Breast Cancer DOI 10.1007/s12282-016-0675-6

SPECIAL FEATURE

Japanese Breast Cancer Society Guidelines 2015

The Japanese Breast Cancer Society clinical practice guidelines for pathological diagnosis of breast cancer, 2015 edition Rie Horii1 • Naoko Honma2 • Akiko Ogiya3 • Yuji Kozuka4 • Kazuya Yoshida5 • Masayuki Yoshida6 • Shin-ichiro Horiguchi7 • Yoshinori Ito8 • Hirofumi Mukai9

Received: 24 November 2015 / Accepted: 27 December 2015 Ó The Japanese Breast Cancer Society 2016

Introduction

Guidelines for pathological diagnosis

The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines were published in Japanese by Kanehara & Co., Ltd in July 2015. This article is an English digest of the guidelines for pathological diagnosis. These guidelines are updated every 2 years. In the 2015 edition, clinical questions regarding Ki67 and cell blocks were newly incorporated. All other content was reviewed and amended based on the current literature.

CQ1: Is fine needle aspiration cytology (FNAC) recommended as a diagnostic procedure for breast lesions or axillary lymph node metastasis? Recommendations 1. 2.

FNAC is recommended as a diagnostic procedure for breast lesions (Grade B). FNAC for axillary lymph nodes should be performed taking into account the sampling failure and difficulty of identifying nodal disease burden (Grade C1).

CQ2: Is core needle biopsy (CNB) recommended as a diagnostic procedure for breast lesions? Recommendation This article is an English digest of the Clinical Practice Guidelines on Breast Cancer 2015, published by Kanehara & Co., Ltd. Details of recommendation grades were explained in the previous report (Breast Cancer. 2015;22:1–4). & Rie Horii [email protected] 1

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Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan Department of Pathology, School of Medicine, Toho University, Tokyo, Japan Breast Surgical Oncology, Breast Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan Department of Pathology, Mie University Hospital, Mie, Japan

CNB is recommended as a diagnostic procedure for breast lesions (Grade B). 5

Breast Center, Northern Fukushima Medical Center, Fukushima, Japan

6

Department of Pathology, National Cancer Center Hospital, Tokyo, Japan

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Department of Pathology, Tokyo Metropolitan Cancer and Infectious disease Center Komagome Hospital, Tokyo, Japan

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Breast Medical Oncology, Breast Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

9

Department of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan

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For palpable breast lesions, FNAC has been in use as one of the most reliable diagnostic modalities for many decades. This technique is valuable because of its simplicity, cost-effectiveness, minimal invasiveness and low rate of complications. However, due to limitations in its diagnostic power, for instance the difficulty of classifying a breast cancer into noninvasive or invasive carcinoma, high inadequacy rates and questionable accuracy, the role of FNAC has been questioned recently [1]. In a previous review, the sensitivity of FNAC was reported to range from 65 to 98 % and its specificity from 34 to 100 % [2]. In Japan, a large-scale survey regarding the accuracy of FNAC was conducted by the Working Group of the Japanese Society of Clinical Cytology [3]. This showed that the cytological diagnosis had an inadequacy rate of 17.7 %, an indeterminate rate of 7.8 %, a sensitivity of 96.7 %, a specificity of 84.3 %, a false-negative value of 3.3 %, a false-positive value of 0.25 % and an accuracy rate of 88.0 %. Thus, the accuracy of FNAC in Japan is considered to be high in daily practice. In comparison to FNAC, CNB showed higher specificity and sensitivity, and lower rates of equivocal and inadequate results, especially for non-palpable lesions [4–7]. A triple assessment comprising physical examination, diagnostic imaging such as mammography and ultrasonography, and FNAC, has been used for preoperative diagnosis. When the diagnoses reached by these 3 methods are discordant, or when the cytological diagnosis is indeterminate, one should not hesitate to perform CNB to obtain more histological information. In addition, FNAC, when performed by physicians without adequate training or diagnosed by inexperienced cytologists, is often misleading and potentially harmful [8]. In such cases, CNB may be regarded as the first choice of diagnostic modality. Preoperative axillary ultrasound with FNAC is sensitive and specific for the diagnosis of breast cancer nodal metastases. The problem with this diagnostic method is a higher false-negative rate for micro-metastatic disease and difficulty in quantifying nodal burden in node-positive patients [9]. CQ3: Is stereotactic vacuum-assisted breast biopsy (ST-VAB) recommended as a diagnostic procedure for non-palpable mammographically-visible lesions?

Recently, ST-VAB has become the method of choice, preferable to surgical biopsy because it is less invasive and has a lower rate of complications. To confirm adequate sampling of microcalcifications, X-ray images of the biopsy specimen should be acquired. The rate of sampling failure is reported to be approximately 0–5 %. Failure may be due to the small size of the target lesion, amorphous calcifications, inappropriate positioning, or insufficient breast volume [10]. Even in breast cancer cases in which microcalcifications are completely removed by ST-VAB, 70 % of surgical specimens still include residual cancer [11]. Accordingly, in breast cancer cases, ST-VAB should not be considered as a therapeutic procedure and follow-up surgery is needed. In the case of a benign lesion that is confirmed by both imaging and histology, follow-up surgery can be avoided. If the findings of diagnostic imaging and histological diagnosis of ST-VAB are contradictory or if histological diagnosis is indeterminate, follow-up surgery should be considered. CQ4: Is the assessment of histological/nuclear grading for invasive breast cancer (IBC) recommended in routine clinical practice? Recommendation The assessment of histological/nuclear grading for IBC is recommended in routine clinical practice, because it is useful when devising treatment strategies (Grade B). Histological/nuclear grading is a morphological assessment of tumor biological characteristics and is one of the established prognostic factors in IBC [12–14]. It can be evaluated using a conventional hematoxylin-eosin stained section. The tumor is graded 1, 2, or 3 in order of increasing malignancy. The Nottingham grading system is the most widely used histological grading system in the world. According to this system, a tumor is evaluated based on the degree of tubule formation, nuclear atypia, and mitotic count [13]. The JBCS nuclear grading system, which is based on the combination of nuclear atypia and mitotic count, was established by a multi-institutional protocol study in Japan. This grading system has been confirmed to reflect the prognosis of Japanese breast cancer patients and is widely used in Japan [14].

Recommendation ST-VAB is recommended as a diagnostic procedure for non-palpable mammographically-visible lesions that are suspected to be breast cancer (Grade B). Both ST-VAB and surgical biopsy are reliable diagnostic procedures for non-palpable mammographicallyvisible lesions that are suspected to be breast cancer.

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CQ5: Is assessment of Ki67 recommended in routine clinical practice for IBC? Recommendations 1.

Ki67 assessment may be considered for the purpose of prognostic prediction for IBC (Grade C1).

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2.

Ki67 assessment is not generally recommended in order to predict the therapeutic response to chemotherapy and endocrine therapy (Grade C2).

Ki67 is a nuclear marker of cell proliferation expressed in all phases of the cell cycle except the G0 phase. For prognostic prediction and clinical decision-making, intrinsic subtype classification defined by immunohistochemical assessment of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki67 is widely used. Many investigators have reported that Ki67 is useful as a prognostic and predictive factor in IBC. However, sample preparation and evaluation methods vary with each study and they are not frequently described in research papers. Standardization of assessment of Ki67 is needed for clinical use. The International Ki67 in Breast Cancer Working Group has proposed recommendations for assessment of Ki67 [15]. Many studies have indicated that breast cancers expressing high levels of Ki67 are associated with worse outcomes [16, 17]. In a meta-analysis of 43 studies, the pooled estimate of the hazard ratio for overall survival was 1.42 (95 % CI 1.14–1.77) and hazard ratio for disease-free survival was 1.76 (95 % CI 1.56–1.98) after adjusting for publication bias [18]. High levels of Ki67 were predictive of benefit from adding taxane as an adjuvant treatment for node-positive patients with ER-positive tumors [19, 20]. On the other hand, results from International Breast Cancer Study Group Trials VIII and IX indicated no predictive value of Ki67 levels for the addition of CMF to endocrine therapy in endocrine-responsive node-negative disease [21]. Concerning neoadjuvant chemotherapy, the significance of Ki67 as a predictive factor is controversial [22– 24]. Some studies have suggested that Ki67 levels in the residual tumor are associated with outcome [25]. Dowsett et al. suggested that changes in Ki67 expression after neoadjuvant endocrine treatment might predict long term outcome [15]. CQ6: Is histological therapeutic assessment for neoadjuvant chemotherapy (NAC) recommended in routine clinical practice for IBC? Recommendation Histological therapeutic assessment for NAC is recommended in routine clinical practice for IBC, becaouse it is useful for confirming the therapeutic effect and prognosis after chemotherapy (Grade B). Histological assessment of the therapeutic response to neoadjuvant therapy provides information on the efficacy of a given treatment in individual patients. Such information is useful in guiding the selection of appropriate

therapeutic strategies after surgery. In many studies of NAC for IBC, both the histological therapeutic effect in the primary lesion and the lymph node metastatic status were shown to be significantly related to prognosis [26–28]. The histological assessment of therapeutic response helps to determine prognosis in breast cancer treated with NAC; however, methodological problems remain. Many different histological criteria are currently used to assess therapeutic response [29]. Although breast cancer patients with pathological complete response (pCR) have significantly better prognosis than those without pCR, the definition of pCR differs in various criteria [29]. Even when the same criteria are used, use of different processing methods for surgical material can result in different findings for the same case. Pathologists should not assess pCR based on examination of non-cancerous areas. For appropriate estimation of therapeutic response, identification of the tumor bed is important. When histological therapeutic effects are reported, pathologists should describe the criteria used and their specimen processing methods. CQ7: Is hormone receptor (HR) testing recommended as routine clinical practice for breast cancer? Recommendation HR testing is strongly recommended to determine whether or not to perform endocrine therapy in all breast cancer cases (Grade A). In IBC, the ER expression status is a prognostic and predictive factor for endocrine therapy. ER-positive IBC shows significantly better prognosis after endocrine therapy than ER-negative IBC [30, 31]. PgR is one of the target genes activated by the ER and is an indicator of the estrogen-ER complex at work. HR positivity is defined as positive staining for ER and/or PgR. Prat et al. recently reported a newly proposed immunohistochemical definition of luminal A tumors as HR-positive, HER2-negative, Ki67 \14 % and PgR [20 % [32]. HR testing is strongly recommended to determine whether or not to administer endocrine therapy in all IBC cases. Ductal carcinoma in situ (DCIS) has a favorable prognosis with regional therapies only. Therefore, HR testing for DCIS is important in cases where endocrine therapy is considered for preventing local recurrence following breast-conserving surgery [33]. HR testing is also strongly recommended for advanced or recurrent breast cancer. It has been reported that primary inoperable advanced breast cancer cases in which more than two-thirds of the cancer cells are ER-positive exhibit a significantly extended time to progression (TTP) in response to first-line endocrine therapy with an aromatase

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inhibitor [34]. Similarly, in cases of recurrent breast cancer, high expression levels of HR correlate well with response to endocrine therapy and favorable prognosis [35]. Hence, HR testing is highly recommended for such cases. Furthermore, additional HR testing in biopsy material for metastatic lesions is encouraged in cases where the HR status of the primary lesion is uncertain or the primary organ for the metastatic lesion is unclear. CQ8: Should we evaluate the proportion of positively stained tumor cells in assessing the immunohistochemical HR status? Recommendation The proportion of positively stained tumor cells should be evaluated in assessing the immunohistochemical HR status (Grade A). Immunohistochemistry (IHC) is now the standard method for determining HR status. Immunohistochemical HR examination is useful to predict the effect of endocrine therapy or clinical outcome not only for primary breast cancers but also for recurrent breast cancer [35–39]. IHC is applicable on a wide range of samples, such as formalinfixed and paraffin-embedded materials, frozen materials, fine needle aspiration materials, cell blocks, etc. There are several guidelines for appropriate HR testing [40–42]. Specimens of breast cancer tissue should be fixed with an adequate amount of formalin fixative (preferably 10 % buffered formalin) as soon after sampling as possible [40–42]. Primary antibodies approved as test reagents by the Japanese health insurance system should be used and the staining processes should be strictly compliant with the manufacturer’s instructions [42]. Immunohistochemical results are assessed by evaluating the proportion of tumor cells with stained nuclei. Breast cancers without nuclear staining are diagnosed as HRnegative and excluded from endocrine therapy. Endocrine therapy may be considered for patients having breast cancer with any fraction of positive cells. However, the therapeutic effect may be poorer in breast cancer with a low proportion (e.g. \10 %) of positive tumor cells [37, 43]. Treatment strategies should be decided after taking into account the risk and benefit for each patient in relation to their HR status. Hence, the proportion of positive cells should be presented as pathological information. Staining intensity is required or recommended to be estimated in some guidelines [37]. It may also be included in the pathological report. The JBCS working group for adequate evaluation of HR status, however, reported that evaluating only the proportion rather than a combined evaluation of proportion and intensity was superior in terms of reproducibility and inter-observer consistency [42].

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As the result of HR testing determines the therapeutic protocol, high accuracy is required for this procedure. The Japan Pathology Quality Assurance System has recently been established for the purpose of accuracy management (http://www.jpqas.jp/). CQ9: Is HER2 testing recommended in routine clinical practice for breast cancer? Recommendation HER2 testing is strongly recommended to determine whether or not to perform anti-HER2 therapy in both IBC and metastatic breast cancer cases (Grade A). HER2 is not only a prognostic factor but also a predictive factor in determining whether anti-HER2 therapy could be effective in IBC. Multiple randomized trials have indicated a significant survival benefit when anti-HER2 therapy was used in the adjuvant setting for HER2-positive IBC [44, 45]. One of the anti-HER2 drugs, trastuzumab, is remarkably effective in combination with cytotoxic chemotherapy in patients with HER2-positive IBC. The effectiveness of anti-HER2 therapy is also established for HER2-positive metastatic breast cancer. Accordingly, HER2 testing in IBC and metastatic breast cancer is strongly recommended in routine practice, as it is useful when devising treatment strategies. For recurrent or metastatic tumors, reexamination is frequently required because discrepancies in HER2 status between primary and metastatic tumors are sometimes observed [46, 47]. CQ10: Is IHC recommended for HER2 testing in breast cancer? Recommendation IHC is strongly recommended for HER2 testing (Grade A). CQ11: Is in situ hybridization (ISH) recommended for HER2 testing in breast cancer? Recommendation ISH is strongly recommended for HER2 testing (Grade A). Because anti-HER2 therapy is used in patients with HER2 protein-overexpressing or HER2 gene-amplified tumors, strict HER2 evaluation is required. IHC or ISH is used to examine protein expression or gene amplification, respectively [48]. Both methods are considered equivalent and are covered by health insurance in Japan. For HER2 testing, specimens should be fixed with an adequate amount of formalin fixative (preferably 10 % buffered formalin) as soon after sampling as possible, and

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for 6–72 h [49]. HER2 testing is performed for the invasive components of tumors, obtained surgically or by biopsy. There are two major guidelines for appropriate HER2 testing, which are published by the American Society of Clinical Oncology/College of American Pathologists [50] and the exploratory committee for HER2 testing in breast cancer in Japan. The scoring method for IHC is described in detail in the guidelines. Briefly, IHC is scored as 0, 1?, 2?, and 3? considering the intensity and positivity rate of membrane staining. IHC 0/1?, 2?, and 3? is considered negative, equivocal, and positive, respectively. In IHC 2? (equivocal) cases, a reflex test (ISH on the same specimen) or a new test (IHC or ISH on a new specimen) must be ordered. ISH includes several methods, such as fluorescence in situ hybridization (FISH), silver in situ hybridization (SISH), chromogenic in situ hybridization (CISH), and dual color in situ hybridization (DISH); these depend on differences in pigmentation to visualize the HER2 gene and chromosome 17 (CEP17) [50–52]. In HER2 testing by ISH, at least 20 non-overlapping invasive cancer cells should be counted. When ISH is performed by a single-probe for the HER2 gene, gene copy number is used to assess HER2 gene status. When ISH is performed using a dual-probe for the HER2 gene and CEP17, both HER2 gene copy number and the HER2/CEP17 ratio have to be considered. Results of HER2 testing by ISH are reported as 3 categories, i.e. HER2 gene amplification positive, equivocal or negative. Definitions for each category are described in the guidelines. In ISH-equivocal cases, a reflex test (IHC on the same specimen) or a new test (IHC or ISH on a new specimen) must be ordered. Re-examination is recommended if there is any discrepancy between HER2 status and other histopathological findings (e.g. HER2 positivity in a low grade and hormone receptor-positive tumor). Because the result of HER2 testing determines the therapeutic protocol, high accuracy is required for the test. The Japan Pathology Quality Assurance System has recently been established for the purpose of accuracy management (http://www.jpqas.jp/). CQ12: Are assessments of HR and HER2 status in a needle biopsy specimen instead of a surgical specimen recommended in routine clinical practice for breast cancer? Recommendations 1.

Assessments of HR and HER2 status in a needle biopsy specimen are strongly recommended for breast cancer patients who can be treated with neoadjuvant systemic therapy (Grade A).

2.

Assessments of HR and HER2 status in a needle biopsy specimen may be considered in breast cancer patients who are surgically treated as the initial approach (Grade C1).

Several previous studies concerning biomarker assessments in breast cancer have shown a wide variability of concordance rate between needle biopsy and surgical specimen results. Concordance rates ranged from 82 to 100 % for ER, 78 to 97 % for PgR and 60 to 98 % for HER2 status [53–55]. Reasons for the discordance are as follows: differences in the methods of handling and assessing the specimens, intra-tumor heterogeneity and changes in biomarker expression due to systemic neoadjuvant treatment [56]. A needle biopsy before initial treatment for cancer allows multidisciplinary treatment planning and appropriate clinical trial enrollment. Especially when planning systemic neoadjuvant treatment, early determination of biomarkers is important and assessments of HR and HER2 status in a needle biopsy specimen are essential when choosing appropriate treatment strategies. On the other hand, when planning surgery as the initial approach, early determination of biomarkers is not necessary. To confirm the homogeneity of the tumor, a surgical specimen in which cancer tissue can be widely observed is desirable to assess HR and HER2 status, rather than a needle biopsy. CQ13: Is assessment of margin status of a partial mastectomy specimen recommended in routine clinical practice for breast cancer? Recommendation Assessment of margin status of a partial mastectomy specimen is strongly recommended for routine clinical practice, as it is useful for the prediction of local recurrence after surgery (Grade A). Many previous studies concerning breast-conserving treatment for both invasive and noninvasive breast cancers showed that surgical margin-positive cases recurred locally at a significantly higher rate than margin-negative cases. Assessment of margin status of partial mastectomy specimens is useful for predicting local recurrence after surgery [57, 58]; however, methodological problems remain. There are many different assessment criteria for margin status used worldwide [59, 60]. In addition, the processing methods of a surgical specimen have an influence on the results of margin assessment [60]. Standardization of criteria and specimen processing methods is needed. The following factors must be stated in a pathological report of a partial mastectomy specimen: specimen processing method, minimum distance between cancer nest and

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margin, types of cancer nests which are in the vicinity of the margin, extent of cancer, histological/nuclear grading of cancer and presence or absence of comedo necrosis. CQ14: Is intraoperative assessment of the margin status of a partial mastectomy specimen recommended in routine clinical practice for breast cancer? Recommendation Intraoperative assessment of the margin status of a partial mastectomy specimen should be performed, taking into account the risk of artifacts, sampling failure, and indeterminate lesions (Grade C1). Intraoperative assessment of the margin status of partial mastectomy specimens can reduce the frequency of reoperation because surgeons can resect additional tissue during the initial operation, if necessary. Common approaches for intraoperative assessment of margin status are frozen section analysis and imprinting cytology. The accuracy of both these methods is high [61, 62]. However, the results of imprinting cytology are easily influenced by artifacts due to drying and burning of the surgical margin. Frozen section analysis also has limitations, because of inadequate tissue sampling and artifacts due to freezing the tissue. In addition, some breast lesions cannot be determined as benign or malignant by intraoperative assessment. CQ15: Is pathological examination of sentinel lymph nodes (SLNs) recommended in routine clinical practice for breast cancer? Recommendations 1.

2.

Pathological examination of SLNs using HE-stained sections is strongly recommended to determine whether or not to perform axillary lymph node dissection (ALND) (Grade A). Immunohistochemical methods should not be routinely used, except in limited cases because minimal metastasis which can only be detected immunohistochemically has been shown to be less clinically important (Grade C2).

Because the metastatic status of SLNs predicts the status of axillary lymph nodes, intraoperative pathological examination of SLNs is recommended to determine whether or not to perform ALND, a procedure which may have severe adverse effects [63]. In the TNM classification of malignant tumors, as edited by the Union Internationale Contra le Cancer (UICC), isolated tumor cells (ITC), micrometastasis, and macrometastasis are designated as

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metastatic tumor ^0.2 mm in size/^200 cells, [0.2 mm in size/[200 cells and ^2 mm in size, and [2 mm in size, respectively [64]. Each node should be cut into slices ^2 mm in thickness, and frozen sections of each slice should be prepared to detect macrometastasis. In the pathology report, the numbers of positive/examined nodes and the size of the largest metastatic tumor should be described. One-step nucleic acid amplification (OSNA), a molecular method for detecting nodal metastasis, can substitute for histological examination and is expected to reduce the pathologist’s workload [65]. Immunohistochemical methods should not be routinely used, except in limited cases such as invasive lobular carcinoma, because minimal metastasis which can only be detected immunohistochemically has been shown to be less clinically important [66]. CQ16: Are assessments of HR and HER2 status using cell blocks recommended in routine clinical practice for recurrent breast cancer? Recommendation Although assessment of HR and HER2 status using cell blocks of the cavity fluid or metastatic tumor provides useful information to devise treatment strategies, the results can easily be affected by sample fixation (Grade C1). Recent guidelines recommend re-evaluation of biomarkers of recurrent breast cancer, and use of the results for the planning treatment [50]. The cell block is a popular technique in the diagnosis of recurrent and metastatic tumors, particularly when a lesion is not suitable for biopsy, or in effusion cytology. Although cell blocks can provide morphological and immunocytological information about tumor cells, including HR and HER2 status, the results can easily be affected by sample fixation. Formalin fixation is recommended to obtain accurate results [50, 67]. Compliance with ethical standards Conflict of interest Yoshinori Ito received lecture frees from Chugai, Esai and Novartis. He also received research Grants from Novartis, Chugai, Parexel, Esai, Sanofi, Taiho, EPS, Dai-ichi-sankyo and Boehringer-ingelheim. The other authors declare that they have no conflict of interest.

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