utility of estrogen receptor, progesterone receptor, and ...€¦ · treatment recommendation....

952 Am J Clin Pathol 2015;144:952-959 DOI: 10.1309/AJCPFWXP54OLILMU

© American Society for Clinical Pathology

AJCP / Original Article

CME/SA

M

Utility of Estrogen Receptor, Progesterone Receptor, and HER-2/neu Analysis of Multiple Foci in Multifocal Ipsilateral Invasive Breast Carcinoma

Ellen G. East, MD,1 Judy C. Pang, MD,1 Kelley M. Kidwell, PhD,2 and Julie M. Jorns, MD1

From the Departments of 1Pathology and 2Biostatistics, University of Michigan, Ann Arbor.

Key Words: Multifocal; Breast; Cancer; Carcinoma; Estrogen receptor; ER; Progesterone receptor; PR; HER-2/neu

Am J Clin Pathol December 2015;144:952-959

DOI: 10.1309/AJCPFWXP54OLILMU

ABSTRACT

Objectives: To determine the frequency of estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu (HER2) testing multiple foci of ipsilateral invasive breast carcinoma at our institution and to evaluate resulting change in treatment recommendation.

Methods: We identified 165 consecutive cases of multifocal invasive breast cancer over a 10-year period (2005-2014). Clinicopathologic features and treatment recommendation were assessed by slide and chart review.

Results: Seventy (42.4%) of 165 patients had two or more foci tested. In the first 6 years (2005-2010), frequency of testing two or more foci was 31.6% and increased to 70.6% in 2014. Seven (10%) of 70 had a clinically significant difference in ER/PR and/or HER2 status, five (7.1%) with a difference in HER2, one (1.4%) in ER/PR, and one (1.4%) in both ER/PR and HER2. All cases with difference in status had different histology and/or the largest focus was the most positive one.

Conclusions: Our findings support current recommendations to evaluate additional smaller tumor foci in multifocal invasive breast cancer if the focus is of different grade or histology. Additional features, including specific histology, grade, and ER, PR, and HER2 status of the largest focus, should also be considered when selecting cases for which testing of additional foci may be of benefit.

The American Joint Committee on Cancer staging man-ual defines multifocal ipsilateral invasive breast carcinomas as “infiltrating carcinomas in the same breast, which are grossly and macroscopically distinct and measureable using available clinical and pathologic techniques.”1 Multifocal invasive breast cancers appear to arise most frequently from a single cancer clone and less often as synchronous inde-pendent primary tumors.2-8 In the largest series to date (n = 8,935), Wolters et al9 report an incidence of 20.8%; howev-er, multifocality appears to be increasing, at least in part due to greater sensitivity of preoperative imaging techniques.10 Multifocality has been previously associated with increased risk of axillary lymph node metastases, locoregional recur-rence, and potentially worse outcome.11-17

Upon completion of this activity you will be able to:•describe the College of American Pathologists (CAP) guidelines

for performing estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu (HER2) analysis in smaller tumor foci in multifocal ipsilateral invasive breast carcinoma.

•predict the likelihood of difference in ER, PR, and HER2 status between largest and smaller tumor foci in multifocal ipsilateral invasive breast carcinoma based on similarities and differences in histology and grade between the tumor foci.

•discuss possible exceptions to CAP guidelines for performing ER, PR, and HER2 analysis in smaller tumor foci in multifocal ipsilateral invasive breast carcinoma.

The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activ-ity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module.

The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

Exam is located at www.ascp.org/ajcpcme.


Am J Clin Pathol 2015;144:952-959 953 DOI: 10.1309/AJCPFWXP54OLILMU


Estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu (HER2) status provides crucial prognostic and predictive information for patients with breast cancer. In the case of multifocal invasive breast cancer, the Ameri-can Society of Clinical Oncology (ASCO) and College of American Pathology (CAP) guidelines recommend ER/PR analysis on “at least one of the tumors, preferably the larg-est,”18 whereas HER2 guidelines do not provide specific recommendations.19 The CAP biomarker template further recommends testing of additional smaller foci if they have different histology or grade than the largest focus.20 How-ever, others advocate for the testing of additional or even all foci, regardless of histology or grade, due to possible tumor heterogeneity and the potential to provide life-saving thera-pies that may not have been recommended based on testing of a single (largest) tumor.21,22 In practice, testing additional foci is variable. We aimed to evaluate the frequency of ER, PR, and HER2 testing of additional tumor foci in patients with multifocal ipsilateral invasive breast cancer at our insti-tution and the resulting clinical therapy decisions.

Materials and Methods

Case SelectionIn accordance with internal review board protocol, we

conducted an electronic database search from January 2005 through December 2014 using keywords breast, invasive, and multifocal, which initially yielded 556 cases. Cases were assessed for multifocality, defined as two or more dis-crete foci of ipsilateral invasive breast cancer separated by intervening normal breast tissue, via chart and slide review (E.G.E., J.C.P., and J.M.J.). Exclusion criteria were neo-adjuvant therapy; recurrent, microinvasive, or transected tumors; or artifactual multifocality due to large biopsy site/hematoma or potentially contiguous satellite foci. Only cases with slides available for re-review and confirmation of multifocality were included. A total of 165 cases meeting these criteria were identified.

ER, PR, and HER2 EvaluationThe cases represented tumors tested from internal

and referral material; however, all immunohistochemical (IHC) (and corresponding H&E) slides and fluorescence in situ hybridization (FISH) reports from referral cases were reviewed at our institution by board-certified pathologists with expertise in breast pathology.

When performed at our institution, ER (clone SP1), PR (clone IE2), and HER2 (clone 4B5) (Ventana Medi-cal Systems, Tucson, AZ) IHC was initially performed. Staining was performed on the Ventana BenchMark XT platform, and results were obtained via US Food and Drug

Administration–approved and validated Ventana Image Analysis System or iScan Coreo System (Ventana Medical Systems), which provided a percentage ER/PR or semiquan-titative (0, 1+, 2+, or 3+) score for HER2 via colorimetric and morphometric analysis of at least four images. Reflex HER2 FISH testing was performed when IHC yielded a (2+) equivocal result and used PathVysion probes (Abbott Molecular Laboratories, Des Plaines, IL).

In referral cases, IHC stains were reported as a percent-age score for ER and PR and semiquantitative (0, 1+, 2+, or 3+) score for HER2; these were assessed via manual review. HER2 FISH reports were reviewed, and HER2 status (nega-tive, equivocal, or positive) based on HER2/CEP17 ratio and HER2 copy number was reported. Reporting was per most recent ASCO/CAP guidelines at the time of review.18,19,23

ER and PR were categorically stratified as negative, weak, and positive if there was less than 1%, 1% to 10%, and more than 10% staining, respectively.

Data Collection and AnalysisClinicopathologic features were assessed by chart and

slide review (E.G.E., J.C.P., and J.M.J.). Descriptive statis-tics and frequencies were tabulated for the sample. Patient and clinical characteristics were compared between those with only one focus tested vs those with two or more foci tested using the Wilcoxon rank sum test for continuous vari-ables and c2 or Fisher exact test for categorical variables. Logistic regression on the binomial proportion of cases test-ing multiple foci out of all cases on year assessed the trend over time. We did not control for multiple comparisons due to the small sample size and descriptive nature of the study. SAS 9.3 (SAS Institute, Cary, NC) was used for all statisti-cal analyses (K.M.K.).

Results

Features of Multifocal Invasive Breast CarcinomasOf the 165 patients, 107 (64.8%) had two foci, 32

(19.4%) had three foci, and 26 (15.8%) had four or more foci. Additional clinicopathologic features are shown in ❚Table 1❚.

Ninety-five (57.6%) of 165 patients had only a single focus and 70 (42.4%) had two or more foci tested for ER, PR, and HER2. Of those with two or more foci tested, 34 (48.6%) had testing on diagnostic specimens (core or excisional biopsy), and 36 (51.4%) had testing on both diagnostic and resection specimens. Testing two or more foci was significantly associated only with different tumor histology, with 11 (15.7%) of 70 with multiple foci tested vs one (1.1%) of 95 with a single focus tested having different tumor histology (P = .0003).

East et al / ER, PR, and HER2 in Multifocal Cancer



Of note, two patients with only a single focus tested had testing performed on diagnostic core biopsy specimens of the tumor that corresponded to the smaller of two foci iden-tified at resection. In both cases, histology and grade were similar. The tumor foci in one case measured 0.7 cm and 0.6 cm and in the second measured 1.9 cm and 0.7 cm.

Overall frequency of testing two or more foci was 31.6% during the first 6 years of this study (2005-2010) and increased to 70.6% in 2014. There was a significant increase in rate of testing multiple foci by year of 6.5% (P = .002) ❚Figure 1❚.

Cases in Which Testing Multiple Foci Yielded Differing ER, PR, and/or HER2 Status

Categorical differences for ER, PR, and/or HER2 were seen in 18 (25.7%) of 70 cases in which two or more foci were tested ❚Table 2❚. Most frequently (10 of 18; 55.6%), the differences were due to categorical changes in ER/PR that did not meaningfully affect therapy decision; in nine patients, there was already a positive ER and/or PR result that supported the use of hormonal therapy ❚Image 1❚, and for one patient, there was weak ER expression in one of two foci that did not change the decision to not recommend hormonal therapy.

❚Table 1❚Clinicopathologic Features of Patients With Multifocal Ipsilateral Invasive Breast Carcinoma (n = 165)a

Characteristic Value

Age, mean (range), y 54 (26-92)No. of foci, median (range) 2 (2-9)Largest tumor Histology IDC 91 (55.2) IDC-L 28 (17.0) ILC 39 (23.6) Other 7 (4.2) mBR grade 1 29 (17.6) 2 92 (55.8) 3 44 (26.7) Size, mean (range), cm 2.2 (0.2-7) ER (n = 163) Negative 19 (11.6) Weak 5 (3.1) Positive 139 (85.3) PR (n = 163) Negative 30 (18.4) Weak 15 (9.2) Positive 118 (72.4) HER2 (n = 163) Negative 144 (88.3) Equivocal 3 (1.8) Positive 16 (9.8)Other foci Different histology 12 (7.3) Different grade 15 (9.1)T stage T1a 6 (3.6) T1b 26 (15.8) T1c 63 (38.2) T2 57 (34.5) T3 13 (7.9)N stage N0 82 (49.7) N1mi 14 (8.5) N1a 35 (21.2) N2a 23 (13.9) N3a 9 (5.5) Unknown 2 (1.2)Final surgery Lumpectomy 54 (32.7) Mastectomy 111 (67.3)Lymph node evaluation SLNB 93 (56.4) ALND 70 (42.4) Not done 2 (1.2)Postsurgical therapy (n = 157; 8 LTF) Radiation 87 (55.4) Endocrine 128 (81.5) Chemotherapy 66 (42.0) Herceptin 22 (14.0)

ALND, axillary lymph node dissection; ER, estrogen receptor; HER2, HER-2/neu; IDC, invasive ductal carcinoma; IDC-L, invasive ductal carcinoma with lobular features; ILC, invasive lobular carcinoma; LTF, lost to follow-up; mBR, modified Bloom-Richardson; PR, progesterone receptor; SLNB, sentinel lymph node biopsy.

a Values are presented as number (%) unless otherwise indicated.

0%

10%

20%

30%

40%

50%

60%

70%

2005 2006 2007

2 or more foci testedClinically signi�cant differencein ER/PR and/or HER2

2008 2009 2010 2011 2012 2013 2014

❚Figure 1❚ Frequency of estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu (HER2) testing of additional tumor foci and clinically significant difference in patients with multifocal ipsilateral invasive breast carcinoma (n = 70).

❚Table 2❚Categorical Differences in ER, PR, and HER2 Status Between Foci Tested in Patients With Multifocal Ipsilateral Invasive Breast Carcinoma (n = 70)

Characteristic

No. (%)

Negative ↔ Weak/Equivocal

Weak/Equivocal ↔ Positive

Negative ↔ Positive

ER 1 (1.4) 1 (1.4) 1 (1.4)a

PR 8 (11.4) 5 (7.1) 1 (1.4)HER2 0 (0) 1 (1.4)a 5 (7.1)a

ER, estrogen receptor; HER2, HER-2/neu; PR, progesterone receptor.a Clinically significant difference resulting in change in treatment recommendation

(see Table 3).




Categorical difference was significantly associated with high grade in the largest focus and weak PR expression in any focus. Specifically, the largest tumor was modified Bloom-Richardson grade 3 in 11 (61.1%) of 18 patients with categorical difference vs nine (17.3%) of 52 without, and weak PR expression was seen in at least one focus in 12 (66.7%) of 18 with categorical difference vs three (5.8%) of 52 without (P < .0001).

Clinically significant differences resulting in change in treatment recommendation were seen in seven (10%) of 70 cases in which multiple foci were tested. Five (7.1%) patients had a significant difference in HER2, one (1.4%) in ER/PR, and one (1.4%) in both ER/PR and HER2 status. Frequency of testing multiple foci and clinically significant difference are shown in Figure 1.

In the seven cases with clinically significant difference in ER, PR, and/or HER2 status, tumor foci had different histology in three (42.9%) of seven cases and different grade in three (42.9%) of seven cases. In cases with HER2 discordance, five (83.3%) of six had grade 3 histology in the positive focus, three (50.0%) of six were HER2 positive in the largest focus, and HER2 IHC was equivocal in one or more focus in three (50.0%) of six cases. The case with differing ER/PR had weak expression in only one (the larg-est) of two foci tested, while the other was negative; in this case, postsurgical endocrine therapy was recommended by the treating oncologist, which the patient subsequently received. Clinicopathologic features of cases with clini-cally significant difference in ER, PR, and/or HER2 status are shown in ❚Table 3❚, and example cases are shown in ❚Image 2❚.

Discussion

Detection of multifocal ipsilateral invasive breast carcinoma is increasing.10 While ASCO/CAP guidelines recommend ER, PR, and HER2 testing of the largest focus, others advocate for testing of additional smaller or all tumor foci.22 Over a 10-year period, we have seen an increase in testing two or more foci at our institution, reaching 70.6% of multifocal cases in 2014. However, only seven (10%) of 70 cases with multiple foci tested had clinically significant difference in ER, PR, and/or HER2 status between foci, resulting in differences in therapy recommendation.

In our cohort, a clinically significant difference was more often due to discordance in HER2 (six of 70; 8.6%) than in ER/PR status (two of 70; 2.9%), and no cases had an ER/PR-positive smaller focus when the largest focus was ER/PR negative. Similarly, when testing multiple tumor foci, Garimella et al24 noted no major difference in ER/PR expression in their pilot study of 11 cases. How-ever, Buggi et al21 noted ER positivity in a smaller focus while the larger focus was ER negative in two (1.8%) of 113 cases, and Choi et al3 noted 3.1% (two of 65) ER discordance between foci. Choi et al further described the discordant foci; in both cases, tumor foci had the same T stage and (high) grade but had different histology and molecular phenotypes, with less aggressive luminal types in ER-positive foci. Thus, it appears unlikely that ER/PR testing of additional, smaller foci is beneficial unless it is of lower grade, similar size, or different histology. Specifically, histologic subtypes that are morphologically

A B

❚Image 1❚ Example case in which categorical difference in estrogen receptor (ER) and progesterone receptor (PR) status did not affect clinical management. The two tumor foci have similar morphology, with one focus (A) having strong positive ER and weak PR staining and the second focus (B) having strong positive ER and negative PR staining. (H&E, immunohistochemistry ×20; insets reduced to approximately 10% original size)




consistent with molecular luminal A/B subtypes and/or are typically ER positive such as invasive lobular, papillary, and mucinous carcinoma especially warrant evaluation due to higher likelihood of discordance.

ASCO/CAP guidelines define ER/PR as positive if as few as 1% of tumor nuclei are positive. However, they also support discussion of pros and cons of endocrine therapy between the oncologist and patient in cases in which ER/PR expression is weak (ie, 1%-10%).18 Thus, in cases with weak expression, staining of additional blocks or additional foci in the case of multifocal disease may be helpful in determining treatment and thus is warranted if requested by the clinical

team. This scenario is relatively infrequent and in our series comprised just 3.0% (five of 165) with weak staining when testing the main tumor focus.

HER2 difference, although also infrequent, more often resulted in clinically significant difference in status (six of 70; 8.6%). However, in three cases, the larger focus was the positive one, and different histology was seen in the other three cases. Thus, no case would have failed to have been identified as HER2 positive by current CAP recommendations.20 However, Buggi et al21 and Choi et al3 noted the low frequency of HER2 positivity in a smaller focus in 3.5% (four of 113) and 6.2% (four of 65) of cases,

❚Table 3❚Clinicopathologic Features of Cases With Clinically Significant Difference in ER, PR, and/or HER2 Status Between Foci Tested in Patients With Multifocal Ipsilateral Invasive Breast Carcinoma (n = 7)Case Focus Histology mBR Grade Size, cm ER PR HER2 IHC HER2 FISH

1 1 IDC 3 0.8 Positive Positive Equivocal Positive (HER2/D17Z1 = 3.75; HER2/cell = 6) 2 IDC 2 0.7 Positive Positive Equivocal Negative (HER2/D17Z1 = 0.95; HER2/cell = 3)

2 1 IDC-L 3 2.2 Positive Positive Positive Not done 2 IDC-L 2 1.9 Positive Positive Negative Not done

3 1 ILC 2 3.3 Positive Positive Equivocal Negative (HER2/D17Z1 = 1.20; HER2/cell = 3)2 IDC 3 2.5 Negative Negative Positive Not done3 ILC 2 1.5 Positive Negative Equivocal Negative (HER2/D17Z1 = 1.18; HER2/cell = 3)

4 1 IDC 3 2.5 Weak Weak Positive Not done2 IDC 3 1.1 Negative Negative Positive Not done

5 1 IDC 3 2.4 Positive Positive Equivocal Positive (HER2/D17Z1 = 2.8)2 IDC 3 1.9 Positive Positive Equivocal Negative (HER2/D17Z1 = 1.43; HER2/cell = 3)

6 1 ILC 2 1.4 Positive Positive Negative Not done2 IDC-L 2 1.3 Positive Positive Positive Not done

7 1 IDC 3 1.0 Positive Positive Negative Not done2 IDC 3 0.8 Positive Positive Positive Not done

ER, estrogen receptor; FISH, fluorescence in situ hybridization; HER2, HER-2/neu; IDC, invasive ductal carcinoma; IDC-L, invasive ductal carcinoma with lobular features; IHC, immunohistochemistry; ILC, invasive lobular carcinoma; mBR, modified Bloom-Richardson; PR, progesterone receptor.

A B

❚Image 2❚ Example cases (case and foci numbers corresponding to those in Table 3) with clinically significant difference in estrogen receptor (ER) (case 3) and HER-2/neu (HER2) testing (cases 1 and 7). Case 1: focus 1 (A), invasive ductal carcinoma (IDC) with (2+) equivocal HER2 immunohistochemistry (IHC) and positive fluorescence in situ hybridization (FISH) (HER2/D17Z1 ratio = 3.75) and focus 2 (B), IDC with (2+) equivocal HER2 IHC and negative FISH (HER2/D17Z1 ratio = 0.95).




respectively. In the study by Choi et al,3 all had different histology and were high grade, and three of four were of the same T stage. Bethune et al25 also studied HER2 dif-ference in multifocal breast carcinoma; they observed that 1.6% (four of 246) of cases were positive in a smaller tumor focus, and these all had either higher grade or differ-ent histology. Overall, these findings support CAP recom-mendations to perform HER2 testing on additional smaller foci if there is different histology or grade. They also sup-port the recommendation by Bethune et al25 for testing of additional foci of similar size.

In our series, half of the cases with HER2 discor-dance also had (2+) equivocal IHC in one or more focus. Although not an equal comparison since more foci were stained in these cases, this was far less than 20.6% (34

of 165) observed in the entire cohort. Also, in our series and those cited previously, the positive focus was almost always high grade. Thus, it could be argued that testing of additional smaller foci could be warranted for those with prior equivocal results or high-grade histology. Changes to the most recent ASCO/CAP HER2 guidelines include recommendations to repeat testing on resection material for unifocal tumors if the tumor is high grade and prior testing was negative.19 This is largely due to concerns for tumor heterogeneity. Although not specified, testing of additional grade 3 foci in multifocal cancer could be inferred; doing so would also likely identify rare cases in which only a smaller focus is HER2 positive. Additional larger studies would be helpful to further investigate these observations.

C D

E F

❚Image 2❚ (cont) Case 3: focus 1 (C), invasive lobular carcinoma with positive ER and (2+) equivocal HER2 IHC and focus 2 (D), IDC with negative ER and (3+) positive HER2 IHC. Case 7: focus 1 (E), IDC with positive ER and (0) negative HER2 IHC and focus 2 (F), IDC with positive ER and (3+) positive HER2. (H&E, IHC ×20; insets reduced to approximately 10% original size)




Conclusions

Multifocal ipsilateral invasive breast carcinoma is increasingly being identified. There has been no change in recommendation for testing of additional smaller foci by accrediting agencies, but we have observed a significant increase in this practice at our institution. Despite increase in use, ours and other studies show high concordance in ER, PR, and HER2 status between foci. They also support cur-rent CAP guidelines recommending additional foci be tested if they are of different histology or grade; however, minor modifications previously discussed and outlined in ❚Figure 2❚ may further improve selection of cases. Investigation of other histopathologic features may also prove beneficial in selection of cases for testing of additional small tumor foci.

Corresponding author: Julie M. Jorns, MD, Dept of Pathology, University of Michigan, 1500 E Medical Center Dr, Rm 2G332, Ann Arbor, MI 48109; [email protected].

This article was presented in part at the United States and Canadian Academy of Pathology (USCAP) annual meeting; March 21-27, 2015; Boston, MA.

References 1. Edge S, Byrd D, Compton C, et al, eds. AJCC Cancer Staging

Manual. 7th ed. New York, NY: Lippincott; 2010. 2. Brommesson S, Jonsson G, Strand C, et al. Tiling array-CGH

for the assessment of genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs. BMC Clin Pathol. 2008;8:6.

3. Choi Y, Kim EJ, Seol H, 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;43:48-55.

4. Dawson PJ, Baekey PA, Clark RA. Mechanisms of multifocal breast cancer: an immunocytochemical study. Hum Pathol. 1995;26:965-969.

5. Middleton LP, Vlastos G, Mirza NQ, et al. Multicentric mammary carcinoma: evidence of monoclonal proliferation. Cancer. 2002;94:1910-1916.

6. Teixeira MR, Pandis N, Bardi G, et al. Discrimination between multicentric and multifocal breast carcinoma by cytogenetic investigation of macroscopically distinct ipsilateral lesions. Genes Chromosomes Cancer. 1997;18:170-174.

7. Ghazani AA, Arneson N, Warren K, et al. Genomic alterations in sporadic synchronous primary breast cancer using array and metaphase comparative genomic hybridization. Neoplasia. 2007;9:511-520.

8. Noguchi S, Aihara T, Koyama H, et al. Discrimination between multicentric and multifocal carcinomas of the breast through clonal analysis. Cancer. 1994;74:872-877.

9. Wolters R, Wockel A, Janni W, et al. Comparing the outcome between multicentric and multifocal breast cancer: what is the impact on survival, and is there a role for guideline-adherent adjuvant therapy? a retrospective multicenter cohort study of 8,935 patients. Breast Cancer Res Treat. 2013;142:579-590.

10. Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol. 2008;26:3248-3258.

11. Chua B, Ung O, Taylor R, et al. Frequency and predictors of axillary lymph node metastases in invasive breast cancer. ANZ J Surg. 2001;71:723-728.

12. Chung AP, Huynh K, Kidner T, et al. Comparison of outcomes of breast conserving therapy in multifocal and unifocal invasive breast cancer. J Am Coll Surg. 2012;215:137-147.

13. Cabioglu N, Ozmen V, Kaya H, et al. Increased lymph node positivity in multifocal and multicentric breast cancer. J Am Coll Surg. 2009;208:67-74.

14. Katz A, Strom EA, Buchholz TA, et al. The influence of pathologic tumor characteristics on locoregional recurrence rates following mastectomy. Int J Radiat Oncol Biol Phys. 2001;50:735-742.

15. Tot T, Pekar G. Multifocality in “basal-like” breast carcinomas and its influence on lymph node status. Ann Surg Oncol. 2011;18:1671-1677.

16. Vlastos G, Rubio IT, Mirza NQ, et al. Impact of multicentricity on clinical outcome in patients with T1-2, N0-1, M0 breast cancer. Ann Surg Oncol. 2000;7:581-587.

17. Weissenbacher TM, Zschage M, Janni W, et al. Multicentric and multifocal versus unifocal breast cancer: is the tumor-node-metastasis classification justified? Breast Cancer Res Treat. 2010;122:27-34.

ER/PR (largest focus)

Positive Weak Negative

Testingadditional

foci isgenerally

not indicated

Testingadditional

foci is oftenindicated and

reasonableif requested

Testingadditional

foci if differenthistology or

grade, especiallyif lower grade

or subtype morelikely to be

positive

HER2 (largest focus)

Positive Equivocal Negative

Testingadditional

foci isgenerally

not indicated

Testingadditional

foci is oftenindicated and

reasonableif requested

Testingadditional

foci if differenthistology,

higher grade,or similar size;

consider testingif smaller focus

is high grade

❚Figure 2❚ Proposed algorithm for estrogen receptor (ER), progesterone receptor (PR), and/or HER-2/neu (HER2) testing of additional tumor foci in multifocal ipsilateral invasive breast carcinoma.




18. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010;134:e48-e72.

19. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med. 2014;138:241-256.

20. Fitzgibbons P, Dillon D, Alsabeth R, et al. CAP template for reporting results of biomarker testing of specimens from patients with carcinoma of the breast. 2013. http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf. Accessed February 17, 2015.

21. Buggi F, Folli S, Curcio A, et al. Multicentric/multifocal breast cancer with a single histotype: is the biological characterization of all individual foci justified? Ann Oncol. 2012;23:2042-2046.

22. Salgado R, Aftimos P, Sotiriou C, et al. Evolving paradigms in multifocal breast cancer. Semin Cancer Biol. 2015;31:111-118.

23. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18-43.

24. Garimella V, Long ED, O’Kane SL, et al. Oestrogen and progesterone receptor status of individual foci in multifocal invasive ductal breast cancer. Acta Oncol. 2007;46:204-207.

25. Bethune GC, Mullen JB, Chang MC. HER2 testing of multifocal invasive breast carcinoma: how many blocks are enough? Am J Clin Pathol. 2013;140:588-592.

utility of estrogen receptor, progesterone receptor, and ...€¦ · treatment recommendation....

Documents