same grade, ER, and HER2 status showed interlesional heterogeneity with respect to oncogenic mutations. Genomically heterogeneous lesions tended to be further apart anatomically in the breast than homogeneous lesions. Thus, the recent data demonstrate that at least a major proportion of MF/MC breast tumors are in fact clonally unrelated multiple primaries with distinct tumor biology.[29]

In the present study, we found homogenous tumor foci in terms of morphology and grade in 68.75% (33 of 48 cases) of cases. Immunohistochemical and genomic features of all these foci were not assessed. A proportion of these tumors might represent intramammary spread of a single tumor, especially those which are close to each other. Morphologically, different lesions were predominantly MC/further apart in our study. These differences in terms of tumor histological subtype further support the claim that these tumors might be multiple synchronous primaries, as the tumor biology and the genetic events underpinning these morphological subtypes are different.[4],[5] The most common histologically distinct secondary focus was that of solid papillary carcinoma (6 cases). Solid papillary carcinomas without invasion are indolent tumors with excellent prognosis.[30] When we excluded MF/MC NST cases with a component of papillary carcinomas in the secondary foci for comparisons, the differences in poor prognostic features in MF/MC tumors when compared to UF NST carcinomas were more distinct. This indirectly demonstrates the importance of tumor biology of each focus in determining the overall prognosis of the patient.

Prognostic stage groups introduced in the latest cancer staging manual of AJCC (8th edition) incorporating the tumor grade, hormonal receptor status, and HER/2neu status of the tumor in staging them, is a revolutionary step forward in objectifying the impact of tumor biology on prognosis.[6] However, the cancer staging manual of AJCC 8th edition does not specify how to incorporate the “worst” pattern in staging of these MF/MC tumors. For instance, if a tumor is classified as pT2, pN1, grade 2, ER positive, PR positive, HER/2neu negative, based on the largest focus alone, it would be staged as prognostic stage 1B. If the smaller secondary focus is pT1 size, grade 2, ER negative, PR positive, and HER/2neu positive, it would merit a prognostic stage of stage 2A for the same nodal status. Hence, the relationship between “anatomic” stage groups and the “prognostic” stage groups are nonlinear and complex. The manual describes 25 instances in which the use of grade and prognostic factors changed the group more than one stage group from the anatomical stage group.[6] Ambiguity in this area will become prominent when “prognostic staging” becomes the standard of care from January 2018 onward. Guidelines are required regarding accurate prognostication of such cases, which are not uncommon in practice.

To summarize, breast carcinomas are remarkably heterogeneous and complex in their biology and outcome. We recommend meticulous sampling of the gross specimens with radiological correlation. Resampling should be done in cases with apparently UF NST tumors with high nodal stage to exclude missed multifocality. We propose that the overall prognosis of patients with MF/MC breast carcinomas depends more on the tumor foci with “worst biology” rather than the tumor bulk. Hence, detailed histological and immunohistochemical characterization of the secondary tumor foci is warranted. The histological type and grades along with IHC of at least all the grossly visible secondary foci, needs to be documented and communicated in the pathology report, highlighting the worst histological subtype and/or highest grade with the corresponding size of the focus, which is likely to influence the overall outcome and adjuvant therapy of the patient.[31] All these data need to be considered in clinicopathological meetings in deciding the appropriate adjuvant therapy.


 > Conclusion Top


The authors concur with current “anatomical” staging methodology of MF/MC carcinomas, where the dimension of only the largest invasive focus is considered. Pathologically proven MF/MC carcinomas appear to have more bad prognostic factors than UF tumors of the same “pT” categories, which could translate into significant differences in further management. The importance of the tumor biology, in terms of histology and immunohistochemical features of each focus, needs to be underscored in the report, though ways to incorporate the characteristics of tumor focus with “worst biology” in prognostic stage grouping (AJCC 8th edition) is not in place yet. Prospective studies need to be undertaken for further clarity regarding this group of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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