ABSTRACT

Objectives:

The aim of this study was to evaluate the correlation between clinical histopathologic features and micropapillary (MP) ratio with the maximum standardized uptake value (SUV_max) derived from ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) in treatment naïve breast cancer.

Methods:

Twenty-nine patients diagnosed with breast cancer with a MP component who underwent PET/CT imaging before any local and/or systemic treatment were included in this retrospective study. All clinical histopathological features were recorded. SUV_max values were measured from ¹⁸F-FDG PET images for primary tumors and metastatic axillary lymph nodes.

Results:

MP component percentage did not correlate with any clinical histopathological features except age. At early ages, the MP component ratio was significantly higher. Our results showed that there is no significant correlation between the SUV_max value and MP component percentage.

Conclusion:

A high SUV_max value is generally expected in aggressive malignancies. However, this assumption may not be valid for the MP subgroup, which has an aggressive course compared to other subgroups in breast cancer.

Introduction

Invasive micropapillary carcinoma (MPC) of the breast is an infrequent type of breast cancer. It was described as a different entity having ‘exfoliative appearance’ by Fisher et al. (1) in 1980 and included in the classification of breast tumors in 1993. These cases present with larger tumor volumes, higher histological grade, and a higher percentage of lymphovascular invasion (2,3).

¹⁸F fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) is an extensively used imaging modality that shows glucose metabolism. PET data could uncover underlying histopathologic features by revealing metabolic tumor characteristics. Whether the MP component ratio negatively influenced disease prognosis is not clear in the literature. High ¹⁸F-FDG uptake generally indicates poor prognosis, as is well known. In this context, we planned a retrospective study to investigate the relationship between the percentage of MP component in treatment-naïve breast cancer patients and metabolic parameters derived from the primary tumor and lymph node metastases derived from the initial ¹⁸F-FDG PET study.

Materials and Methods

Results

Twenty-nine patients with a median age of 55 (range: 27-76) were included in this study. All patients were female. In 52% of the cases (n=15), the tumor was located in the right breast. Bone metastases were detected in 3 patients, and bone and lung metastases were detected in 1 patient. The median tumor size was 2.5 cm (range: 0.4-14). Percentages of MP components ranged between 10-100%. SUV_max values of the tumor ranged between 2.0-32.6 (median 9.0). The median SUV_max value for patients with 100% MP component (n=15) was 9.4 (range: 2-32.6); for patients with 10% MP component (n=3) was 11.4 (range: 7.7-21.4). The clinical, histopathological, and PET characteristics are listed in Table 1.

Table 1

In eighteen cases, hypermetabolic axillary lymph nodes were detected on PET images, which were histopathologically verified as metastasis. In one case, because of the temporal resolution, PET could not detect lymph node metastasis whose size was 0.2 cm. The median metastatic lymph node size was 1.9 cm (range: 0.2-4.0). SUV_max values of metastatic lymph nodes ranged from 1.6 and 41.2 g/mL (median 8.0 g/mL).

The median Ki-67 value was 33 (range: 10-70). Four cases were luminal A, only one was triple negative, and the rest were luminal B.

At early ages, Ki-67 values and probability of hypermetabolic lymph node detection were higher (r=-0.38, p=0.04; r=-0.39, p=0.03; respectively). Between Ki-67 value and nuclear grade, axillary lymph node metastasis had a moderate positive correlation (r=0.50, p=0.01; r=0.48, p=0.01; respectively).

Luminal B and triple-negative cases were prone to axillary lymph node metastasis (p=0.03). Tumor size was positively correlated with tumor SUV_max value (r=0.42, p=0.02). There were no data showing that more axilla lymph node metastases were detected in cases with high tumor SUV_max value (r=0.26, p=0.18).

There was no significant correlation between MPC percentage and tumor SUV_max value (r=-0.02, p=0.91). When the cases were grouped as positive and negative lymph node metastases, no significant difference was found in the percentages of MPC (p=0.50). No significant differences were detected between MPC percentage, clinical histopathologic features, and SUV_max values. There was a negative correlation between age and MPC (r=-0.40; p=0.03).

Two demonstrative cases are shown in Figures 1 and 2.

Figure 1

Figure 2

Discussion

The pure form of MP breast cancer is rare (0.9-2.0%) among other types of breast carcinoma (2). In our series, which included only patients with MPC, 51.7% (n=15) of cases presented with pure invasive MPC.

One of the largest studies with pure invasive MPC showed regional lymph node metastasis in 55.2% of the cases (4). This ratio was 65.5% in our study. This difference could be attributed to the fact that PET/CT was performed in patients with a high risk of metastasis.

Many previous studies have reported that MPC tends to be in the luminal B category (5,6,7). Consistent with the literature, most of our cases (82.8%, n=24) were in the luminal B category.

Vingiani et al. (8) reported that tumor size was higher in invasive MPC patients than in invasive ductal cancer patients. Our data showed that tumor size did not significantly change with MPC percentage. In these cases, even if the MP component rate is low, close follow-up is important in terms of aggressive prognosis.

Breast cancer with MPC presents with a higher histological grade, lymphovascular invasion, and higher percentage of lymph node metastasis (2,3). Worse recurrence-free survival was attributed to a higher incidence of lymph node recurrence in the MPC group (9,10).

It is still not clear whether locoregional recurrence negatively influenced the overall survival of patients with MPC compared with other subtypes of breast cancer with similar nodal stage. Although there are some discrepancies in the literature, one recent meta-analysis demonstrated no statistically significant difference in overall survival and disease-free survival between patients with MPC and those with invasive ductal carcinoma (11). Our results showed that MPC percentage did not differ with any histopathologic features and SUV_max value of tumor/lymph nodes. Only younger patients had a statistically higher rate of MPC. These results led us to believe that there may not be a significant difference between the prognosis of cases with pure form and mixed components.

To our knowledge, the largest study in the literature with sixteen PET/CT imaging in MPC cases revealed that the mean SUV_max value of the primary tumor was 11.2, which is similar to our result 9.0 mg/dL (12). High ¹⁸F-FDG uptake is an indicator of poor prognosis in breast cancer (13,14,15,16). SUV_max did not correlate with MPC ratio, only tumor size was positively correlated with SUV_max value. Kaya et al. (17) stated that there was no significant difference in demographic characteristics, tumor diameter, lymph node metastasis status, histological grade, multicentricity, local recurrence, distant metastasis, and overall survival between their groups (group 1: MPC ratio 10-75%; group 2: MPC ratio >75%). These findings made us think that MPC might not be an aggressive subtype in which to expect high ¹⁸F-FDG uptake.

There is limited literature regarding the metabolic imaging features of breast carcinoma with MPC. As far as we know, this is the biggest cohort in the literature.

Conclusion

Our results showed that the MPC percentage did not show a significant correlation with the tumor SUV_max value. In light of the ¹⁸F-FDG PET findings, we believe that the MP subtype ratio is not a poor prognostic factor for breast cancer. New studies are needed to evaluate whether a high SUV_max could indicate a poor prognosis with the same MPC percentage.

Study Population

Cases diagnosed with invasive ductal carcinoma with MP features who did not receive any systemic/local therapy were included in the study. The study period of interest was from 2016 to 2021. The duration between pretreatment PET/CT imaging and histopathological analysis of the surgical specimen was 30 days. Cases with secondary malignancies were excluded from the study.

All clinical data of patients were recorded, including age, location of the tumor (right-left breast), percentage of MP component, histological grade, nuclear grade, Ki-67 value, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 receptor statuses, molecular subtypes, axillary lymph node status, tumor size, and metastatic lymph node size (Table 1). All lymph node metastases were verified as histopathological.

Table 1

Patient Imaging and PET/CT Data Analysis

Patients were injected with 3.7 MBq/kg of ¹⁸F-FDG after fasting for at least 6 hours (h) with blood glucose level <180 mg/dL and scanned approximately 60 minutes after injection on PET/CT scanners (Ingenuity TF, Philips Healthcare, Cleveland, Ohio, USA). CT was first acquired using a low-dose technique without contrast agent injection, and a PET scan was obtained immediately after the CT scan. Attenuation correction was performed on the PET images using the corresponding CT images.

The standardized uptake value (SUV) is a commonly used parameter for semi-quantitative analysis of PET images and is calculated either as the ratio of tissue radioactivity concentration to the injected dose adjusted by body weight. The maximum SUV (SUV_max) is obtained for a 1-pixel region of interest corresponding to the maximum pixel value in the tumor.

Initial PET/CT was analyzed by 2 experienced nuclear medicine specialists who were blinded to patients’ clinicopathological information and percentage of MP component. SUV_max was measured separately for the primary tumor and metastatic lymph nodes. If there were multiple hypermetabolic primary tumors and metastatic lymph nodes, the lesion with the highest SUV_max was selected.

University of Health Sciences Türkiye, Başakşehir Çam and Sakura City Hospital Ethics Committee approved this study (decision no: 2023.01.43).

Statistical Analysis

The median values and ranges for quantitative variables are presented. The Mann-Whitney U test was used to compare MP component percentage between lymph node metastasis -positive and -negative cases. SUV_max clinicohistopathologic features were compared using Spearman correlation matrix. The r value was interpreted as 0.00-0.19 very weak, 0.20-0.39 weak, 0.40-0.59 moderate, 0.60-0.79 high, 0.80-1.0 very high level correlation. Statistical analyzes were performed using IBM SPSS-25 software (SPSS Inc, Chicago, IL, USA). Any p-value <0.05 was considered statistically significant.

Study Limitations

The number of cases in our study may be considered small. It must be taken into consideration that the incidence of MPC is quite low. To increase the case number and statistical examination reliability, we included cases with under 1 cm tumor size. This could be considered a study limitation because of the partial volume effect.

References

Fisher ER, Gregorio R, Redmond C, Dekker A, Fisher B. Pathologic findings from the national surgical adjuvant breast project (protocol no. 4). II. The significance of regional node histology other than sinus histiocytosis in invasive mammary cancer. Am J Clin Pathol 1976;65:21-30.

Akiyoshi T, Nagaie T, Tokunaga M, Tajima M, Morita M, Nakatsuka A, Taga S, Wakiyama S, Ikebe M, Nakanishi K, Hashimoto M, Toyomasu T, Nakanishi K. Invasive micropapillary carcinoma of the breast with minimal regional lymph node metastasis regardless of the huge size: report of a case. Breast Cancer 2003;10:356-360.

Chen H, Wu K, Wang M, Wang F, Zhang M, Zhang P. Invasive micropapillary carcinoma of the breast has a better long-term survival than invasive ductal carcinoma of the breast in spite of its aggressive clinical presentations: a comparison based on large population database and case-control analysis. Cancer Med 2017;6:2775-2786.

Lewis GD, Xing Y, Haque W, Patel T, Schwartz MR, Chen AC, Farach A, Hatch SS, Butler EB, Chang JC, Teh BS. The impact of molecular status on survival outcomes for invasive micropapillary carcinoma of the breast. Breast J 2019;25:1171-1176.

Stewart RL, Caron JE, Gulbahce EH, Factor RE, Geiersbach KB, Downs-Kelly E. HER2 immunohistochemical and fluorescence in situ hybridization discordances in invasive breast carcinoma with micropapillary features. Mod Pathol 2017;30:1561-1566.

Bandyopadhyay S, Bluth MH, Ali-Fehmi R. Breast Carcinoma: Updates in Molecular Profiling 2018. Clin Lab Med 2018;38:401-420.

Min SY, Jung E-J, Seol H, Park IA. Cancer subtypes of breast carcinoma with micropapillary and mucinous component based on immunohistochemical profile. Korean J Pathol 2011;45:125-131.

Vingiani A, Maisonneuve P, Dell’orto P, Farante G, Rotmensz N, Lissidini G, Del Castillo A, Renne G, Luini A, Colleoni M, Viale G, Pruneri G. The clinical relevance of micropapillary carcinoma of the breast: a case-control study. Histopathology 2013;63:217-224.

Yu JI, Choi DH, Huh SJ, Cho EY, Kim K, Chie EK, Ha SW, Park IA, Ahn SJ, Lee JS, Shin KH, Kwon Y, Kim YB, Suh CO, Koo JS, Kim JH, Jeong BG, Kim IA, Lee JH, Park W. Differences in Prognostic Factors and Failure Patterns Between Invasive Micropapillary Carcinoma and Carcinoma With Micropapillary Component Versus Invasive Ductal Carcinoma of the Breast: Retrospective Multicenter Case-Control Study (KROG 13-06). Clin Breast Cancer 2015;15:353-361.

Wu Y, Zhang N, Yang Q. The prognosis of invasive micropapillary carcinoma compared with invasive ductal carcinoma in the breast: a meta-analysis. BMC Cancer 2017;17:839.

Hao S, Zhao YY, Peng JJ, Ren F, Yang WT, Yu KD, Shao ZM. Invasive micropapillary carcinoma of the breast had no difference in prognosis compared with invasive ductal carcinoma: a propensity-matched analysis. Sci Rep 2019;9:286.

Yun SU, Choi BB, Shu KS, Kim SM, Seo YD, Lee JS, Chang ES. Imaging findings of invasive micropapillary carcinoma of the breast. J Breast Cancer 2012;15:57-64.

Guo X, Chen L, Lang R, Fan Y, Zhang X, Fu L. Invasive micropapillary carcinoma of the breast: association of pathologic features with lymph node metastasis. Am J Clin Pathol 2006;126:740-746.

Wong SI, Cheung H, Tse GM. Fine needle aspiration cytology of invasive micropapillary carcinoma of the breast. A case report. Acta Cytol 2000;44:1085-1089.

Gil-Rendo A, Martínez-Regueira F, Zornoza G, García-Velloso MJ, Beorlegui C, Rodriguez-Spiteri N. Association between [18F]fluorodeoxyglucose uptake and prognostic parameters in breast cancer. Br J Surg 2009;96:166-170.

Ueda S, Tsuda H, Asakawa H, Shigekawa T, Fukatsu K, Kondo N, Yamamoto M, Hama Y, Tamura K, Ishida J, Abe Y, Mochizuki H. Clinicopathological and prognostic relevance of uptake level using 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in primary breast cancer. Jpn J Clin Oncol 2008;38:250-258.

Kaya C, Uçak R, Bozkurt E, Ömeroğlu S, Kartal K, Yazıcı P, İdiz UO, Mihmanlı M. The Impact of Micropapillary Component Ratio on the Prognosis of Patients With Invasive Micropapillary Breast Carcinoma. J Invest Surg 2020;33:31-39.

Investigation of Clinical Histopathologic Features and Metabolic Parameters of 18F-FDG PET/CT in Invasive Breast Carcinoma with a Micropapillary Component