Role of SUV and ADC values as a predictors of grade and molecular subtypes of breast malignancy

INTRODUCTION

Breast cancer has ranked number one among Indian females with an age-adjusted rate of 25.8 per 1,00,000 women and mortality of 12.7 per 1,00,000 women.^[1] Multiple risk factors, such as age, parity, family history, BReast CAncer (BRCA) gene mutation, sedentary lifestyle, hormonal replacement therapy, and radiation exposure that are involved in the development of breast cancer have been studied.^[2–7] Several clinico-pathological factors have been studied and correlated with the prognosis of breast cancer.

Predicting the prognosis of breast cancer is important for determining the treatment protocol. Currently histopathological grading is the most commonly used factor for assessing the aggressiveness of the lesion and is a strong predictor of prognosis^[8,9] that needs invasive procedure such as incision or excision biopsy for evaluation. Nottingham Histologic Score system is used to classify the tumor as Grade 1, 2, or 3 by taking into consideration the amount of gland formation (cell “differentiation”), nuclear features (degree of “pleomorphism”), and mitotic activity (how much the tumor cells are dividing, or proliferating).

Another recently used factor for predicting prognosis is the receptor status that is also proved to be useful in determining targeted therapy. Immunohistochemical (IHC) techniques are utilized to measure the expression of receptors such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).^[10–12]

Based on the receptor status molecular subtyping (luminal and non-luminal) is done.

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  Luminal subtype:

  • Luminal A: A high expression of ER-related genes and low expression of HER2 and proliferation-related genes (ki67 index). ER+ PR+ HER2–, usually low grade. Most common among the luminal types and have the best prognosis

  • Luminal B: A lower expression of ER-related genes, variable expression of HER2 gene clusters, and higher expression of proliferation-related genes (ki67 index) ER+ PR+ HER2+, usually intermediate to high grade

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  Non-luminal subtypes

  • HER2-Enriched: A high expression of HER2 and low expression of ER and PR, usually mid to high grade

  • Triple-negative: ER-negative, PR-negative, and HER2-negative. These tumors have worse prognosis among all subtypes^[13]; with higher proliferation rates, and predominantly high-grade tumors.

Imaging plays an important role in screening, diagnosis, and staging of breast cancer. Commonly used modalities are mammography, ultrasound, positron emission tomography–computed tomography (PET-CT), and Magnetic Resonance Imaging (MRI). Few imaging features have been correlated with the risk and prognosis of breast cancer. For example, there is increased risk of breast cancer in patients with increased parenchymal density.^[14,15] Poor prognosis is seen in patients with larger lesion, nodal involvement, tumor necrosis, extensive intraductal component, lymphovascular invasion, and multifocal or multicentric disease.^[16–21]

Functional imaging techniques such as MRI and PET are used primarily for staging, but were found to have a role to play in assessing the tumor aggressiveness.

18F-fluorodeoxyglucose (FDG) PET-CT is used for the staging, assessment of recurrence and treatment response.^[22] FDG avidity reflects the cellularity of the lesion and glucose metabolism in cancer cells. It also helps in predicting the prognosis of primary breast cancer as it is associated with few histopathological and immunohistochemical prognostic factors,^[23,24] such as the grade of malignancy in breast carcinoma.

MRI is known to be a highly sensitive, noninvasive technique for the detection and local staging of breast cancer. The diffusion-weighted image (DWI) in MRI is used to evaluate the microstructural characteristics of water diffusion in biological tissues.^[25] As malignant mass has increased the cell proliferation, it shows restricted diffusion as a result of inhibition of water diffusion. The apparent diffusion coefficient (ADC) is a quantitative measure of the diffusion of water molecules within the tissues. Several studies have shown that the ADC value is useful for differentiating benign and malignant breast lesions.^[26,27] Recently, various studies have evaluated the relationship between tumor prognostic factors and DWI or ADC values.^[28–32] Thus, it can help us identify tumors with high malignant potential and can provide preoperative prognostic information.

Additionally, information about background parenchymal uptake, background parenchymal enhancement, and fibroglandular tissue can serve as an important imaging biomarker in breast cancer, which has to be further evaluated.^[33]

In this study, we intend to correlate these imaging findings with histological and immunohistochemical prognostic factors. By studying all these factors, imaging can have a better role to perform as a non-invasive tool in predicting the aggressiveness of the tumor and thus the prognosis.

MATERIAL AND METHODS

This is a prospective observational study including patients with biopsy-proven breast carcinoma who were referred for PET-CT. The study has been approved by the Institutional Ethics Committee (IEC) of Apollo Hospitals, Chennai; the approval reference number being - ECR/37/Inst/TN/2013/RR-16.

RESULTS

In our prospective study, 53 patients with biopsy-proven unilateral breast cancer were included. Clinical, histopathological, and imaging characteristics of the patient are provided in Table 1. There is a significant difference in mean SUV_max values between the grades of malignancy (P = 0.003) [Figure 1], positive and negative estrogen receptor tumors [P = 0.04], positive and negative progesterone receptor tumors [P = 0.001] and among different molecular subtypes (P = 0.018) [Figure 2 and Table 2]. Higher mean SUV_max values were seen in Grade 3 tumors (11.41 ± 4.76) [Figure 1], ER negative (10.64 ± 4.37), PR negative tumors (11.64 ± 4.12), and triple-negative molecular subtype (12.27 ± 4.22) [Figure 2]. No significant difference was observed between SUV values of positive and negative HER2 receptor tumors.

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Figure 1:

(a) Error bar showing difference between SUV_max and histopathological grades [p value - 0.003]. (b) Examples: Grade 1 invasive ductal carcinoma in right breast with minimal FDG uptake (SUV ~ 3.77). (c) Grade 2 carcinoma in right breast with moderate FDG uptake (SUV ~ 6.97). (d) Grade 3 carcinoma in left breast with marked FDG uptake (SUV ~ 11.7). SUV: Standardized Uptake Value, FDG: fluorodeoxyglucose.

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Figure 2:

(a) Error bar showing difference between SUV_max in different molecular subtypes [p value - 0.018]. Example: Patient with Triple negative molecular subtype – CT (b) and fused PET-CT (c) images showed markedly FDG avid irregular lesion with microlobulated margins in inner quadrant of right breast (SUV ~ 17.5) HP: HER2-Enriched, LA: Luminal A, LB: Luminal B, TN: Triple negative molecular subtype, SUV: Standardized Uptake Value, CT: Computed Tomography, PET-CT: positron emission tomography–computed tomography, FDG: fluorodeoxyglucose.

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Statistically significant difference was seen in ADC values between positive and negative estrogen receptor tumors (P = 0.02) and different molecular subtypes (P = 0.009) [Figures 3–5; and Table 2]. Higher mean ADC values were seen in HER2-Enriched molecular subtype (1.03 ± 0.25) [Figure 3]. Lower mean ADC values were seen in ER-positive tumors (0.85 ± 0.16) and luminal A molecular subtype (0.79 ± 0.13) [Figure 4]. There was no statistically significant correlation between ADC values of different grades of malignancy, PR, and HER2 receptor status [Table 2].

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Figure 3:

(a) Error bar showing difference between ADC values in different molecular subtypes [p value - 0.009]. Example: 58-year-old postmenopausal female with HER2-Enriched molecular subtype AxT1. HP: HER2-Enriched, LA: Luminal A, LB: Luminal B, TN: Triple negative molecular subtype. (b) and post contrast (c) sequences show heterogeneous fibroglandular tissue with malignant lesion in inner quadrant of right breast showing heterogeneous enhancement, central non-enhancing areas and restricted diffusion (ADC values, 1.231 × 10⁻³ mm²/s) (d & e). ADC: Apparent Diffusion Coefficient, HER2: Human epidermal growth factor receptor 2.

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Figure 4:

52-year-old female with Luminal A (ER+, PR+) molecular subtype and grade 2 invasive ductal carcinoma in right breast. Ax T1 (a) and post contrast (b) sequences shows malignant lesion in right breast with heterogeneous enhancement and satellite lesion anterior to the index lesion. The index lesion and the satellite nodule show restricted diffusion with low ADC values, 0.752 × 10⁻³ mm²/s (c & d). Also note the metastatic right axillary node with restricted diffusion (c). ER+: estrogen receptor-positive, PR+: progesterone receptor-positive, ADC: Apparent Diffusion Coefficient.

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Figure 5:

53-years-old female with Triple negative molecular subtype and grade 3 carcinoma, Ax T1 (a) and post contrast (b) sequences show heterogeneous fibroglandular tissue with heterogeneously enhancing irregular micro lobulated lesion in 6 O’ clock position of right breast. The lesion shows restricted diffusion with low ADC values, 0.731 × 10⁻³ mm²/s (c&d). ADC: Apparent Diffusion Coefficient.

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Twenty-five out of 53 patients in our study had heterogenous or extreme fibroglandular pattern in which 24 patients (95%) had a higher grade of malignancy. Among the patients with marked background parenchymal enhancement (5 out of 53), 80% of them had Grade 3 malignancies. There was no statistically significant correlation between background SUV of the contralateral breast, with the grades of malignancy, receptor status, or molecular subtypes.

DISCUSSION

Tumor grade, receptor status, and molecular subtypes are important histological prognostic factors. Higher grade of malignancy and triple negative molecular subtype are aggressive with poor prognosis.

18F-fluorodeoxyglucose PET detects enhanced glycolysis of cancer cells, which is primarily used for staging, response assessment and identifying disease recurrence. FDG uptake is expressed in a quantitative parameter, that is, SUV_max, and it carries clinical as well as biological information. In our study, higher SUV values were seen in tumors with Grade 3, ER or PR negative and triple negative molecular subtype. These results are similar to those of few previously published studies such Groheux et al,^[13] Nakajo et al,^[22] Ueda et al,^[34] Choi et al,^[35] Abubakar et al.^[36]

In our study, no correlation was found between grade of tumors and ADC values. In accordance with Yoshikawa et al.,^[37] the ADC value depends on a number of factors including cell density, the spatial organization, and characteristics of the cells such as wall or nuclear size and the type of the stroma. It is not unusual to find high-grade invasive tumors with ADC values higher than expected. It is likely that these types of tumors have a microstructure that promotes water diffusion. Kim et al.,^[25] concluded that the ADC value was a helpful parameter in detecting malignant breast tumors, but it could not predict patient prognosis.

In our study, statistically significant variation in ADC values among various molecular subtypes. Higher ADC values were seen in HER2-Enriched tumors. Similar results were seen in Horvat et al.^[38] and Kim et al.^[32] Kim et al.^[32] stated, it is known that HER2 expression increases angiogenesis which leads to increase in tumor vascularity. These new vessels are larger and discontinuous that increases the extracellular fluid volume thereby increasing the ADC values.^[19] Low ADC values were seen in luminal A subtype and ER-positive tumors were consistent with the results of Horvat et al.^[38] as these tumors have low neovascularity and high cellularity. It is important to differentiate luminal and non-luminal tumors for the reason that the luminal tumors require endocrine therapy rather than a cytotoxic chemotherapy. Horvat et al.^[38] expressed that in future the improvements in DWI technology may increase the accuracy of ADC metrics and it can have clinical applicability in the preoperative classification of tumor subtypes.

However, there was no statistically significant variation in ADC values between progesterone/HER2 receptor-positive and negative lesions in our study. Similar results were also observed with Nakajo et al.^[22] and Kim et al.^[25]

Larger number of patients with heterogeneous fibroglandular pattern had higher grade of malignancies. These results were in agreement with the previously published studies by McCormack et al.,^[14] and Boyd et al.,^[15] which proved that the risk of malignancy is higher in patients with denser breast.

This study has some limitations. It was a short-duration prospective study with a relatively low number of patients. Heterogeneous sample of patients were examined that showed uneven distribution of histologic (low number of lobular carcinoma and Grade 1 tumors) and molecular subtypes (low number of HER2-Enriched type) which can influence the significance of the results

CONCLUSION

PET-CT and MRI can be used as a complementary imaging tool in evaluating the patient with breast carcinoma for noninvasive assessment of the aggressiveness, and biological characteristics of tumor such as grade, hormone receptor status, and to differentiate molecular subtypes.

Our study showed higher SUV values in Grade III, ER- or PR-negative and triple-negative tumors. Therefore, in essence, the SUV values obtained from 18F-FDG PET-CT shows a positive correlation with the aggressiveness of the tumor. ADC values helps to analyze the cellularity and neo angiogenesis of the tumor