Factors predictive of invasive ductal carcinoma in cases preoperatively diagnosed as ductal carcinoma in situ

Ductal carcinoma in situ (DCIS) is not an invasive malignant tumor; hence, it does not have the ability to metastasize. Therefore, the necessity of surgical treatment and sentinel lymph node biopsy for DCIS has been studied [1‐4]. However, DCIS is diagnosed by histological examinations such as core needle biopsy (CNB) or vacuum-assisted biopsy (VAB), and invasion is often found in the postoperative pathological examination. A meta-analysis reported 25.9% (18.6–37.2%) of invasive ductal carcinomas (IDCs) are preoperatively diagnosed as DCIS by CNB [5]. Although risk factors have been examined, no such factors exist that can be identified easily using blood tests.

Cancer affects the general body condition as it progresses. In particular, changes in the blood composition are often observed starting from an early stage. Tumor markers are often correlated with progression and they have been reported to change following recurrence before other symptoms can be detected using different tests [6‐8]. Carcinoembryonic antigen (CEA) and cancer antigen 15–3 (CA15–3) are commonly used as tumor markers for breast cancer. The white blood cell population and blood chemistry can also change. Lactate dehydrogenase (LDH) is one of the most important metabolic enzymes involved in glycolysis [9]. An increase in serum LDH is observed with tissue destruction caused by cancerous growth [10], and serum LDH values ​​have been reported to be consistent with clinical TNM staging [10, 11]. Furthermore, the peripheral blood platelet–lymphocyte ratio (PLR) has been reported to be useful for predicting prognosis [12‐14], and results from a meta-analysis suggested a correlation between the PLR and progression in breast cancer [12].

Therefore, we hypothesized that there may be a difference in blood test results if invasion occurs in patients diagnosed with DCIS by preoperative biopsy. In this study, we identified predictors of invasion from preoperative blood tests in patients diagnosed with DCIS by preoperative biopsy.

IDC may be misdiagnosed as DCIS by preoperative biopsy. As mentioned above, 25.9% (18.6–37.2%) of cases preoperatively diagnosed as DCIS have been reported to be IDC according to a meta-analysis [5]. However, the ratio of misdiagnosis in this study was 40.7%, higher than that previously reported. This was greatly influenced by the biopsy method. The meta-analysis found that one of the risk factors for underestimation of invasion was sampling by 14-Gauge CNB instead of 11-Gauge CNB. In contrast, for more than half of the cases in our study 16-Gauge CNB was used for biopsy. Therefore, in patients diagnosed with DCIS by VAB, the rate of postoperative invasion detection was 27.1%, in contrast with that found in patients diagnosed by CNB, which was 52.2%. Certainly, the use of VAB causes stronger pain and has higher medical costs than CNB. However, in the future, CNB with a thicker puncture needle or VAB is considered necessary for a more accurate preoperative diagnosis.

In addition to the different rate of postoperative invasion detected in our study, clinicopathological features also differed from those shown in the meta-analysis [5]. According to the meta-analysis, only 8.3% of all cases diagnosed with DCIS by preoperative biopsy were palpable, and 98.3% were detected by breast cancer screening. While, the pathological diagnosis of high grade was 49.4%, accounting for about half of the cases, in this study, 64.4% of patients had symptoms and 72.0% were palpable. The pathological diagnosis of high grade was 16.9%, which was low. This may be due to the low screening rate in Japan. It is reported that the screening rate in Japan is about 40%, lower than in other countries [19]. The number of DCIS detected early that could not be palpated was small; however, as they progressed, the proportion of patients with symptoms increased, and they became palpable. High grade DCIS may have been diagnosed as invasive ductal carcinoma at biopsy because it has already acquired invasiveness. The reason for a low ratio of a score of 3+ for HER2 may be the same. Although the rate of HER2 overexpression in DCIS has been reported to be from 28 to 65% [20], the rate shown in this study was still lower. We considered that the low ratio of high grade DCIS caused this discrepancy because high grade DCIS was reported to be frequently negative for ER and overexpress HER2 [20].

Various factors other than biopsy devices are considered risk factors for underestimation of invasion; high grade, tumor size larger than 20 mm, and palpability have been previously identified as risk factors [5]. One study also reported hormone receptor negativity as a risk factor [21]. There are reports suggesting that comedonecrosis, intraductal calcification, and lymphoid infiltrate are risk factors [16, 17]. Although this study showed differences in the ratio of invasion by postoperative pathology and clinicopathological features from those presented in previous reports, similar results were found regarding risk factors. However, this study focused on preoperative blood test results, and invasion in postoperative pathology was found significantly more frequently in patients with a high PLR than in patients with a low PLR. Platelets and growth factors such as platelet-derived growth factor and transforming growth factor-β are known to promote tumor growth [22‐26]. In addition, immunity is involved in the progression of cancer, and lymphocytes play a key role in the host anti-tumor immune function [27]. This study was based on the hypothesis that blood test changes may occur as cancer progresses. LDH and tumor markers showed no significant difference based on pre- and postoperative concordance, but invasion was significantly more likely to be found in the high PLR group than in the low PLR group. Perhaps PLR did not rise because of the invasion, but in an environment with a high PLR, the tumor could easily acquire invasive ability. High proliferative potential and malignancy, such as HER2-positive and high nuclear grade, cause comedonecrosis and intraductal calcification. If invasion appears, the invasive cancer may have caused inflammation in the surrounding interstitium. In recent years, one study has reported changes in the immune microenvironment of tumors in DCIS and IDC. According to this report, immune escape is progressing in the invasion part [28]. In other words, the trigger of invasion requires a deterioration of the immune environment, and PLR may be the indicator for such deterioration. Although the actions of platelets and lymphocytes are generally reported, it is uncertain whether they actually affect DCIS. In future, we need to examine the biological effects of platelets and lymphocytes on DCIS by immunostaining, gene analysis, and protein quantification in vitro.

There are some limitations to this study. First, there were many cases, in which biopsy was performed with 16-Gauge CNB, so the rate of IDC detection after the surgery was higher than that shown in previous reports. Secondly, some clinicopathological features, such as the ratio of palpability or the grade of DCIS, also differed from those shown in previous reports. The usefulness of mammography scores, so-called the Breast Imaging Reporting and Data System (BI-RADS), has also been reported as a predictor [5]. Third, in this study only 65 patients (55.1%) had mammography performed. Finally, since liver diseases and inflammation easily affect the absolute platelet count and lymphocyte count, it is also a limitation that the comorbidities were not included in the study. However, randomized trials are currently underway to investigate the outcomes during follow-up for low-grade DCIS [29, 30]. One strength of this study is that the PLR can be evaluated relatively easily in clinical practice, and changes in DCIS can be found by evaluating the PLR over time. Furthermore, the current trend is that sentinel lymph node biopsy is being omitted in the diagnosis of DCIS [31, 32]. Some studies reported that metastasis to the sentinel lymph node is unlikely to be found by sentinel lymph node biopsy during surgery for DCIS [31, 33]. If the PLR is high, the invasion may be found by postoperative pathological examination. In addition, chemotherapy may be less effective among these patients. Therefore, we believe that sentinel lymph node biopsy may still be needed in patients with high PLR.

The PLR may be a predictor of invasion in postoperative pathology for patients diagnosed with DCIS by preoperative biopsy.