Does focal heterogeneity affect survival in postoperative ipsilateral multifocal and multicentric breast cancers?

SUMMARY

OBJECTIVE:

In multicentric/multifocal breast tumors, there may be immunological and histological differences between foci that may affect survival and treatment choice. We aimed to evaluate the effect of focal heterogeneity seen in multicentric/multifocal breast tumors on survival.

METHODS:

We retrospectively collected and analyzed the clinicopathological data of 89 female patients with multifocal/multicentric breast cancer, whose surgical and medical treatment was completed and who were followed up for 5 years.

RESULTS:

Of all patients, 29.2% (26/89) were heterogeneous. Heterogeneity of these foci was as follows: histologic heterogeneity of index foci (mix type): 15.7% (14/89), histologic heterogeneity of inter-foci: 7.9% (7/89), and immunohistochemical heterogeneity of inter-foci: 10.1% (9/89). When additional foci were evaluated, oncological therapy was changed for 3 (3.3%) of 89 patients. Heterogeneity does not have a significant (p>0.05) effect on recurrence and survival in multicentric/multifocal breast cancers. Pathological N stage is an independent risk factor for disease-free survival (hazard ratio=2.29, 95% confidence interval=1.39–3.76, p=0.001).

CONCLUSIONS:

In multifocal/multicentric breast cancers, less than 4% of patients may experience heterogeneity requiring change in the therapeutic decision. However, heterogeneity does not have a significant effect on recurrence and survival in multifocal/multicentric breast cancers. The pathological N stage is an independent risk factor for disease-free survival.

KEYWORDS:
Breas cancer; Multifocal; Multicentric; Tumor heterogeneity; Survival

INTRODUCTION

Invasive ductal carcinoma (IDC) is the most frequently diagnosed and the most common type of breast cancer among women. In the latest classification of the World Health Organization, at least 17 different special histological types have been described, which constitute 25% of all breast cancers. Histological types are associated with the morphological and cytological features of the cell, derived from the growth pattern of breast cancer¹. Depending on different histological methods employed and the cases selected, 6–75% of these tumors are multicentric (MC) or multifocal (MF) breast tumors².

The presence of multiple foci on the same quadrant or different quadrants of breast is defined as MC/MF³. The development of MF/MC breast cancers may be explained through two mechanisms in the literature. The first mechanism (polyclonal) may occur as multiple independent tumor foci. In these foci, different phenotypes may occur due to underlying molecular changes. The second mechanism (monoclonal) may be the genetic or phenotypic change in the foci during the intramammary spread of the tumor or the progression of the tumor⁴. In case of multiple breast cancers, there may be different histological types and/or histological grades between tumors in 3–37.5% of cases⁵. This situation may affect survival and treatment choice⁶.

We aimed to investigate the effect of focal heterogeneity on 5-year disease-free survival (DFS) in MC/MF breast cancers because there is limited number of publications in the literature regarding intra- and inter-focal heterogeneity in MC/MF breast tumors.

METHODS

Ethical approval

Local ethics committee approval (dated November 13, 2020, Decision no.: 2588) was obtained.

Patient selection

Inclusion criteria: The patient files of Health Sciences University, Istanbul Training and Research Hospital, were retrospectively scanned and 89 female patients who underwent operation between January 1, 2010 and January 1, 2015, had surgical, immunohistochemical, and histopathological results [i.e., estrogen receptor (ER), progesterone receptor (PR), human epithelial growth factor receptor-2 (HER-2), proliferation index (KI-67)] for MC/MF breast cancer and who were given postoperative complementary medical treatments and followed up were identified and included in the study.

Exclusion criteria: Male patients; patients with preoperative stage 4 metastatic breast cancer, unifocal breast cancer, or bilateral breast cancer; and patients who received neoadjuvant chemotherapy, who did not undergo surgery and who did not have immunohistochemical and histopathological results, and follow-up records were excluded from the study.

Immunohistochemical subtypes classification

ER, PR (if ER or PR ≥1%, positive; if ER or PR <1%, negative), and HER-2 [HER-2 score=1–0, negative; HER-2 score=3, positive; and HER-2 score =2, positive which was tested using the Silver-enhanced in situ hybridization (SISH)] were accepted. The recommendations in the St. Gallen International Consensus Guidelines were taken into consideration in the immunohistochemical classification of subtypes.

Luminal A: ER+, PR+, HER-2-, Ki67<20% and/or PR≥20%, and/or low grade (G1/2).

Luminal B: ER+, PR+/-, HER-2-, Ki67≥20% and/or PR<20%, and/or high grade (G3) or ER+, PR +/-, HER-2+, any Ki67, any PR.

HER-2-positive: ER-, PR-, and HER-2+.

Triple-negative: ER-, PR-, and HER-2-⁷.

Focal heterogeneity

Histologic heterogeneity of index intra-foci (HhİİF) (mix type=intra-focal): Heterogeneity of index focus observed in histological type, which is the large tumor size.

Histologic heterogeneity of inter-foci (HhİF): Heterogeneity observed in histological type between foci.

Immunohistochemical heterogeneity of inter-foci (İhİF): Heterogeneity observed in immunohistochemical (phenotypic) subtype between foci.

Statistical analysis

The analyses were carried out using SPSS version 26.0.

RESULTS

The median age of 89 patients included in the study was 48 years. The most dominant findings in the study were as follows: ER+=78.7% (70/89), PR+=73% (65/89), HER-2-=75.3% (67/89), Ki67≥20%=51.7% (46/89), LVI+=61.8% (55/89), G2=65.2% (58/89), two foci=74.2% (66/89), IDC=70.8% (63/89), and homogeneity with the rates of 70.7% (63/89). In total, 29.2% (26/89) of MF/MC breast carcinomas were heterogeneous. Heterogeneity distribution of the relative foci was HhİİF (15.7%, 14/89), HhİF (7.9%, 7/89), and İhİF (10.1%, 9/89). Evaluation of additional foci resulted in alteration of postoperative oncology treatment of three patients according to the histopathology of index focus. In those three (3.3%, 3/89) patients, there was heterogeneity in immunohistochemical subtypes, and the tumor grade was G3 in two patients and G2 in one patient (Tables 1 and 2).

Table 1
Comparison of clinicopathological, recurrent and non-recurrent patients after postoperative oncological treatment.

		Clinicopathological data				Recurrence (-)			Recurrence (+)			p
		Min.–Max.	Median	Mean±SD/n-%		Mean±SD/n-%		Median	Mean±SD/n-%		Median
		28.0–79.0	48.0	50.4±12.5		50.0±12.5		48.0	53.8±12.9		55.5	0.498m
Age	≤50			50	56.2%	39	57.4%		11	52.4%		0.688m
	>50			39	43.8%	29	42.6%		10	47.6%
İndex focus T size (cm)		0.3–9.0	2.5	2.9±1.8		2.8±1.8		2.5	3.8±2.2		3.3	0.186m
Surgery type	Breast conserving			17	19.1%	16	23.5%		1	4.8%		0.056x2
	Mastectomy			72	80.9%	52	76.5%		20	95.2%
Histologic types of index foci	Ductal carcinoma			63	70.8%	51	75.0%		12	57.1%		0.194x2
	Lobular carcinoma			3	3.4%	2	2.9%		1	4.8%		0.558x2
	Mix types			14	15.7%	8	11.8%		6	28.6%		0.132x2
	Special types			9	10.1%	7	10.3%		2	9.5%		0.755x2
Pathological T category	pT1≤2 cm			29	32.6%	24	35.3%		5	23.8%		0.148x2
	2 cm<pT2≤5 cm			35	39.3%	28	41.2%		7	33.3%
	pT3			5	5.6%	4	5.9%		1	4.8%
	pT4			20	22.5%	12	17.6%		8	38.1%
Pathological N category	pN0			20	22.5%	20	29.4%		0	0.0%		0.003×2
	pN1			25	28.1%	19	27.9%		6	28.6%
	pN2			23	25.8%	18	26.5%		5	23.8%
	pN3			20	22.5%	10	14.7%		10	47.6%
	Missing			1	1.1%
Grade of index foci	I			5	5.6%	5	7.5%		0	0.0%		0.258x2
	II			58	65.2%	46	68.7%		12	60.0%
	III			24	27.0%	16	23.9%		8	40.0%
	Missing			2	2.2%
Number of foci	II			66	74.2%	52	76.5%		14	66.7%		0.540x2
	III			18	20.2%	12	17.6%		6	28.6%
	IV			4	4.5%	4	5.9%		0	0.0%
	V			1	1.1%	0	0.0%		1	4.8%
İndex focus ER status	≥1%			70	78.7%	55	80.9%		15	71.4%		0.355x2
	<1%			19	21.3%	13	19.1%		6	28.6%
İndex focus PR status	≥1%			65	73.0%	53	77.9%		12	57.1%		0.060x2
	<1%			24	27.0%	15	22.1%		9	42.9%
İndex focus HER2 (SİSH) status	Positive			22	24.7%	18	26.5%		4	19.0%		0.491x2
	Negative			67	75.3%	50	73.5%		17	81,0%
Index focus Ki67 status	≥ 20%			46	51.7%	33	48.5%		13	61.9%		0.284x2
	< 20%			43	48.3%	35	51.5%		8	38.1%
Lymphovascular invasion	Yes			55	61.8%	39	58.2%		16	76.2%		0.137x2
	No			33	37.1%	28	41.8%		5	23.8%
	Missing			1	1.1%
Perineural invasion	Yes			18	20.2%	14	21.9%		4	20.0%		0.252x2
	No			66	74.2%	50	78.1%		16	80.0%
	Missing			5	5.6%
Perinodal invasion	Yes			39	43.8%	27	40.3%		12	57.1%		0.1752
	No			49	55.1%	40	%59.7%		9	42.9%
	Missing			1	1.1%
Histologic heterogeneity of index foci	Homogeneity			75	84.4%	59	86.8%		15	71.4%		0.101x2
	Heterogeneity			14	15.7%	8	11.8%		6	28.6%
Histologic heterogeneity inter-foci	Homogeneity			82	92.1%	63	92.6%		19	90.5%		0.888x2
	Heterogeneity			7	7.9%	5	7.4%		2	9.5%
Immunohistochemical heterogeneity inter-foci	Homogeneity			80	89.9%	60	88.2%		20	95.2%		0.352x2
	Heterogeneity			9	10.1%	8	11.8%		1	4.8%
Follow-up time						84.9±20.6		89.0	45.0±27.7		38.0	0.106m
Disease-related mortality	No					68	100%		13	61.9%		0.000x2
	Yes					0	0.0%		8	38.1%
Recurrence	No			68	76.6%
	Yes			21	23.6%
Recurrence location	Local			4	4.5%
	Visceral			5	5.6%
	Bone			11	12.4%
	Bone+visceral			1	1.1%

• ^m
  Mann–Whitney U test/
• ^x2
  Chi-square test (Fischer's exact); T: tumor size, N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.

Table 2
Heterogeneity distribution of MF/MC breast cancers.

Patient	Number of foci	Size (cm)	Grade of index foci	Histology of intra- index and inter-foci	Histology of inter foci	Immunohistology of inter-foci (St. Galen)	Those whose medical treatment changed
1	2	1.2/0.3	2	D-MP/D-MP	D-MP/D-MP	LuA/LuA	−
2	2	1.9/1.6	3	L-T/L-T	L-T/L-T	LuA/LuA	−
3	2	2.3/2	3	D-MP/D-MP	D-MP/D-MP	LuB/LuB	−
4	2	2.5/1.5	2	M-D/M-D	M-D/M-D	LuB/LuB	−
5	2	3.5/0.2	2	D-M/D-M	D-M/D-M	LuB/LuB	−
6	2	4/2.5	2	D-MP/D-MP	D-MP/D-MP	LuB/LuB	−
7	2	5/0.2	2	N-D/N-D	N-D/N-D	LuB/LuB	−
8	2	2.5/0.3	2	D-MP/D-MP	D-MP/D-MP	HER/HER	−
9	2	5.5/1	2	D-MP/D-MP	D-MP/D-MP	HER/HER	−
10	2	6/0.9	3	M-MP/M-MP	M-MP/M-MP	HER/HER	−
11	3	6/4/1	2	D-L/D-L/D	D-L/D-L/D	LuA/LuA/LuA	−
12	3	3.5/1.9/1.4	3	D-MP/D-MP/D-MP	D-MP/D-MP/D-MP	LuB/LuB/LuB	−
13	2	0.9/0.6	1	C/T	C/T	LuA/LuA	−
14	2	1/0.6	2	D/T	D/T	LuA/LuA	−
15	2	2/0.2	2	C/L	C/L	LuA/LuA	−
16	2	2/1.8	3	D/D-L	D/D-L	Tn/Tn	−
17	3	2.8/2/0.2	2	D/L/L	D/L/L	LuA/LuA/LuA	−
18	2	1.5/1.2	2	D/D	D/D	LuB/LuA	−
19	2	1.8/1.5	2	D-P/D-P	D-P/D-P	LuB/LuA	−
20	2	2.5/2.5	2	D-L/D-L	D-L/D-L	LuB/LuA	−
21	2	4/3	2	D/D	D/D	LuB/LuA	−
22	3	2.4/1.8/1.5	2	D/D/D	D/D/D	LuB/LuB/LuA	−
23	3	2.6/1.1/0.3	2	D/D/D	D/D/D	LuB/LuA/LuA	−
24	2	2.5/2.1	3	D/D	D/D	LuA/LuB	+
25	2	3/1.6	2	D/D	D/D	LuA/LuB	+
26	2	1/1	3	D/D	D/D	Tn/LuB	+

• D: invasive ductal carcinoma; L: invasive lobular carcinoma; MP: invasive micropapillary carcinoma; M: mucinous carcinoma; N: neuroendocrine carcinoma; T: invasive tubular carcinoma; C: invasive cribriform carcinoma; LuA: Luminal A; LuB: Luminal B; HER: human epidermal growth factor receptor; Tn: triple negative.

The median duration of clinical follow-up was 83 months (min–max: 5–120 months, mean: 81.3±24 months). Recurrence was recorded in 23.6% (21/89) of the patients during follow-up. The most common postoperative recurrence types were local recurrence (4.5%, 4/89), visceral organ (5.6%, 5/89), bone (12.4%, 11/89), and bone plus visceral organ (1.1%, 1/89). The pathological N (pN) stage and mortality rate were significantly higher (38.1%, 8/21) in the recurrence group as compared to the group without recurrence (p<0.05) (Table 1).

The univariate analysis assessing DFS showed that pathological T (pT) stage, pN stage, and histological grade of index focus were significantly effective (p<0.05). Similarly, the multivariate analysis indicated that pN stage had a significantly independent (HR=2.29, 95%CI 1.39–3.76, p=0.001) effect on DFS. In the univariate analysis evaluating overall survival (OS), however, pN stage had significant effect only on OS (HR=5.82, 95%CI 1.580–21.43, p=0.008) (Table 3).

Table 3
Univariate and multivariate analyses for disease-free survival and overall survival.

Survival		Disease-free survival						Overall survival
		Univariate model			Multivariate model			Univariate model			Multivariate model
Disease-free survival		HR	95%CI	p	HR	95%CI	p	HR	95%CI	p	HR	95%CI	p
Age (≤50/>50)		0.99	0.96–1.03	0.628				1.02	0.969–1.08	0.411
Index focus size (cm)		1.13	0.93–1.37	0.230				1.22	0.912–1.64	0.178
Surgery type (breast conserving/mastectomy)		4.38	0.59–32.70	0.149				28.28	0.016–>100	0.383
Histological types of index foci		1.24	0.87–1.79	0.239				1.52	0.891–2.59	0.125
	Pathological T stage	1.58	1.07–2.33	0.021				1.82	0.987–3.34	0.055
	Pathological N stage	2.29	1.39–3.76	0.001	2.29	1.39–3.76	0.001	5.82	1.580–21.43	0.008
Grade of index foci		2.32	1.01–5.32	0.048				1.85	0.500–6.85	0.356
Number of foci		1.52	0.76–3.02	0.236				11.19	0.408–3.47	0.750
Index focus ER status (ER≥1%/ER<1%)		1.64	0.64–4.23	0.306				2.41	0.575–10.09	0.229
Index focus PR status (PR≥1%/PR<1%)		2.71	1.14–6.45	0.024				2.81	0.701–11.24	0.145
Index focus HER-2 (SİSH) status (+/−)		1.15	0.39–3.41	0.805				2.21	0.272–17.98	0.458
Index focus Ki67 status (≥20%/<20%)		0.52	0.21–1.15	0.145				0.61	0.146–2.55	0.499
Lymphovascular invasion (yes/no)		0.46	0.17–1.27	0.133				0.21	0.025–1.70	0.143
Perineural invasion (yes/no)		1.36	0.45–4.07	0.586				1.85	2.223–15.46	0.568
Perinodal invasion (yes/no)		0.67	0.28–1.58	0.356				0.24	0.049–1.21	0.084
Histologic heterogeneity of index foci (homogeneity/heterogeneity)		1.90	0.73–4.89	0.186				3.47	0.823–14.60	0.090
Histologic heterogeneity of inter-foci (homogeneity/heterogeneity)		1.10	0.26–4.74	0.895				1.71	0.210–13.93	0.616
Immunohistochemical heterogeneity of inter-foci (homogeneity/heterogeneity)		0.32	0.04–2.39	0.267				0.04	0.000–984.83	0.537

• Cox regression (forward LR); T: tumor size; N: lymph node; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epithelial growth factor receptor-2; SİSH: Silver-enhanced in situ hybridization; Ki67: proliferation index. Bold indicates statistically significant values.

DISCUSSION

TNM classification is accepted as the gold standard in breast cancer staging. In its latest version, the largest diameter in MF/MC breast cancers is taken into account, and other foci are not⁸. As a result, cumulative tumor burden does not affect the choice of treatment. In many studies in the literature, it is known that MF/MC breast cancers have higher metastases, recurrence, and decreased survival when compared with similar stage unifocal (UF) breast cancers⁶,⁹–¹¹. The state of the axillary lymph node (ALN) (or pN stage) is one of the most important prognostic factors. An increase in the number of the state of ALN metastases proportionally decreases DFS and OS. In the literature, the factors indicative of the presence of the state of ALN metastases are large tumor size, presence of lymphovascular invasion, high grade (G3), molecular status, and tumors with lateral or central localization⁵,⁸,¹². This situation has brought along discussions on subjects such as survival, mortality, cost, staging, biological, and morphological behaviors in MF/MC breast tumors at a time when personalized surgical and oncological treatments gain momentum.

Breast cancer is a heterogeneous group of neoplasms with clinical, morphological, and immunohistochemical differences within a single tumor or between tumors. Depending on different histological methods employed and the cases selected, 6–75% of these tumors are MC/MF breast tumors. Inter-focal heterogeneity is one of the major discussion topics in MF/MC breast tumors. In the literature, the rates of HhİİF, HhİF, and İhİF in MF/MC breast cancers are reported as 0–17.1, 0–37, 0–12.7%, respectively²,⁶,¹³,¹⁴. Similar to the literature, we found the rates of 15.7, 7.9, and 10.1%, respectively.

In their series dated 2012 of 65 cases with MF/MC IDC, Choi et al. found additional heterogeneous tumor foci that would change the treatment decision in 8% (5/65) of the patients. Choi et al. suggested that immunohistochemical analysis of the index tumor may be sufficient in routine practice, but if there is high-grade, different histological features or heterogeneous ductal carcinoma in situ component in the index tumor, additional foci should be examined². In 2014, Parker et al. evaluated HhİİF (heterogeneity in histological type and grade) and HhİF using three classification systems (i.e., modified Nielsen¹⁵, St. Gallen 2011¹⁶, and Sotiriou¹⁷] in their study of 100 cases. In the evaluation of additional heterogeneous tumor foci using the modified Nielsen, St. Gallen 2011, and Sotiriou systems, the rate of changes in treatment decision were as follows: 3.63% (4/110), 7.27% (8/118), and 7.27% (8/110), respectively. In MF/MC breast cancers that were classified according to the modified Nielsen system, the risk of death was significantly higher (p<0.05) and survival was shorter in the İhİF group. However, there was no significant difference (p>0.05) between the groups according to the classifications by the St. Gallen 2011 and Sotiriou classification systems. There was no significant difference (p>0.05) between HhİİF MF/MC breast cancers and the other homogeneous group of the series. The authors reported that in patients with inter-focal histological type and/or degree of heterogeneity, up to five foci of inter-focal immunohistochemical evaluation may reduce the risk of death from the disease⁶. Mosbah et al. did not detect any heterogeneity that could change the treatment decision in the study they conducted in 2015 on 205 cases, in which they performed histopathological evaluations of up to two foci. Mosbah et al. reported that even if there is a discrepancy between tumor foci, it had little effect on the treatment decision, and that even if the focus showed different tumor grades, performing immunohistochemical evaluation on the index tumor focus only may be sufficient¹⁴. In our study, evaluation of additional foci changed postoperative oncological treatment for three patients. In those three (3.3%, 3/89) patients, the number of foci was two and there was heterogeneity in immunohistochemical subtypes. The histological grade of index tumor foci was G3 in three patients and G2 in one patient (Tables 1 and 2). When compared with the literature considering the cost and individualized oncological treatments, it seems sufficient to evaluate grades 2–3 tumors in the index focus up to two foci. Nevertheless, it should also be noted that heterogeneity (i.e., HhİİF, HhİF, and İhİF) does not have a statistically significant effect on recurrence and survival (DFS and OS) in MF/MC breast cancer (Tables 1 and 3).

Boros et al. evaluated the risk of ALN metastasis in their study of 155 cases with MF/MC breast cancer in 2015 and found that there was not a statistically significant difference between homogeneous patients (73.91%, 85/115) and those (80%, 32/40) with mismatches between histological type, grade, or both regarding the rate of ALN metastases (p>0.05). The rate of heterogeneous MF/MC breast cancer determined ALN metastases as follows: 72.73% (8/11) with histological type heterogeneity, 87.5% (14/16) with inter-focal grade heterogeneity, and 76.92% (10/13) with histological type and grade heterogeneity. Most (33.33%, 8/24) of the heterogeneous MF/MC tumors with differences in inter-focal grade (87.5%, 21/24) had a high histological grade. In that study, the authors stated that the histological features (e.g., type and grade) of ALN metastases in MF/MC breast cancers correspond to the histological type with unfavorable prognosis or the highest histological grade, which is not necessarily of the index focus, and emphasized that it is necessary to conduct an individual histopathological evaluation for each tumor focus with high grade⁵. It is known that before the inclusion of prognostic biomarkers (e.g., grade, hormone receptor, oncogene expression, and multigene panel recurrence score) in the current TNM classification, hormonotherapy increased the long-term survival by decreasing the recurrence rate of ER+/PR+ breast tumors, yet had no effect on long-term survival in ER+/PR- breast tumors⁸,¹⁸. In our study, a significant (p<0.05) effect of pT stage, pN stage, and index focus histological grade was observed in univariate analysis in which DFS was evaluated. In multivariate analysis, pN stage had a significantly independent (HR=2.29, 95%CI 1.39–3.76, p=0.001) effect on DFS. In the univariate analysis evaluating OS, however, pN stage had a significant effect only on OS (HR=5.82, 95%CI 1.580–21.43, p=0.008) (Table 3). This result supports the literature.

The limitations of the study are as follows: it evaluated the long-term effects, it had a retrospective design, and it could not evaluate the histological/immunohistochemical footprints of the foci in metastatic ALN.

CONCLUSIONS

At present, when oncological treatments are personalized with a multidisciplinary approach, less than 4% of patients have heterogeneity in MF/MC breast cancers, which necessitate an alteration in therapeutic decisions. As evaluating multiple foci would increase the cost and labor, it may be enough to evaluate grade 2–3 tumors in the index focus up to two foci. However, heterogeneity does not have a significant effect on recurrence and survival in MF/MC breast cancers. The pN is an independent risk factor for DFS.

• Funding: none.
• ETHICAL APPROVAL
  All procedures performed in this study, involving human participants, were in accordance with the ethical standards of the İnstitutional Research Committee and 1964 Helsinki Declaration. Local ethics committee approval was obtained from Health Sciences University, Istanbul Training and Research Hospital (dated November 13, 2020, Decision no.: 2588).
• AVAILABILITY OF DATA
  All data generated or analyzed during this study are included in this published article (and its supplementary information files). But restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with the permission of Health Sciences University Turkish Ministry of Health İstanbul Research and Training Hospital.

ACKNOWLEDGMENTS

As authors, we thank the Health Sciences University Turkish Ministry of Health İstanbul Research and Training Hospital Research Projects Unit.

REFERENCES

• ¹
  Yılmaz TU, Trabzonlu L, Güler SA, Baran MA, Pösteki G, Erçin C, et al. Characteristics of special type breast tumors in our center. Eur J Breast Health. 2018;14(1):17-22. https://doi.org/10.5152/ejbh.2017.3219
  » https://doi.org/10.5152/ejbh.2017.3219
• ²
  Choi Y, Kim EJ, Seol H, Lee HE, Jang MJ, Kim SM, et al. The hormone receptor, human epidermal growth factor receptor 2, and molecular subtype status of individual tumor foci in multifocal/multicentric invasive ductal carcinoma of breast. Hum Pathol. 2012;43(1):48-55. https://doi.org/10.1016/j.humpath.2010.08.026
  » https://doi.org/10.1016/j.humpath.2010.08.026
• ³
  Fisher ER, Gregorio R, Redmond C, Vellios F, Sommers SC, Fisher B. Pathologic findings from the National Surgical Adjuvant Breast Project (protocol no. 4). I. Observations concerning the multicentricity of mammary cancer. Cancer. 1975;35(1):247-54. https://doi.org/10.1002/1097-0142(197501)35:1<247::aid-cncr2820350130>3.0.co;2-s
  » https://doi.org/10.1002/1097-0142(197501)35:1<247::aid-cncr2820350130>3.0.co;2-s
• ⁴
  Boros M, Georgescu R, Podoleanu C, Stolnicu S. Review on practical approach in multiple breast carcinomas: does each focus matter? Chirurgia (Bucur). 2017;112(4):418-28. https://doi.org/10.21614/chirurgia.112.4.418
  » https://doi.org/10.21614/chirurgia.112.4.418
• ⁵
  Boros M, Podoleanu C, Georgescu R, Moldovan C, Molnar C, Stolnicu S. Multifocal/multicentric breast carcinomas showing intertumoural heterogeneity: a comparison of histological tumour type and Nottingham histological grade of primary tumour and lymph node metastasis. Pol J Pathol. 2015;66(2):125-32. https://doi.org/10.5114/pjp.2015.53008
  » https://doi.org/10.5114/pjp.2015.53008
• ⁶
  Pekar G, Gere M, Tarjan M, Hellberg D, Tot T. Molecular phenotype of the foci in multifocal invasive breast carcinomas: intertumoral heterogeneity is related to shorter survival and may influence the choice of therapy. Cancer. 2014;120(1):26-34. https://doi.org/10.1002/cncr.28375
  » https://doi.org/10.1002/cncr.28375
• ⁷
  Burstein HJ, Curigliano G, Loibl S, Dubsky P, Gnant M, Poortmans P, et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol. 2019;30(10):1541-57. https://doi.org/10.1093/annonc/mdz235
  » https://doi.org/10.1093/annonc/mdz235
• ⁸
  Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-9. https://doi.org/10.3322/caac.21388
  » https://doi.org/10.3322/caac.21388
• ⁹
  Lang Z, Wu Y, Li C, Li X, Wang X, Qu G. Multifocal and multicentric breast carcinoma: a significantly more aggressive tumor than unifocal breast cancer. Anticancer Res. 2017;37(8):4593-8. https://doi.org/10.21873/anticanres.11858
  » https://doi.org/10.21873/anticanres.11858
• ¹⁰
  Panuţa A, Radu I, Gafton B, Ioanid N, Terinte C, Ferariu D, et al. Multiple versus unifocal breast cancer: clinicopathological and immunohistochemical differences. Rom J Morphol Embryol. 2019;60(1):103-10. PMID: 31263833
• ¹¹
  Onisâi M, Dumitru A, Iordan I, Aliuş C, Teodor O, Alexandru A, et al. Synchronous multiple breast cancers — do we need to reshape staging? Medicina (Kaunas). 2020;56(5):230. https://doi.org/10.3390/medicina56050230
  » https://doi.org/10.3390/medicina56050230
• ¹²
  Tan PH, Ellis I, Allison K, Brogi E, Fox SB, Lakhani S, et al. The 2019 World Health Organization classification of tumours of the breast. Histopathology. 2020;77(2):181-5. https://doi.org/10.1111/his.14091
  » https://doi.org/10.1111/his.14091
• ¹³
  Garimella V, Long ED, O’Kane SL, Drew PJ, Cawkwell L. Oestrogen and progesterone receptor status of individual foci in multifocal invasive ductal breast cancer. Acta Oncol 2007;46(2): 204-7. https://doi.org/10.1080/02841860600897884
  » https://doi.org/10.1080/02841860600897884
• ¹⁴
  Mosbah R, Rouzier R, Guinebretiere JM, Falcou MC, Stevens D, Hequet D. Pathological characteristics of both tumors in bifocal and bicentric breast cancer. Anticancer Res. 2015;35(9):5111-6. PMID: 26254415
• ¹⁵
  Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367-74. https://doi.org/10.1158/1078-0432.CCR-04-0220
  » https://doi.org/10.1158/1078-0432.CCR-04-0220
• ¹⁶
  Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ. Strategies for subtypes — dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22(8):1736-47. https://doi.org/10.1093/annonc/mdr304
  » https://doi.org/10.1093/annonc/mdr304
• ¹⁷
  Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst. 2006;98(4):262-72. https://doi.org/10.1093/jnci/djj052
  » https://doi.org/10.1093/jnci/djj052
• ¹⁸
  Nordenskjöld A, Fohlin H, Fornander T, Löfdahl B, Skoog L, Stål O. Progesterone receptor positivity is a predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2016;160(2):313-22. https://doi.org/10.1007/s10549-016-4007-5
  » https://doi.org/10.1007/s10549-016-4007-5

Publication Dates

• Publication in this collection
  15 Apr 2022
• Date of issue
  Mar 2022

History

• Received
  15 Dec 2021
• Accepted
  04 Jan 2022