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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 312-317

Detailed analyses about predictive value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in invasive lobular breast cancer


Clinic of Nuclear Medicine, University of Health and Sciences, Istanbul Training and Research Hospital, Istanbul, Turkey

Date of Submission09-May-2020
Date of Acceptance27-Jun-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Dr. Esra Arslan
Nukleer Tip Klini.i, Org. Nafiz Gurman Caddesi, Samatya, Kocamustafapasa, Fatih, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_72_20

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  Abstract 


Backgrounds: Management of invasive lobular breast cancer (ILC) is limited with only using standard uptake value (SUV) max of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography. We aimed detailed predictive, prognostic and clinical value of parameters, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) with survival data. Methods: Forty-nine ILC was included in this study. SUVmax, MTV, and TLG documented in molecular and histopathological subtypes. SUVmax, MTV, and TLG compared with nodal involvement, distant metastasis, estrogen receptor (ER), progesterone receptors (PR) and HER status, Ki-67 and survival data. Results: 61.2% luminal A, 36.7% luminal B and 2.0% TN. 53.1% classic and 46.9% pleomorphic. 93.9% ER + and 81.6% had e-cadherin loss. Mean SUVmax was 8.32 ± 4.73. No statistically significant relationship found between classical and pleomorphic with SUVmax (P = 0.616). FDG uptake found significantly higher with tumor >2 cm (P = 0.039). Luminal B SUVmax significantly higher than luminal A (P = 0.013). PR-, Ki-67 high expression, axillary involvement and luminal B significantly reduced survival time (P = 0.034, 0.019, 0.032, and 0.005, respectively). Statistically significant correlation found between high MTV and TLG, tumor diameter (TD) (P = 0.001 and 0.000, respectively). Conclusions: Loss e-cadherin and pleomorphic types did not affect the prognosis. ILC shows low FDG sensitivity compared other breast cancer types, it found to be significantly associated with prognostic factors; TD, molecular subtype, Ki-67 and metastasis. Although volumetric parameters did not add extrapredictive value to FDG involvement pattern, it was found that method remains in diagnosis, staging, and treatment follow-up of ILC.

Keywords: 18F-fluorodeoxyglucose positron emission tomography/computed tomography, invasive lobular breast cancer, metabolic tumor volume, survival, total lesion glycolysis


How to cite this article:
Arslan E, Aksoy T. Detailed analyses about predictive value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in invasive lobular breast cancer. Biomed Biotechnol Res J 2020;4:312-7

How to cite this URL:
Arslan E, Aksoy T. Detailed analyses about predictive value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in invasive lobular breast cancer. Biomed Biotechnol Res J [serial online] 2020 [cited 2021 Jan 22];4:312-7. Available from: https://www.bmbtrj.org/text.asp?2020/4/4/312/305649




  Introduction Top


Invasive lobular cancer (ILC) is the second common breast cancer (BC) after invasive ductal BC.[1] ILC is characterized by infiltration of discohesive cells into stroma and loss of membranous e-cadherin. Mostly, estrogen receptor (ER) + and luminal A. Specific molecular-histopathological character of ILC defined as biologically distinct subtype, generally good prognosis-survival data.[2],[3]

Although 18F-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (18F FDG-PET/CT) is useful for staging, prognosis and follow-up in BC,[4],[5] weak FDG affinity reported in ILC.[6],[7] Predictive value of 18F FDG-PET/CT for ILC considered controversial by authors, which often exhibits lowest FDG uptake of all types.[6],[7],[8],[9]

Poor FDG sensitivity reported in ER+/ HER2-and luminal subtypes that exhibit low aggressive properties. Published data emphasized method is inadequate in the evaluation of staging, lymph node (LN), and distant metastasis using standard uptake value (SUV) max alone.[10],[11] Studies reported that metabolic tumor volume (MTV) and total lesion glycolysis (TLG) will provide great diagnostic and prognostic benefit.[12],[13]

We aimed to evaluate detailed predictive, prognostic and clinical value of 18F FDG-PET/CT related strategies in the management of ILC by SUVmax, MTV, and TLG together with diagnosis and evaluate survival data.


  Methods Top


Patients

Seven hundred and seventeen BC refereed our institution for 18F FDG-PET/CT between September 2011 and September 2019, 49 ILC enrolled. Study approved by Istanbul Training and Research Hospital local ethical committee (2015/598), and verbal-written informed consents obtained.

Histological analysis

BC histopathological analysis obtained by biopsy prior 18F FDG-PET/CT and differentiate to pleomorphic/classical type excisional biopsy performed. Histological staging; Scarff-Bloom-Richardson classification system used. Receptors considered + if ER/progesterone receptors (PR) showed 10% or more in immunohistochemical (IHC) staining in tumor cells. Scoring HER2 is;









  1. Score 0: No immunostaining
  2. Score 1: poor staining/staining in tumor cell below 30%
  3. Score 2: Uniform/complete membranous staining, even if staining is weak (at least 10%)
  4. Score 3: Dense membranous/uniform staining of tumor cells at least 30%.


Cut-off for Ki-67 determined 15% by IHC, gene expression profiling methods used in differentiation of Luminal A and B considered as <15% (-) and =15% (+).[7]

Molecular subgroups according to hormone receptor status;









  1. Luminal A: ER (+) and/or PR (+), HER2 (-) and Low Ki-67 (<14%)
  2. Luminal B: ER (+) and/or PR (+), HER2 (+)/HER2 (-) and High Ki-67 (=15%)
  3. Triple negative/basal like: ER (-), PR (-), HER2 (-)
  4. HER2: ER (-), PR (-), HER2 (+).


18F-fluoro-2-deoxy-glucose positron emission tomography/computed tomography Imaging

Patients with blood glucose level <150 mg/dl at least 6 h of fasting before administration included in the study. 3.7–5.2 MBq/kg 18F-FDG injection administered intravenously. 18F FDG-PET/CT performed from vertex-upper thigh in the supine position after 45. - 60 min (7 patients imaged with Siemens Biograph 6 HD LSO, 42 with Siemens mCT 20 ultra HD LSO PET/CT; IL, USA). SUVmax calculated according to formula; maximum activity in ROI (MBq/ml)/injected dose (MBq/kg body-weight). MTV and TLG calculated from; injected dose, blood glucose level, and body-weight and obtained at 40% threshold. Histopathological-molecular types, receptor status, nodal involvement, distant metastasis, and survival data reported according to SUVmax, MTV, and TLG.

Statistical analysis

Data were analyzed with the SPSS (Statistical Package for the Social Sciences) software (version 21.0; IBM, Armonk, NY, USA). Individual and aggregate data summarized using descriptive statistics including mean, standard deviations, medians (min-max), frequency distributions, and percentages. Normality of data distribution was verified by Kolmogorov–Smirnov test. The comparison of variables with normal distribution made with Student t-test, paired-sample t-test. Variables without normally distributed, Mann–Whitney and Kruskal–Wallis tests conducted. Categorical variables were performed by the Chi-square test. Survival rates were estimated by Kaplan–Meier analysis. P < 0.05 considered statistically significant.


  Results Top


Mean age 55.20 ± 12.67 (range: 27–87 year); 69.4% =50 and 30.6% <50-year-old. 42.9% showed low (<15%), 57.1% high Ki-67 (=15%). 61.2% luminal A, 36.7% luminal B and 2.0% triple negative type. 53.1% classic and 46.9% were pleomorphic type.

18F-FDG uptake detected in all lesions (n = 49); mean SUVmax 8.32 ± 4.73 (median: 7.32, distribution range: 1.70–19.48). There was no statistically significant relationship between SUVmax of classical (7.84 ± 4.37) and pleomorphic type (8.85 ± 5.15) (P = 0.616). Primary tumors <2 cm and =2 cm; SUVmax of = 2 cm (9.15 ± 4.75) was significantly higher than < 2 cm (6.24 ± 4.13) (P = 0.039). 93.9% ER +, 95.9% PR + and 4.1% HER2+. Mean SUVmax (9.48 ± 5.0) with high Ki-67 found close statistically significantly higher than low Ki-67 (6.77 ± 3.9) (P = 0.0052). E-cadherin staining was + in 18.4%, (-) in 81.6% [Table 1].
Table 1: Relationship between mean±SD SUVmax, clinical, molecular and histopathological features and mean survival times

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73.5% axillary LN (ALN) involvement observed with PET. When evaluated for ALN metastasis; compliance of PET results with histopathological data found 87.8% in total, 69.4% pathology positive and 18.4% for negative cases. Mean ALN diameter with ALN dimensions 1.40 ± 1.00 (range: 0.6–4.00 cm). 18 of lesions, 18F-FDG uptake detected in ALN, mean SUVmax; 6.19 ± 7.59 (Median = 4.00, distribution range: 1.3–40.40). Statistically significant correlation found between ALN FDG uptake and primary tumor SUVmax (r = 0.447, P = 0.002). Statistically significant correlation found between ALN SUVmax and LN size (r = 0.664, P = 0.000). SUVmax (12.82 ± 12.3) of ALN with largest axial diameter =2 cm found statistically significantly higher than LNs <2 cm (4.54 ± 4.3) (P = 0.005) [Table 1].

Fifteen had distant metastasis; 11 bone-bone marrow, 2 multilocalized, 1 liver and 1 skin. No statistically significant relationship found between primary tumors SUVmax of metastatic (10.38 ± 5.3) and nonmetastatic (7.40 ± 4.2) groups (P = 0.059) [Table 1]. The bone-bone marrow metastatic case is presented in [Figure 1].
Figure 1: Maximum intensity projection (MIP) image shows FDG involvement of foci; in the upper outer quadrant of the left breast (SUV max:6,7), left axillary lymph nodes (SUV max:8,2), bone marrow more than one focus. Axial PET/CT fusion images (b,d,f,h,) showing increased 18F-FDG in the upper outer quadrant of the left breast, left axillary lymph nodes, L 5 vertebrae, proximal of left femur (white arrows) and corresponding CT slices (a,c,e,g,) showing accompanying anatomical findings. (maximum intensity projection image [MIP], computerized tomography[a,c,e,g], and fusion [b,d,f,h] images).

Click here to view


Thirty luminal A, 18 luminal B, and 1 triple negative. Mean SUVmax luminal: 7.18 ± 4.39, 10.43 ± 4.72 in luminal B and 4.41 in triple negative. Mean SUVmax luminal B found statistically significantly higher than luminal A (P = 0.013) [Table 1].

Mean follow-up period was 30.93 ± 24.63 (range: 0.77–106.3 months). Comparison of survival time and clinical characteristics is presented in [Table 1].

PR negativity, Ki-67 high expression, ALN metastasis, and luminal B significantly reduced mean survival time (P = 0.034, 0.019, 0.032 and 0.005, respectively) (log rank = 0.001, 0.741, 0.436, and 0.000, respectively) [Figure 2],[Figure 3],[Figure 4],[Figure 5].
Figure 2: Survival schedule based on PR receptor status (Log Rank=0.001).

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Figure 3: Survival chart according to Ki-67 expression (LogRank=0.741).

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Figure 4: Survival schedule based on axillary LN involvement (Log Rank=0.436).

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Figure 5: Survival schedule by molecular subtype (Log Rank=0.000).

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Forty-nine patients mean TLG 40%: 72.40 ± 92.73 (median = 33.06, distribution range: 1.61–344.68), and mean MTV 40%:17.65 ± 27.36 (median = 7.12, distribution range: 0.55–143.42). Statistically significant correlation found between high MTV and TLG, increased TD (P = 0.001 and 0.000, respectively) [Table 2].
Table 2: Comparison between mean MTV and TLG in clinical and histopathological features of the patients

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  Discussion Top


Studies reporting low FDG uptake by ILC has made the role of 18F FDG-PET/CT controversial, particularly in ILC management.[6],[7] In our previous studies, lowest SUVmax reported in ILC when compared other BC subtypes.[8] Method should be examined in detail to clearly determine the place of ILC in the diagnosis. A study conducted by Fujii et al., 196 IDC and ILC, size in all ER (+) ILCs, low FDG uptake and statistically significant increasing FDG uptake with increasing tumor size reported.[9] Jung et al. with 32 ILC and 73 IDC significantly reduced FDG sensitivity reported in ILC's[14] and increased SUVmax accompanied by high Ki-67 and SUVmax correlation with low FDG uptake and tumor volume reported. Orevi et al. evaluate 49 18F FDG-PET/CT of 24 patients commented that method showed high sensitivity and specificity for metastasis evaluation.[15] Consistent with all published data, no significant relationship found between hormone receptor and FDG uptake pattern in ILC. Increasing TD and luminal B, high Ki-67 found statistically significant (P = 0.052). Similarly, with distant metastatic ILC, FDG uptake found statistically significant (P = 0.059). Low e-cadherin, which is thought to play a role in cell adhesion and whose deficiency, has been reported to trigger invasion and metastasis generally associated with poor prognosis.[16] Although increased FDG uptake was significantly associated with poor prognostic features in many studies, in our study, e-cadherin loss in ILC was not statistically related to SUVmax.

The prognosis in ILC defined as equal/better than IDC. The prognosis will vary according to molecular, histopathological-clinical characteristics.[17] Many studies have detailed survival analysis involving only clinical and histopathological-molecular characteristics of ILC alone is limited. Some reported pleomorphic type is associated with aggressive clinical behavior, poor prognosis. Totally 233 ILC Sahin et al. identified 23 as pleomorphic and 5-year survival found significantly lower than classical.[18] Bello et al. analyzed 843 ILC; survival is statistically negatively associated with age < 40 years (P = 0.032), axillary involvement (P < 0.0001), ER (P < 0.001) and PR (P < 0.001)[19] In our study, no significant difference observed between pleomorphic and classical type in terms of survival. However, survival is worsening with PR(-) and axillary involvement in accordance with findings of Bello et al. Correlation high Ki-67 and FDG uptake, luminal B and decreased survival are remarkable.

Adequacy of 18F FDG-PET/CT for diagnosis, staging, and treatment follow-up in BC has become controversial. In fact, frequently reported that method exhibits false-negativity with low-aggressive types and poor FDG sensitivity in ER+/HER2 (-).[10],[11] These handicaps of 18F FDG PET/CT and low FDG affinity of ILC, it becomes inevitable to concentrate alternative methods. We think that evaluating the role of volumetric parameters of PET/CT might contribute to clinical, prognostic, and predictive value in ILC with low FDG sensitivity, as they proposed as a promising tool for evaluating nodal/distant organ involvement in studies.[12],[20] However, many published studies investigating volumetric parameters on clinical and prognostic factors in ILC is limited. Ulaner et al. with 19 IDCs and 8 ILCs, authors concluded method was useful in detecting unexpected extra-ALN metastasis in both subtypes by using MTV.[21] Groheux et al. involving ER+/HER2-143 BC concluded that all PET parameters including MTV and TLG had prognostic value and would contribute to follow-up and selection of risky patients.[11] Similarly, 171 ER + BC without distant metastasis, Lemarignier et al. reported MTV had predictive value in histopathological-types and TLG in treatment response.[22] In our study, statistically significant correlation found between high MTV, TLG and increased tumor diameter (TD).

As a result; in this study, we have investigated not only FDG involvement pattern of 18F FDG-PET/CT modality on clinical, histopathological, and molecular basis in ILC, but also value of MTV, TLG on prognostic and predictive survival analysis. Accordingly, loss of e-cadherin and pleomorphic type did not affect the prognosis. Although the diagnosis of ILC shows low FDG sensitivity compared to other BC, has been found significantly associated with increased TD, molecular subtype, high Ki-67 and presence of metastasis. Therefore, although volumetric parameters did not add any extrapredictive value to FDG involvement pattern, it was found that method remains its role in the diagnosis, staging, and treatment follow-up of ILC. We believe that determining cutoff values for SUVmax, which will be performed with the large number of sample groups, will contribute to subject, especially in ILC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Arslan E, Aksoy T, Cermik T. The prognostic value of 18 FDG PET/CT metabolic tumor volume (MTV) in distant metastatic breast cancer. J Nucl Med 2019;60:1235.  Back to cited text no. 12
    
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Jung NY, Kim SH, Choi BB, Kim SH, Sung MS. Associations between the standardized uptake value of (18) F-FDG PET/CT and the prognostic factors of invasive lobular carcinoma: In comparison with invasive ductal carcinoma. World J Surg Oncol 2015;13:113.  Back to cited text no. 14
    
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Ulaner GA, Goldman DA, Gönen M, Pham H, Castillo R, Lyashchenko SK, et al. Initial Results of a prospective clinical trial of 18F-fluciclovine PET/CT in newly diagnosed invasive ductal and invasive lobular breast cancers. J Nucl Med 2016;57:1350-6.  Back to cited text no. 21
    
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Lemarignier C, Martineau A, Teixeira L, Vercellino L, Espié M, Merlet P, et al. Correlation between tumour characteristics, SUV measurements, metabolic tumour volume, TLG and textural features assessed with 18 F-FDG PET in a large cohort of oestrogen receptor-positive breast cancer patients. Eur J Nucl Med Mole Imaging 2017;44:1145-54.  Back to cited text no. 22
    


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