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Relationship between primary tumour 18F-FDG uptake and immunohistochemical and clinical prognostic parameters in breast carcinoma
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Original article
Relationship between primary tumour 18 F-FDG uptake and immunohistochemical and clinical prognostic parameters in breast carcinoma G.K. Gedik ∗ , F. Yilmaz, O. Sari Selcuk University, Medical Faculty, Department of Nuclear Medicine, Konya, Turkey
a r t i c l e
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Article history: Received 1 June 2016 Accepted 27 September 2016 Available online xxx Keywords: Breast carcinoma Prognosis Tumour to background ratio 18 F-FDG
a b s t r a c t Objective: The objective of this study was to investigate the relationship between level of 18 F-fluorodeoxyglucose (18 F-FDG) accumulation in primary breast tumour assessed by positron emission tomography/computed tomography (PET/CT) and histopathological and clinical prognostic factors. Material and methods: A retrospective analysis was performed using the medical records of 58 female patients (age range: 31-86 years, mean age: 56) with biopsy of proven breast carcinoma, and who had undergone 18 F-FDG PET/CT examination before chemotherapy/surgery. The 18 F-FDG uptake of breast tumours was calculated as tumour to background ratio (TBR), which was compared with histopathological and clinical prognostic parameters. Results: The histology of the breast tumour in the 58 patients was ductal type in 52 (90%), lobular in 4 (7%), and mucinous in 2 (3%). Tumour size was ≤ 2 cm in 31 (53%) patients, and > 2 cm in 27 (47%). The levels of TBRs were not significantly different between the patients groups with tumours of 2 cm or less and greater than 2 cm (P = 0.131). No significant difference between levels of TBR was observed neither with regards to axillary lymph node involvement (P = 0.065) nor in terms of distant metastases (p = 0.123). No statistically significant difference was found in levels of TBRs between patients with c-erbB-2 receptor positive and negative ones (P = 0.107). Progesterone receptor (PR) expression was observed in 33 patients (57%), and 25 patients (43%) were PR negative. As regards progesterone receptor status, a statistically significant difference was observed in mean TBR levels between patients with and without progesterone receptor expression (P = 0.020). Oestrogen receptor expression was positive in 41 (71%) patients, and negative in 17 (29%) patients. The difference in the levels of TBRs between patients with and without oestrogen receptor expression was at the level of significancy (P = 0.050). Conclusions: It is concluded that 18 F-FDG uptake correlates with progesterone negativity of the tumour. However, a significant association with clinical prognostic parameters and level of 18 F-FDG uptake levels could not be demonstrated. ˜ S.L.U. y SEMNIM. All rights reserved. © 2016 Elsevier Espana,
Asociación entre la captación de 18 F-FDG y las características inmunohistoquímicas y factores pronósticos en el cáncer de mama r e s u m e n Palabras clave: Carcinoma de mama Pronóstico Índice tumor/fondo 18 F-FDG
Objetivo: El objetivo de este estudio fue investigar la asociación entre el nivel de captación de 18 F-fluorodeoxiglucosa (18 F-FDG) en el tumor de mama primario, valorado mediante tomografía por emisión de positrones/tomografía computarizada (PET/TC) y correlacionarlo con los factores pronósticos histopatológicos y clínicos. Material y métodos: Se analizaron retrospectivamente las historias clínicas de 58 mujeres (rango de ˜ ˜ edad: 31-86 anos, edad media: 56 anos) con biopsia de carcinoma de mama, que se sometieron a una exploración 18 F-FDG PET/TC antes de la quimioterapia/cirugía. El grado de captación de 18 F-FDG en los tumores de mama se calculó como el índice tumor/fondo (ITF) que se comparó con parámetros pronósticos histopatológicos y clínicos. Resultados: La histología del tumor de mama en las 58 pacientes fue de tipo ductal en 52 (90%), lobular ˜ del tumor fue ≤ 2 cm y en 27 (47%) fue en 4 (7%) y mucinoso en 2 (3%). En 31 pacientes (53%) el tamano > 2 cm. Los niveles de ITF no fueron significativamente diferentes entre el grupo de pacientes con un tumor ≤ 2 cm y el grupo con tumor > 2 cm (p = 0,131). No se observaron diferencias significativas entre los ITF ni
∗ Corresponding author. Associate Professor of Nuclear Medicine Selcuk University, Faculty of Medicine, Department of Nuclear Medicine, Selcuklu Konya, Turkey. Tel.: +00903322415000; fax: +00903322416065. E-mail address: [email protected] (G.K. Gedik). http://dx.doi.org/10.1016/j.remn.2016.09.006 ˜ S.L.U. y SEMNIM. All rights reserved. 2253-654X/© 2016 Elsevier Espana,
Please cite this article in press as: Gedik GK, et al. Relationship between primary tumour 18 F-FDG uptake and immunohistochemical and clinical prognostic parameters in breast carcinoma. Rev Esp Med Nucl Imagen Mol. 2016. http://dx.doi.org/10.1016/j.remn.2016.09.006
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con respecto a la afectación de los ganglios linfáticos axilares (p = 0,065), ni en términos de metástasis a distancia (p = 0,123). Tampoco hubo diferencias estadísticamente significativas en los niveles de ITF entre los pacientes con los receptores de c-erbB-2 positivos y negativos (p = 0,107). Treinta y tres pacientes (57%) presentaron receptores de progesterona positivos y en 25 pacientes (43%) eran negativos. Respecto al estado de los receptores de progesterona, se observó una diferencia estadísticamente significativa en los niveles medios de ITF entre pacientes con y sin la expresión del receptor de progesterona (p = 0,020). Los receptores estrogénicos fueron positivos en 41 pacientes (71%) y negativos en 17 (29%). Con relación a los receptores estrogénicos, la diferencia en el ITF entre los casos con receptores positivos y los negativos estaba en el nivel de significación (p = 0,050). Conclusiones: Se concluye que la captación de 18 F-FDG se relaciona con la negatividad de los receptores de progesterona del tumor. Sin embargo, no se demostró una asociación significativa con los parámetros pronósticos clínicos y el grado de captación de 18 F-FDG. ˜ S.L.U. y SEMNIM. Todos los derechos reservados. © 2016 Elsevier Espana,
Introduction 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography/computed tomography (PET/CT) is a widely used diagnostic modality in oncologic imaging. Reflecting their glucose hypermetabolism, uptake of 18 F-FDG by breast cancer cells and the ability of 18 F-FDG PET/CT in visualizing the primary tumor both in primary and recurrent settings has been shown in breast carcinoma.1 Apart from primary tumor diagnosis, accurate staging of patients with breast carcinoma is also required for planning the optimal therapy. 18 F-FDG PET/CT has been reported to be more accurate than conventional imaging methods in initial and recurrent staging of breast cancer.2 As well as preoperative determination of tumor extent, prognosis stratification is also essential in patients with breast carcinoma. Several biological and clinical prognostic factors related to breast carcinoma have been described in the literature such as estrogen (ER) and progesterone receptor (PR) status, expression of the proto-oncogene c-erbB-2, axillary nodal status, size of the primary tumor and presence of metastases.3,4 Among these, determination of ER and PR status in tumor cells is important for appropriate hormone therapy. Hormone sensitive breast cancer is less aggressive than hormone resistant one and overall, the median survival in patients with ER positive tumors is longer than for patients with ER negative breast cancer.5 Absence of PR is independent predictor of poor response and is associated with higher recurrence rates and shorter survival time.6 Overexpression of c-erbB-2 receptor is associated with increased mitogenesis, invasiveness and determination of c-erbB-2 receptor is useful for selecting patients with advanced breast cancer for the therapy with therapeutic antibodies like trastuzumab.7 It has been reported that, 18 F-FDG PET/CT can also be used to assess the proliferative activity/or biological aggressiveness of malignant tissue by calculating the level of 18 F-FDG uptake in primary breast tumors.2 Pretherapeutic overview of the entire body and evaluation of the tumor proliferation rate, which will help to stratify patients according to risk for recurrence and to tailor the aggressiveness of therapy for an individual patient with 18 FFDG PET/CT in a single examination, is a challenging approach. The probable relationship between 18 F-FDG uptake expressed as SUV and other clinical and biologic prognostic factors in breast carcinoma were investigated previously and some positive and statistically significant differences were found between SUV and clinicopathological parameters such as high tumor size, presence of axillary lymph node metastases, ER and PR negativity.2–4,8 In all of these studies, standardized uptake value (SUV) was used as the quantitative analysis and the association of SUV and other prognostic factors were investigated. The aim of this study was to evaluate the possible correlation between proliferative activity of primary tumor and other biologic and clinical
prognostic markers in breast carcinoma by using a different quantitative method of tumor to background ratio (TBR), with 18 F-FDG PET/CT. Material and methods Patients Files of patients with breast carcinoma, who underwent 18 F-FDG PET/CT examination between October 2012 and May 2016,
were retrospectively reviewed. Of these, 58 female patients (age range: 31-86 years, mean age: 56) with biopsy proven breast carcinoma who were examined with 18 F-FDG PET/CT before any initial therapy and surgery, were enrolled to the study. Patients with bilateral breast cancer or patients in whom 18 F-FDG PET/CT was performed after surgery or neoadjuvant/primary chemotherapy, were excluded from the study. This study was approved by the local ethics committee of our faculty (meeting date: 13.04.2016 decision number: 2016/122) and written informed consent was obtained from all patients. 18 F-
fluorodeoxyglucose positron emission tomography/computed tomography scanning procedure
Images from the skull base to the midthigh were acquired in 8 or 9 bed positions with an acquisition time of 2 minutes per bed position with integrated 18 F-FDG PET/CT scanner (Biograph mCT, Siemens, Germany). Patients were advised to fast for at least 6 hours and 370 MBq of 18 F-FDG was injected to the patients whose blood glucose level was <200 mg/dl. PET/CT studies were performed 1 hour after the administration of the radiopharmaceutical. The CT part of the integrated scan was carried out without contrast enhancement by using 16 slice CT with the acquisition parameters of 190 mA, 5 mm slice thickness and 140 kV. Right after the CT imaging, PET scan was performed without changing the position. The CT data were used for the attenuation correction of PET scanning. Image analysis and quantification Acquired images of 18 F-FDG PET/CT were analysed on Siemens Syngo.via PET/CT workstation. For axillary involvement, lymph nodes showing 18 F-FDG uptake without fatty hilum were considered as metastatic. Any lesion showing 18 F-FDG accumulation in sites different from the primary tumor and axillary region presenting radiological aspects of metastases, were regarded as distant metastases. Tumor-to-background ratios (TBRs) were calculated in all breast tumors for semiquantitative analysis of tumor 18 F-FDG uptake. For this purpose, a region of interest was drawn around the site of the primary breast lesion. For background uptake, a
Please cite this article in press as: Gedik GK, et al. Relationship between primary tumour 18 F-FDG uptake and immunohistochemical and clinical prognostic parameters in breast carcinoma. Rev Esp Med Nucl Imagen Mol. 2016. http://dx.doi.org/10.1016/j.remn.2016.09.006
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Table 1 Clinicopathological characteristics and results of patients.
Figure 1. A region of interest was drawn around the site of the primary breast lesion (thick arrow). For background uptake, a corresponding region of interest was drawn on the contralateral breast (thin arrow).
corresponding region of interest was drawn on the contralateral breast (Figure 1). From these regions of interest, maximum count rates as SUVmax were calculated. The SUV was calculated using the below formula: activity in the region of interest (MBq/ml)/injected dose (MBq/kg body weight). TBR was defined as SUVmax in primary tumor/SUVmax in background tissue. All the patients in this study were then enrolled to surgery with sentinel node biopsy or axillary dissection or to systemic therapy. Clinicopathological evaluation and Immunohistochemical analysis Clinical and immunohistochemical results including, histopathologic type of tumor, tumor size, axillar lymph node metastases, distant metastases, expression of ER, PR and c-erbB-2 receptor were reviewed. For histopathological type determination, modified Bloom-Richardson criteria was used. Immunohistochemical results of all patients were collected from the files of the patients and were classified as positive or as negative for ER, PR and c-erbB-2 receptor. For ER and PR, results were classified as positive when at least 10% of tumor cell staining was reported.1 For c-erbB-2, results were considered as positive when 2 or 3+ membrane staining or as negative when 0 or 1 + membrane staining was reported, as suggested in the literature.3,7 Statistical analysis Mann-Whitney U test was used to test the associations between mean TBRs and the prognostic parameters of tumor size, axillary lymph node metastases, distant metastases, ER, PR and c-erbB2 receptor status by using SPSS 16.0 statistical software package. Results were considered statistically significant at a p value of <0.05. Results The histology of the breast tumor in 58 patients was ductal type in 52 (90%), lobular in 4 (7%) and mucinous in 2 (3%). Since majority (90%) of patients had ductal type breast tumor, the significance of difference of TBRs between different types of breast tumors was not assessed. In 31 patients (53%) tumor size was ≤ 2 cm and in 27 (47%) it was > 2 cm. The levels of meanTBRs were not significantly different between the patients tumor groups of 2 cm or less and greater than 2 cm (p = 0.131). Twentytwo patients were reported to have axillary lymph node metastases with 18 F-FDG PET/CT and remaining 36 were reported as free of
18
F-FDG PET/CT analysis of
Number of patients (%)
Tumor to background ratio Mean (range)
P value
Histology ductal lobular mucinous
52 (90) 4 (7) 2 (3)
4.34 (1.23-11.48) 3.31 (2.5-5.35) 2.25 (1.78-2.73)
Tumor size ≤2 cm >2 cm
31 (53) 27 (47)
2.27 (1.50-10.37) 2.40 (1.23-11.48)
0.131
Axillary lymph node metastases 22 (44) Negative 28 (56) Positive
3.66 (1.23-8.79) 4.90 (1.39-11.48)
0.065
Distant metastases 35 (60) Negative 23 (40) Positive
3.84 (1.23-10.37) 4.74 (1.55-11.48)
0.123
ER Negative Positive
17 (29) 41 (71)
5.36 (1.50-11.48) 3.72 (1.23-7.45)
0.050
PR Negative Positive
25 (43) 33 (57)
5.04(1.50-11.48) 3,56 (1,23-7,14)
0.020
c-erbB-2 Negative Positive
17 (31) 39 (69)
5.14 (1.50-11.48) 3.91 (1.23-7.37)
0.107
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axillary involvement. Pathologic examination revealed metastases in 6 of 36 patients who were negatively reported in terms of axillary lymph node metastases with 18 F-FDG PET/CT. In 22 of 36 patients, absence of metastases was confirmed by pathology. In the remaining 8 patients, pathological clarification of axillary lymph node status could not be identified. So statistical analysis investigating the association between 18 F-FDG uptake and prognostic parameters was performed over 50 patients including positively reported 22 patients with 18 F-FDG PET/CT and 28 patients in whom absence or presence of metastatic disease was proved by pathology. Finally there were 28 patients with axillary lymph node involvement (56%, Figure 2) and 22 (44%) without metastases. There was no significant difference between levels of TBR with regards to axillary lymph node involvement (p = 0.065). Distant metastases were observed in 23 patients (40%, Figure 3) and distribution of metastases were mediastinal lymph nodes in 11 patients, bone in 10, lung in 4, liver in 2 and cervical and supraclavicular lymph nodes in 4 patients. The difference of mean TBRs between patients with and without distant metastases was not statistically significant (p = 0.123). ER expression was observed in 41 (71%, Figure 2) patients and in 17 patients (29%, Figure 4a-c) ER status was negative. The difference was at the level of significance in values of TBRs between patients with ER negative tumors and in patients with ER positive tumors (p = 0.050). PR expression was observed in 33 patients (57%, Figure 4d-f) and 25 patients (43%) were PR negative. In patients with PR positive and PR negative tumors, the mean levels of TBRs were 3.56 (range: 1.23-7.14) and 5.04 (range: 1.50-11.48), respectively. With regard to PR receptor status, statistically significant difference was observed in mean TBR levels between patients with and without PR expression (p = 0.020). The results of c-erbB-2 analyses could be reached in 56 patients, among these, c-erbB-2 positivity was reported in 39 patients (69%) and receptor expression was not reported in 17 (31%) of them. The difference of levels of TBRs in patients with and without c-erbB-2 expression was not statistically significant (p = 0.107). The results of 18 F-FDG PET/CT analysis and clinicopathological characteristics of patients are summarized in Table 1.
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Figure 2. Transaxial PET (a), CT (b) and fusion (c) images of 18 F-FDG PET/CT study of sixty-one years old patient; ER, PR and c-erbB-2 receptor status positive patient with ductal type breast carcinoma (arrow, c). TBR of the primary tumor was calculated as 6.60. Distant and left axillary lymph nodes metastases were recognized in this patient. Transaxial PET (d), CT (e) and fusion (f) images from the lower demonstrates the metastatic left axillary lymph nodes (arrow, f).
Figure 3. Transaxial PET (a), CT (b) and fusion (c) images of 18 F-FDG PET/CT of a seventy-two years old patient with ductal type carcinoma in left breast (arrow, c). Calculated TBR of the primary tumor was 7.41. ER and PR negativity, c-erbB-2 positivity, axillary nodal involvement and distant metastases were noted about this patient. Transaxial PET (d), CT (e) and fusion (f) images of 18 F-FDG PET/CT of the same patient from the lower part, depicts metastatic liver lesion at the dome of the liver (arrow, f).
Discussion 18 F-FDG PET/CT is a noninvasive modality of imaging of glucose metabolism and plays a significant role in diagnosis, staging, detecting recurrences and monitoring response to therapy in variety of malignant tumors. Besides enabling visual interpretation, it gives quantitative information about the level of metabolic activity of the tumor by calculating the degree of 18 F-FDG uptake known as SUV. In breast carcinoma, 18 F-FDG uptake shows variability and lower SUVs than in other malignancies have been reported.7 The role of histologic type in this wide range of sensitivity of 18 F-FDG PET/CT has been evaluated in breast carcinoma and pooled results supported that 18 F-FDG uptake is higher in ductal breast cancer than
in lobular cancer.3,8 Concordant with the results reported in the literature, 18 F-FDG accumulation was found higher in ductal type compared to lobular and mucinous type breast carcinomas also in our study (4.34 vs 3.31 and 2.25, respectively). But due to the low number of patients in lobular and mucinous group, statistical analysis was not performed and the correlation of TBR with histologic type was not assessed. Although providing useful information in most patients with breast carcinoma, the limited role of 18 F-FDG PET/CT in primary breast cancer detection, caused to raise questions about the prognostic relevance of the level of 18 F-FDG uptake in breast cancer. Association between 18 F-FDG accumulation in primary breast tumor and other clinical and biological prognostic parameters have
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Figure 4. A forty-six years old, estrogen and progesterone receptor status negative patient. Transaxial PET (a), CT (b) and fusion (c) images of 18 F-FDG PET/CT shows the primary tumor in the left breast (c, arrow). Neither distant nor axillary lymph nodes metastases were not observed. Calculated TBR of the primary tumor was 8.79. Transaxial PET (d), CT (e) and fusion (f) images of 18 F-FDG PET/CT scanning of another patient shows ductal type breast carcinoma in the right breast (arrow, f). Calculated TBR was 2.6. ER and PR expression was positive and no distant and axillary lymph nodes were shown with 18 F-FDG PET/CT.
been investigated. In the study conducted by Dehdashti et al.,5 the relationship between metabolic activity of breast cancer and ER status was investigated and no association between SUVs for 18 F-FDG in malignant lesions and ER status was demonstrated. Although depicting a positive correlation between histologic tumor type and 18 F-FDG uptake, taking clinical prognostic parameters also into analysis, Avril et al.,9 could not find a correlation with SUVs and axillary lymph node status, tumor size, expression of ER and PR of the tumor. Similarly, Crowe et al.10 et al. and Buck et al.11 , was not able to demonstrate any correlation between 18 F-FDG uptake in breast tumor and ER and PR receptor status, axillary metastases and tumor size. On the contrary to these results, Ueda, Gil-Rendo and Kim et al.3,4,8 , reported that tumor size, axillary lymph node status, histologic grade and estrogen receptor status were significantly related to SUV and a positive association between SUV and prognostic parameters were shown. Besides reporting an association with increased SUV and ER and PR negativity, Koolen et al.1 , also demonstrated that presence of distant metastases at staging examination was significantly associated with higher SUV of the primary tumor. In the light of these conflicting results reported in the literature, we investigated the probable relationship between tumor 18 F-FDG uptake and other clinicopathologic prognostic parameters in breast carcinoma. However, instead of SUV, we used TBR as a quantitative method for tumor 18 F-FDG uptake. With regard to clinical prognostic factors, we could not find any correlation of TBR with tumor size, axillary lymph node involvement and presence of distant metastases. PET imaging has been reported to have a low sensitivity for detecting small breast carcinomas which is partly due to partial volume effect and partly to increased metabolic activity with tumor growth. Higher 18 F-FDG uptake in tumors greater than 2 cm in diameter than those smaller than 2 cm was reported by Gil-Rendo, Ueda and Kim et al.3,4,8 . However, in our study, we did not recognize a relationship between 18 F-FDG accumulation and tumor size which is consistent with the results of other groups1,9–11 . The status of axillary lymph nodes is the most important prognostic factor in breast carcinoma.12 Expecting a relation between metabolic rate of primary tumor measured with 18 F-FDG PET/CT and tumor spread to axilla, in some conducted studies it has
been shown that significant correlation exists between high SUV level of the primary tumor and positive axillary lymph node metastases.3,4,8 Moreover, García Vicente et al.,12 analysed the relation of biologic prognostic factors and 18 F-FDG uptake of lymph nodes and reported that bad prognostic biological factors including negative ER status were correlated with higher levels of SUV which revealed biological significance of lymph node 18 F-FDG accumulation. In our study, the difference of mean TBRs of primary tumors between patients with positive axillary lymph metastases and cases with node negative tumors, did not reach a significant level. Absence of this correlation was also noted by Avril et al.,9 Crowe et al.10 and Buck et al.11 . An association of higher SUV of primary tumor and presence of distant metastases at staging examination was demonstrated by Koolen et al.1 . Morris et al.,13 examined the prognostic role of SUV max calculated in metastatic tissue in patients with newly diagnosed metastatic breast cancer. Emphasizing not assessing the TBR as a limitation of their study, they concluded that an increased SUV max in bone was correlated with inferior survival. In our study, like other clinical prognostic factors, no association was observed between the mean levels of TBRs of primary tumors in patients with and without distant metastases. With regard to biological prognostic factors, consistent with the most previous reports, c-erbB-2 receptor status was not found to be associated with 18 F-FDG accumulation in our study.1,4,8,11 It is postulated that c-erbB-2 receptor status might not have any influence on glycolytic pathway.8 However, Ueda et al.3 , demonstrated a positive association with positive c-erbB-2 receptor expression and degree of 18 F-FDG uptake. When state of ER status was taken into consideration, the difference of mean TBRs between patients with ER positive and negative tumors was found at the level of significance. Interestingly, in our study statistically significant difference of mean TBRs was only observed between levels of patients with and without PR expression. This solely significance of PR state of tumor and 18 F-FDG uptake was also demonstrated by García Vicente et al.12 in 18 F-FDG accumulated metastatic axillary lymph nodes. Except the correlation between PR state and level of 18 F-FDG uptake, our results were concordant with the results of 2 groups
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who used TBR as a quantitative method for calculating the degree of 18 F-FDG uptake, like us.10,11 In all of these two studies, in which TBR was calculated as an index of tumoral 18 F-FDG uptake, 18 FFDG PET scanner was used.10,11 The unusual point of our study was using current 18 F-FDG PET/CT device as a scanner and taking background activity into consideration while calculating tumoral 18 F-FDG uptake. The discordancy of our results and other groups who used TBR, about the correlation of degree of 18 F-FDG uptake and PR status, may be secondary to omitting or using different techniques for attenuation correction.10,11 Quantitative assessment is generally recommended as a complementary way of visual image interpretation and also plays role in reducing interobserver variability. In breast carcinoma it is shown that, various quantitative analysis methods including, SUV max, mean SUV of the lesion (SUV mean) and TBR, provides stable parameters for differentiation of benign and malignant breast tumors.14 However, SUV is subjective to sources of variability such as glucose level, body weight, recovery coefficient and partial volume effect.15 Moreover, since PET/CT devices differ, length of uptake period is not standardized so caution must be taken while drawing conclusions from direct comparisons between studies. Some of these factors such as time of measurement of SUV after tracer injection and normalization to patient’s blood glucose level at the time of tracer administration can be standardized. But in addition to these technical factors, when the case is breast carcinoma, patients will have a history of diagnostic biopsy and this may cause inflammatory reaction which may contribute to the measured uptake in the tumor lesion. Animal studies showed that inflammatory cells significantly contribute to 18 F-FDG uptake in tumors.9 Kubota et al.16 reported that, up to 29% of 18 F-FDG uptake comes from non tumoral granulation tissue around the tumor. That’s why we wanted to exclude the interference of background activity from the SUV calculation, analyzed TBR as an indicator of disease activity and used SUV max instead of SUV mean which is operator dependent. In our study mean of the calculated background SUV max levels was found as 2.00. We thought that this level may interfere with the tumoral 18 F-FDG uptake and may cause false decisions to be drawn about its metabolic rate and biologic aggressiveness. Results about correlation of 18 F-FDG uptake and clinical prognostic parameters supported our hypothesis and none of the clinical prognostic parameters were found to be associated with degree of 18 F-FDG uptake. However, PR state of tumor still remained to be associated with level of 18 F-FDG accumulation and the results of statistical analysis with regard to ER expression was at the level of significance. This may be secondary to low number of ER negative patients in our study, if there were more patients with ER negative tumors, the calculated value might reach the significant level. The small number of individuals composing each subgroup analysed may also have an effect on the results of statistical analyses so the lack of significance of 18 F-FDG uptake and clinical prognostic factors and erbB-2 receptor status can be explained by the small number of patients in subgroups. The limitation of our study was its retrospective origin which reduced the number of patients and caused heterogeneity. The accessibility of results of immunohistochemistry of the primary tumor was also limited in some patients. Since currently any standardized method exists for partial volume effect correction and SUV or TBR is affected by partial volume effects, another important limitation of our study was the probability of underestimation of 18 F-FDG uptake in small tumors.
In conclusion background corrected 18 F-FDG uptake in primary breast tumor is associated with PR negativity. There may also be an association between ER receptor status and TBR. The effect of background activity on tumoral 18 F-FDG uptake should be tested in other studies with larger number of patients in order to reach definite conclusions about prognostic significance of 18 F-FDG accumulation and correlation of 18 F-FDG uptake with clinical prognostic parameters. Conflict of interest None declared References 1. Koolen BB, Vrancken Peeters MJ, Wesseling J, Lips EH, Vogel WV, Aukema TS, et al. Association of primary tumour FDG uptake with clinical, histopathological and molecular charactestics in breast cancer patients scheduled for neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging. 2012;39:1830–8. 2. Ohara M, Shigematsu H, Tsutani Y, Emi A, Masumoto N, Ozaki S, et al. Role of FDG PET/CT in evaluating surgical outcomes of operable breast cancer-Usefulness for malignant grade of triple-negative cancer. Breast. 2013;22:958–63. 3. Ueda S, Tsuda H, Asakawa H, Shigekawa T, Fukatsu K, Kondo N, et al. Clinicopathological and prognostic relevance of uptake level using 18 Fflurodeoxyglucose positron emission tomography fusion imaging (18 F-FDG PET/CT) in primary breast cancer. Jpn J Clin Oncol. 2008;38:250–8. 4. Gil-Rendo A, Martinez-Regueira F, Zornoza G, Garcia-Velloso MJ, Beorlegui C, Rodriguez-Spiteri N. Association between 18 F-flurodeoxyglucose uptake and prognostic parameters in breast cancer. Br J Surg. 2009;96:166–70. 5. Dehdashti F, Mortimer JE, Siegel BA, Griffeth LK, Bonasera TJ, Fusselman MJ, et al. Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays. J Nucl Med. 1995;36:1766–74. 6. Chaudhary L, Jawa Z, Szabo A, Visotcky A, Chitambar CR. Relevance of progesterone receptor immunohistochemical staining to oncotype DX recurrence score. Hematol Oncol Stem Cell Ther. 2016;9:48–54. 7. Mavi A, Cermik TF, Urhan M, Puskulcu H, Basu S, Yu JQ, et al. The effects of estrogen, progesterone and C-erbB-2 receptor states on 18 F-FDG uptake of primary breast cancer lesions. J Nucl Med. 2007;48:1266–72. 8. Kim YH, Lee JA, Baek JM, Sung GY, Lee DS, Won JM. The clinical significance of standardized uptake value in breast cancer measured using 18 F-flurodeoxyglucose positron emission tomography/computed tomography. Nucl Med Commun. 2015;36:790–4. 9. Avril N, Enzel M, Dose J, Schelling M, Weber W, Janicke F, et al. Glucose metabolism of breast cancer assessed by 18F-FDG PET: Histologic and immunohistochemical tissue analysis. J Nucl Med. 2001;42:9–16. 10. Crowe JP, Adler LP, Shenk RR, Sunshine J. Positron emission tomography and breast masses: comparison with clinical, mammographic and pathological findings. Ann Surg Oncol. 1994;1:132–40. 11. Buck A, Schirrmeister H, Kühn T, Shen C, Kalker T, Kotzerke J, et al. FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters. Eur J Nucl Med. 2002;29:1317–23. 12. García Vicente AM, Soriano Castrejón A, Cruz Mora MA, González Ageitos A, ˜ Munoz Sánchez Mdel M, León Martín A, et al. Semi-quantitative lymph node assessment of 18F-FDG PET/CT in locally advanced breast cancer: correlation with biological prognostic factors. Eur J Nucl Med Mol Imaging. 2013;40: 72–9. 13. Morris PG, Ulaner GA, Eaton A, Fazio M, Jhaveri K, Patil S, et al. Standardized uptake value by positron emission tomography/computed tomography as a prognostic variable in metastatic breast cancer. Cancer. 2012;118: 5454–62. 14. Avril N, Bense S, Ziegler SI, Dose J, Weber W, Laubenbacher C, et al. Breast imaging with fluorine-18-FDG PET: quantitative image analysis. J Nucl Med. 1997;38:1186–91. 15. Wiyaporn K, Tocharoenchhai C, Pusuwan P, Ekjeen T, Leaungwutiwong S, Thanyarak S. Factors effecting standardized uptake value (SUV) of positron emission tomography (PET) imaging wih 18 F-FDG. J Med Assoc Thai. 2010;93: 108–14. 16. Kubota R, Yamada Kubota K, Ishiwata K, Tamahashi N, Ido T. Intratumoal distribution of fluorine-18- fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissue studied by microautoradiography. J Nucl Med. 1992;33:1972–809.
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Original article
Relationship between primary tumour 18 F-FDG uptake and immunohistochemical and clinical prognostic parameters in breast carcinoma G.K. Gedik ∗ , F. Yilmaz, O. Sari Selcuk University, Medical Faculty, Department of Nuclear Medicine, Konya, Turkey
a r t i c l e
i n f o
Article history: Received 1 June 2016 Accepted 27 September 2016 Available online xxx Keywords: Breast carcinoma Prognosis Tumour to background ratio 18 F-FDG
a b s t r a c t Objective: The objective of this study was to investigate the relationship between level of 18 F-fluorodeoxyglucose (18 F-FDG) accumulation in primary breast tumour assessed by positron emission tomography/computed tomography (PET/CT) and histopathological and clinical prognostic factors. Material and methods: A retrospective analysis was performed using the medical records of 58 female patients (age range: 31-86 years, mean age: 56) with biopsy of proven breast carcinoma, and who had undergone 18 F-FDG PET/CT examination before chemotherapy/surgery. The 18 F-FDG uptake of breast tumours was calculated as tumour to background ratio (TBR), which was compared with histopathological and clinical prognostic parameters. Results: The histology of the breast tumour in the 58 patients was ductal type in 52 (90%), lobular in 4 (7%), and mucinous in 2 (3%). Tumour size was ≤ 2 cm in 31 (53%) patients, and > 2 cm in 27 (47%). The levels of TBRs were not significantly different between the patients groups with tumours of 2 cm or less and greater than 2 cm (P = 0.131). No significant difference between levels of TBR was observed neither with regards to axillary lymph node involvement (P = 0.065) nor in terms of distant metastases (p = 0.123). No statistically significant difference was found in levels of TBRs between patients with c-erbB-2 receptor positive and negative ones (P = 0.107). Progesterone receptor (PR) expression was observed in 33 patients (57%), and 25 patients (43%) were PR negative. As regards progesterone receptor status, a statistically significant difference was observed in mean TBR levels between patients with and without progesterone receptor expression (P = 0.020). Oestrogen receptor expression was positive in 41 (71%) patients, and negative in 17 (29%) patients. The difference in the levels of TBRs between patients with and without oestrogen receptor expression was at the level of significancy (P = 0.050). Conclusions: It is concluded that 18 F-FDG uptake correlates with progesterone negativity of the tumour. However, a significant association with clinical prognostic parameters and level of 18 F-FDG uptake levels could not be demonstrated. ˜ S.L.U. y SEMNIM. All rights reserved. © 2016 Elsevier Espana,
Asociación entre la captación de 18 F-FDG y las características inmunohistoquímicas y factores pronósticos en el cáncer de mama r e s u m e n Palabras clave: Carcinoma de mama Pronóstico Índice tumor/fondo 18 F-FDG
Objetivo: El objetivo de este estudio fue investigar la asociación entre el nivel de captación de 18 F-fluorodeoxiglucosa (18 F-FDG) en el tumor de mama primario, valorado mediante tomografía por emisión de positrones/tomografía computarizada (PET/TC) y correlacionarlo con los factores pronósticos histopatológicos y clínicos. Material y métodos: Se analizaron retrospectivamente las historias clínicas de 58 mujeres (rango de ˜ ˜ edad: 31-86 anos, edad media: 56 anos) con biopsia de carcinoma de mama, que se sometieron a una exploración 18 F-FDG PET/TC antes de la quimioterapia/cirugía. El grado de captación de 18 F-FDG en los tumores de mama se calculó como el índice tumor/fondo (ITF) que se comparó con parámetros pronósticos histopatológicos y clínicos. Resultados: La histología del tumor de mama en las 58 pacientes fue de tipo ductal en 52 (90%), lobular ˜ del tumor fue ≤ 2 cm y en 27 (47%) fue en 4 (7%) y mucinoso en 2 (3%). En 31 pacientes (53%) el tamano > 2 cm. Los niveles de ITF no fueron significativamente diferentes entre el grupo de pacientes con un tumor ≤ 2 cm y el grupo con tumor > 2 cm (p = 0,131). No se observaron diferencias significativas entre los ITF ni
∗ Corresponding author. Associate Professor of Nuclear Medicine Selcuk University, Faculty of Medicine, Department of Nuclear Medicine, Selcuklu Konya, Turkey. Tel.: +00903322415000; fax: +00903322416065. E-mail address: [email protected] (G.K. Gedik). http://dx.doi.org/10.1016/j.remn.2016.09.006 ˜ S.L.U. y SEMNIM. All rights reserved. 2253-654X/© 2016 Elsevier Espana,
Please cite this article in press as: Gedik GK, et al. Relationship between primary tumour 18 F-FDG uptake and immunohistochemical and clinical prognostic parameters in breast carcinoma. Rev Esp Med Nucl Imagen Mol. 2016. http://dx.doi.org/10.1016/j.remn.2016.09.006
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con respecto a la afectación de los ganglios linfáticos axilares (p = 0,065), ni en términos de metástasis a distancia (p = 0,123). Tampoco hubo diferencias estadísticamente significativas en los niveles de ITF entre los pacientes con los receptores de c-erbB-2 positivos y negativos (p = 0,107). Treinta y tres pacientes (57%) presentaron receptores de progesterona positivos y en 25 pacientes (43%) eran negativos. Respecto al estado de los receptores de progesterona, se observó una diferencia estadísticamente significativa en los niveles medios de ITF entre pacientes con y sin la expresión del receptor de progesterona (p = 0,020). Los receptores estrogénicos fueron positivos en 41 pacientes (71%) y negativos en 17 (29%). Con relación a los receptores estrogénicos, la diferencia en el ITF entre los casos con receptores positivos y los negativos estaba en el nivel de significación (p = 0,050). Conclusiones: Se concluye que la captación de 18 F-FDG se relaciona con la negatividad de los receptores de progesterona del tumor. Sin embargo, no se demostró una asociación significativa con los parámetros pronósticos clínicos y el grado de captación de 18 F-FDG. ˜ S.L.U. y SEMNIM. Todos los derechos reservados. © 2016 Elsevier Espana,
Introduction 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography/computed tomography (PET/CT) is a widely used diagnostic modality in oncologic imaging. Reflecting their glucose hypermetabolism, uptake of 18 F-FDG by breast cancer cells and the ability of 18 F-FDG PET/CT in visualizing the primary tumor both in primary and recurrent settings has been shown in breast carcinoma.1 Apart from primary tumor diagnosis, accurate staging of patients with breast carcinoma is also required for planning the optimal therapy. 18 F-FDG PET/CT has been reported to be more accurate than conventional imaging methods in initial and recurrent staging of breast cancer.2 As well as preoperative determination of tumor extent, prognosis stratification is also essential in patients with breast carcinoma. Several biological and clinical prognostic factors related to breast carcinoma have been described in the literature such as estrogen (ER) and progesterone receptor (PR) status, expression of the proto-oncogene c-erbB-2, axillary nodal status, size of the primary tumor and presence of metastases.3,4 Among these, determination of ER and PR status in tumor cells is important for appropriate hormone therapy. Hormone sensitive breast cancer is less aggressive than hormone resistant one and overall, the median survival in patients with ER positive tumors is longer than for patients with ER negative breast cancer.5 Absence of PR is independent predictor of poor response and is associated with higher recurrence rates and shorter survival time.6 Overexpression of c-erbB-2 receptor is associated with increased mitogenesis, invasiveness and determination of c-erbB-2 receptor is useful for selecting patients with advanced breast cancer for the therapy with therapeutic antibodies like trastuzumab.7 It has been reported that, 18 F-FDG PET/CT can also be used to assess the proliferative activity/or biological aggressiveness of malignant tissue by calculating the level of 18 F-FDG uptake in primary breast tumors.2 Pretherapeutic overview of the entire body and evaluation of the tumor proliferation rate, which will help to stratify patients according to risk for recurrence and to tailor the aggressiveness of therapy for an individual patient with 18 FFDG PET/CT in a single examination, is a challenging approach. The probable relationship between 18 F-FDG uptake expressed as SUV and other clinical and biologic prognostic factors in breast carcinoma were investigated previously and some positive and statistically significant differences were found between SUV and clinicopathological parameters such as high tumor size, presence of axillary lymph node metastases, ER and PR negativity.2–4,8 In all of these studies, standardized uptake value (SUV) was used as the quantitative analysis and the association of SUV and other prognostic factors were investigated. The aim of this study was to evaluate the possible correlation between proliferative activity of primary tumor and other biologic and clinical
prognostic markers in breast carcinoma by using a different quantitative method of tumor to background ratio (TBR), with 18 F-FDG PET/CT. Material and methods Patients Files of patients with breast carcinoma, who underwent 18 F-FDG PET/CT examination between October 2012 and May 2016,
were retrospectively reviewed. Of these, 58 female patients (age range: 31-86 years, mean age: 56) with biopsy proven breast carcinoma who were examined with 18 F-FDG PET/CT before any initial therapy and surgery, were enrolled to the study. Patients with bilateral breast cancer or patients in whom 18 F-FDG PET/CT was performed after surgery or neoadjuvant/primary chemotherapy, were excluded from the study. This study was approved by the local ethics committee of our faculty (meeting date: 13.04.2016 decision number: 2016/122) and written informed consent was obtained from all patients. 18 F-
fluorodeoxyglucose positron emission tomography/computed tomography scanning procedure
Images from the skull base to the midthigh were acquired in 8 or 9 bed positions with an acquisition time of 2 minutes per bed position with integrated 18 F-FDG PET/CT scanner (Biograph mCT, Siemens, Germany). Patients were advised to fast for at least 6 hours and 370 MBq of 18 F-FDG was injected to the patients whose blood glucose level was <200 mg/dl. PET/CT studies were performed 1 hour after the administration of the radiopharmaceutical. The CT part of the integrated scan was carried out without contrast enhancement by using 16 slice CT with the acquisition parameters of 190 mA, 5 mm slice thickness and 140 kV. Right after the CT imaging, PET scan was performed without changing the position. The CT data were used for the attenuation correction of PET scanning. Image analysis and quantification Acquired images of 18 F-FDG PET/CT were analysed on Siemens Syngo.via PET/CT workstation. For axillary involvement, lymph nodes showing 18 F-FDG uptake without fatty hilum were considered as metastatic. Any lesion showing 18 F-FDG accumulation in sites different from the primary tumor and axillary region presenting radiological aspects of metastases, were regarded as distant metastases. Tumor-to-background ratios (TBRs) were calculated in all breast tumors for semiquantitative analysis of tumor 18 F-FDG uptake. For this purpose, a region of interest was drawn around the site of the primary breast lesion. For background uptake, a
Please cite this article in press as: Gedik GK, et al. Relationship between primary tumour 18 F-FDG uptake and immunohistochemical and clinical prognostic parameters in breast carcinoma. Rev Esp Med Nucl Imagen Mol. 2016. http://dx.doi.org/10.1016/j.remn.2016.09.006
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Table 1 Clinicopathological characteristics and results of patients.
Figure 1. A region of interest was drawn around the site of the primary breast lesion (thick arrow). For background uptake, a corresponding region of interest was drawn on the contralateral breast (thin arrow).
corresponding region of interest was drawn on the contralateral breast (Figure 1). From these regions of interest, maximum count rates as SUVmax were calculated. The SUV was calculated using the below formula: activity in the region of interest (MBq/ml)/injected dose (MBq/kg body weight). TBR was defined as SUVmax in primary tumor/SUVmax in background tissue. All the patients in this study were then enrolled to surgery with sentinel node biopsy or axillary dissection or to systemic therapy. Clinicopathological evaluation and Immunohistochemical analysis Clinical and immunohistochemical results including, histopathologic type of tumor, tumor size, axillar lymph node metastases, distant metastases, expression of ER, PR and c-erbB-2 receptor were reviewed. For histopathological type determination, modified Bloom-Richardson criteria was used. Immunohistochemical results of all patients were collected from the files of the patients and were classified as positive or as negative for ER, PR and c-erbB-2 receptor. For ER and PR, results were classified as positive when at least 10% of tumor cell staining was reported.1 For c-erbB-2, results were considered as positive when 2 or 3+ membrane staining or as negative when 0 or 1 + membrane staining was reported, as suggested in the literature.3,7 Statistical analysis Mann-Whitney U test was used to test the associations between mean TBRs and the prognostic parameters of tumor size, axillary lymph node metastases, distant metastases, ER, PR and c-erbB2 receptor status by using SPSS 16.0 statistical software package. Results were considered statistically significant at a p value of <0.05. Results The histology of the breast tumor in 58 patients was ductal type in 52 (90%), lobular in 4 (7%) and mucinous in 2 (3%). Since majority (90%) of patients had ductal type breast tumor, the significance of difference of TBRs between different types of breast tumors was not assessed. In 31 patients (53%) tumor size was ≤ 2 cm and in 27 (47%) it was > 2 cm. The levels of meanTBRs were not significantly different between the patients tumor groups of 2 cm or less and greater than 2 cm (p = 0.131). Twentytwo patients were reported to have axillary lymph node metastases with 18 F-FDG PET/CT and remaining 36 were reported as free of
18
F-FDG PET/CT analysis of
Number of patients (%)
Tumor to background ratio Mean (range)
P value
Histology ductal lobular mucinous
52 (90) 4 (7) 2 (3)
4.34 (1.23-11.48) 3.31 (2.5-5.35) 2.25 (1.78-2.73)
Tumor size ≤2 cm >2 cm
31 (53) 27 (47)
2.27 (1.50-10.37) 2.40 (1.23-11.48)
0.131
Axillary lymph node metastases 22 (44) Negative 28 (56) Positive
3.66 (1.23-8.79) 4.90 (1.39-11.48)
0.065
Distant metastases 35 (60) Negative 23 (40) Positive
3.84 (1.23-10.37) 4.74 (1.55-11.48)
0.123
ER Negative Positive
17 (29) 41 (71)
5.36 (1.50-11.48) 3.72 (1.23-7.45)
0.050
PR Negative Positive
25 (43) 33 (57)
5.04(1.50-11.48) 3,56 (1,23-7,14)
0.020
c-erbB-2 Negative Positive
17 (31) 39 (69)
5.14 (1.50-11.48) 3.91 (1.23-7.37)
0.107
-
axillary involvement. Pathologic examination revealed metastases in 6 of 36 patients who were negatively reported in terms of axillary lymph node metastases with 18 F-FDG PET/CT. In 22 of 36 patients, absence of metastases was confirmed by pathology. In the remaining 8 patients, pathological clarification of axillary lymph node status could not be identified. So statistical analysis investigating the association between 18 F-FDG uptake and prognostic parameters was performed over 50 patients including positively reported 22 patients with 18 F-FDG PET/CT and 28 patients in whom absence or presence of metastatic disease was proved by pathology. Finally there were 28 patients with axillary lymph node involvement (56%, Figure 2) and 22 (44%) without metastases. There was no significant difference between levels of TBR with regards to axillary lymph node involvement (p = 0.065). Distant metastases were observed in 23 patients (40%, Figure 3) and distribution of metastases were mediastinal lymph nodes in 11 patients, bone in 10, lung in 4, liver in 2 and cervical and supraclavicular lymph nodes in 4 patients. The difference of mean TBRs between patients with and without distant metastases was not statistically significant (p = 0.123). ER expression was observed in 41 (71%, Figure 2) patients and in 17 patients (29%, Figure 4a-c) ER status was negative. The difference was at the level of significance in values of TBRs between patients with ER negative tumors and in patients with ER positive tumors (p = 0.050). PR expression was observed in 33 patients (57%, Figure 4d-f) and 25 patients (43%) were PR negative. In patients with PR positive and PR negative tumors, the mean levels of TBRs were 3.56 (range: 1.23-7.14) and 5.04 (range: 1.50-11.48), respectively. With regard to PR receptor status, statistically significant difference was observed in mean TBR levels between patients with and without PR expression (p = 0.020). The results of c-erbB-2 analyses could be reached in 56 patients, among these, c-erbB-2 positivity was reported in 39 patients (69%) and receptor expression was not reported in 17 (31%) of them. The difference of levels of TBRs in patients with and without c-erbB-2 expression was not statistically significant (p = 0.107). The results of 18 F-FDG PET/CT analysis and clinicopathological characteristics of patients are summarized in Table 1.
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Figure 2. Transaxial PET (a), CT (b) and fusion (c) images of 18 F-FDG PET/CT study of sixty-one years old patient; ER, PR and c-erbB-2 receptor status positive patient with ductal type breast carcinoma (arrow, c). TBR of the primary tumor was calculated as 6.60. Distant and left axillary lymph nodes metastases were recognized in this patient. Transaxial PET (d), CT (e) and fusion (f) images from the lower demonstrates the metastatic left axillary lymph nodes (arrow, f).
Figure 3. Transaxial PET (a), CT (b) and fusion (c) images of 18 F-FDG PET/CT of a seventy-two years old patient with ductal type carcinoma in left breast (arrow, c). Calculated TBR of the primary tumor was 7.41. ER and PR negativity, c-erbB-2 positivity, axillary nodal involvement and distant metastases were noted about this patient. Transaxial PET (d), CT (e) and fusion (f) images of 18 F-FDG PET/CT of the same patient from the lower part, depicts metastatic liver lesion at the dome of the liver (arrow, f).
Discussion 18 F-FDG PET/CT is a noninvasive modality of imaging of glucose metabolism and plays a significant role in diagnosis, staging, detecting recurrences and monitoring response to therapy in variety of malignant tumors. Besides enabling visual interpretation, it gives quantitative information about the level of metabolic activity of the tumor by calculating the degree of 18 F-FDG uptake known as SUV. In breast carcinoma, 18 F-FDG uptake shows variability and lower SUVs than in other malignancies have been reported.7 The role of histologic type in this wide range of sensitivity of 18 F-FDG PET/CT has been evaluated in breast carcinoma and pooled results supported that 18 F-FDG uptake is higher in ductal breast cancer than
in lobular cancer.3,8 Concordant with the results reported in the literature, 18 F-FDG accumulation was found higher in ductal type compared to lobular and mucinous type breast carcinomas also in our study (4.34 vs 3.31 and 2.25, respectively). But due to the low number of patients in lobular and mucinous group, statistical analysis was not performed and the correlation of TBR with histologic type was not assessed. Although providing useful information in most patients with breast carcinoma, the limited role of 18 F-FDG PET/CT in primary breast cancer detection, caused to raise questions about the prognostic relevance of the level of 18 F-FDG uptake in breast cancer. Association between 18 F-FDG accumulation in primary breast tumor and other clinical and biological prognostic parameters have
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Figure 4. A forty-six years old, estrogen and progesterone receptor status negative patient. Transaxial PET (a), CT (b) and fusion (c) images of 18 F-FDG PET/CT shows the primary tumor in the left breast (c, arrow). Neither distant nor axillary lymph nodes metastases were not observed. Calculated TBR of the primary tumor was 8.79. Transaxial PET (d), CT (e) and fusion (f) images of 18 F-FDG PET/CT scanning of another patient shows ductal type breast carcinoma in the right breast (arrow, f). Calculated TBR was 2.6. ER and PR expression was positive and no distant and axillary lymph nodes were shown with 18 F-FDG PET/CT.
been investigated. In the study conducted by Dehdashti et al.,5 the relationship between metabolic activity of breast cancer and ER status was investigated and no association between SUVs for 18 F-FDG in malignant lesions and ER status was demonstrated. Although depicting a positive correlation between histologic tumor type and 18 F-FDG uptake, taking clinical prognostic parameters also into analysis, Avril et al.,9 could not find a correlation with SUVs and axillary lymph node status, tumor size, expression of ER and PR of the tumor. Similarly, Crowe et al.10 et al. and Buck et al.11 , was not able to demonstrate any correlation between 18 F-FDG uptake in breast tumor and ER and PR receptor status, axillary metastases and tumor size. On the contrary to these results, Ueda, Gil-Rendo and Kim et al.3,4,8 , reported that tumor size, axillary lymph node status, histologic grade and estrogen receptor status were significantly related to SUV and a positive association between SUV and prognostic parameters were shown. Besides reporting an association with increased SUV and ER and PR negativity, Koolen et al.1 , also demonstrated that presence of distant metastases at staging examination was significantly associated with higher SUV of the primary tumor. In the light of these conflicting results reported in the literature, we investigated the probable relationship between tumor 18 F-FDG uptake and other clinicopathologic prognostic parameters in breast carcinoma. However, instead of SUV, we used TBR as a quantitative method for tumor 18 F-FDG uptake. With regard to clinical prognostic factors, we could not find any correlation of TBR with tumor size, axillary lymph node involvement and presence of distant metastases. PET imaging has been reported to have a low sensitivity for detecting small breast carcinomas which is partly due to partial volume effect and partly to increased metabolic activity with tumor growth. Higher 18 F-FDG uptake in tumors greater than 2 cm in diameter than those smaller than 2 cm was reported by Gil-Rendo, Ueda and Kim et al.3,4,8 . However, in our study, we did not recognize a relationship between 18 F-FDG accumulation and tumor size which is consistent with the results of other groups1,9–11 . The status of axillary lymph nodes is the most important prognostic factor in breast carcinoma.12 Expecting a relation between metabolic rate of primary tumor measured with 18 F-FDG PET/CT and tumor spread to axilla, in some conducted studies it has
been shown that significant correlation exists between high SUV level of the primary tumor and positive axillary lymph node metastases.3,4,8 Moreover, García Vicente et al.,12 analysed the relation of biologic prognostic factors and 18 F-FDG uptake of lymph nodes and reported that bad prognostic biological factors including negative ER status were correlated with higher levels of SUV which revealed biological significance of lymph node 18 F-FDG accumulation. In our study, the difference of mean TBRs of primary tumors between patients with positive axillary lymph metastases and cases with node negative tumors, did not reach a significant level. Absence of this correlation was also noted by Avril et al.,9 Crowe et al.10 and Buck et al.11 . An association of higher SUV of primary tumor and presence of distant metastases at staging examination was demonstrated by Koolen et al.1 . Morris et al.,13 examined the prognostic role of SUV max calculated in metastatic tissue in patients with newly diagnosed metastatic breast cancer. Emphasizing not assessing the TBR as a limitation of their study, they concluded that an increased SUV max in bone was correlated with inferior survival. In our study, like other clinical prognostic factors, no association was observed between the mean levels of TBRs of primary tumors in patients with and without distant metastases. With regard to biological prognostic factors, consistent with the most previous reports, c-erbB-2 receptor status was not found to be associated with 18 F-FDG accumulation in our study.1,4,8,11 It is postulated that c-erbB-2 receptor status might not have any influence on glycolytic pathway.8 However, Ueda et al.3 , demonstrated a positive association with positive c-erbB-2 receptor expression and degree of 18 F-FDG uptake. When state of ER status was taken into consideration, the difference of mean TBRs between patients with ER positive and negative tumors was found at the level of significance. Interestingly, in our study statistically significant difference of mean TBRs was only observed between levels of patients with and without PR expression. This solely significance of PR state of tumor and 18 F-FDG uptake was also demonstrated by García Vicente et al.12 in 18 F-FDG accumulated metastatic axillary lymph nodes. Except the correlation between PR state and level of 18 F-FDG uptake, our results were concordant with the results of 2 groups
Please cite this article in press as: Gedik GK, et al. Relationship between primary tumour 18 F-FDG uptake and immunohistochemical and clinical prognostic parameters in breast carcinoma. Rev Esp Med Nucl Imagen Mol. 2016. http://dx.doi.org/10.1016/j.remn.2016.09.006
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who used TBR as a quantitative method for calculating the degree of 18 F-FDG uptake, like us.10,11 In all of these two studies, in which TBR was calculated as an index of tumoral 18 F-FDG uptake, 18 FFDG PET scanner was used.10,11 The unusual point of our study was using current 18 F-FDG PET/CT device as a scanner and taking background activity into consideration while calculating tumoral 18 F-FDG uptake. The discordancy of our results and other groups who used TBR, about the correlation of degree of 18 F-FDG uptake and PR status, may be secondary to omitting or using different techniques for attenuation correction.10,11 Quantitative assessment is generally recommended as a complementary way of visual image interpretation and also plays role in reducing interobserver variability. In breast carcinoma it is shown that, various quantitative analysis methods including, SUV max, mean SUV of the lesion (SUV mean) and TBR, provides stable parameters for differentiation of benign and malignant breast tumors.14 However, SUV is subjective to sources of variability such as glucose level, body weight, recovery coefficient and partial volume effect.15 Moreover, since PET/CT devices differ, length of uptake period is not standardized so caution must be taken while drawing conclusions from direct comparisons between studies. Some of these factors such as time of measurement of SUV after tracer injection and normalization to patient’s blood glucose level at the time of tracer administration can be standardized. But in addition to these technical factors, when the case is breast carcinoma, patients will have a history of diagnostic biopsy and this may cause inflammatory reaction which may contribute to the measured uptake in the tumor lesion. Animal studies showed that inflammatory cells significantly contribute to 18 F-FDG uptake in tumors.9 Kubota et al.16 reported that, up to 29% of 18 F-FDG uptake comes from non tumoral granulation tissue around the tumor. That’s why we wanted to exclude the interference of background activity from the SUV calculation, analyzed TBR as an indicator of disease activity and used SUV max instead of SUV mean which is operator dependent. In our study mean of the calculated background SUV max levels was found as 2.00. We thought that this level may interfere with the tumoral 18 F-FDG uptake and may cause false decisions to be drawn about its metabolic rate and biologic aggressiveness. Results about correlation of 18 F-FDG uptake and clinical prognostic parameters supported our hypothesis and none of the clinical prognostic parameters were found to be associated with degree of 18 F-FDG uptake. However, PR state of tumor still remained to be associated with level of 18 F-FDG accumulation and the results of statistical analysis with regard to ER expression was at the level of significance. This may be secondary to low number of ER negative patients in our study, if there were more patients with ER negative tumors, the calculated value might reach the significant level. The small number of individuals composing each subgroup analysed may also have an effect on the results of statistical analyses so the lack of significance of 18 F-FDG uptake and clinical prognostic factors and erbB-2 receptor status can be explained by the small number of patients in subgroups. The limitation of our study was its retrospective origin which reduced the number of patients and caused heterogeneity. The accessibility of results of immunohistochemistry of the primary tumor was also limited in some patients. Since currently any standardized method exists for partial volume effect correction and SUV or TBR is affected by partial volume effects, another important limitation of our study was the probability of underestimation of 18 F-FDG uptake in small tumors.
In conclusion background corrected 18 F-FDG uptake in primary breast tumor is associated with PR negativity. There may also be an association between ER receptor status and TBR. The effect of background activity on tumoral 18 F-FDG uptake should be tested in other studies with larger number of patients in order to reach definite conclusions about prognostic significance of 18 F-FDG accumulation and correlation of 18 F-FDG uptake with clinical prognostic parameters. Conflict of interest None declared References 1. Koolen BB, Vrancken Peeters MJ, Wesseling J, Lips EH, Vogel WV, Aukema TS, et al. Association of primary tumour FDG uptake with clinical, histopathological and molecular charactestics in breast cancer patients scheduled for neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging. 2012;39:1830–8. 2. Ohara M, Shigematsu H, Tsutani Y, Emi A, Masumoto N, Ozaki S, et al. Role of FDG PET/CT in evaluating surgical outcomes of operable breast cancer-Usefulness for malignant grade of triple-negative cancer. Breast. 2013;22:958–63. 3. Ueda S, Tsuda H, Asakawa H, Shigekawa T, Fukatsu K, Kondo N, et al. Clinicopathological and prognostic relevance of uptake level using 18 Fflurodeoxyglucose positron emission tomography fusion imaging (18 F-FDG PET/CT) in primary breast cancer. Jpn J Clin Oncol. 2008;38:250–8. 4. Gil-Rendo A, Martinez-Regueira F, Zornoza G, Garcia-Velloso MJ, Beorlegui C, Rodriguez-Spiteri N. Association between 18 F-flurodeoxyglucose uptake and prognostic parameters in breast cancer. Br J Surg. 2009;96:166–70. 5. Dehdashti F, Mortimer JE, Siegel BA, Griffeth LK, Bonasera TJ, Fusselman MJ, et al. Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays. J Nucl Med. 1995;36:1766–74. 6. Chaudhary L, Jawa Z, Szabo A, Visotcky A, Chitambar CR. Relevance of progesterone receptor immunohistochemical staining to oncotype DX recurrence score. Hematol Oncol Stem Cell Ther. 2016;9:48–54. 7. Mavi A, Cermik TF, Urhan M, Puskulcu H, Basu S, Yu JQ, et al. The effects of estrogen, progesterone and C-erbB-2 receptor states on 18 F-FDG uptake of primary breast cancer lesions. J Nucl Med. 2007;48:1266–72. 8. Kim YH, Lee JA, Baek JM, Sung GY, Lee DS, Won JM. The clinical significance of standardized uptake value in breast cancer measured using 18 F-flurodeoxyglucose positron emission tomography/computed tomography. Nucl Med Commun. 2015;36:790–4. 9. Avril N, Enzel M, Dose J, Schelling M, Weber W, Janicke F, et al. Glucose metabolism of breast cancer assessed by 18F-FDG PET: Histologic and immunohistochemical tissue analysis. J Nucl Med. 2001;42:9–16. 10. Crowe JP, Adler LP, Shenk RR, Sunshine J. Positron emission tomography and breast masses: comparison with clinical, mammographic and pathological findings. Ann Surg Oncol. 1994;1:132–40. 11. Buck A, Schirrmeister H, Kühn T, Shen C, Kalker T, Kotzerke J, et al. FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters. Eur J Nucl Med. 2002;29:1317–23. 12. García Vicente AM, Soriano Castrejón A, Cruz Mora MA, González Ageitos A, ˜ Munoz Sánchez Mdel M, León Martín A, et al. Semi-quantitative lymph node assessment of 18F-FDG PET/CT in locally advanced breast cancer: correlation with biological prognostic factors. Eur J Nucl Med Mol Imaging. 2013;40: 72–9. 13. Morris PG, Ulaner GA, Eaton A, Fazio M, Jhaveri K, Patil S, et al. Standardized uptake value by positron emission tomography/computed tomography as a prognostic variable in metastatic breast cancer. Cancer. 2012;118: 5454–62. 14. Avril N, Bense S, Ziegler SI, Dose J, Weber W, Laubenbacher C, et al. Breast imaging with fluorine-18-FDG PET: quantitative image analysis. J Nucl Med. 1997;38:1186–91. 15. Wiyaporn K, Tocharoenchhai C, Pusuwan P, Ekjeen T, Leaungwutiwong S, Thanyarak S. Factors effecting standardized uptake value (SUV) of positron emission tomography (PET) imaging wih 18 F-FDG. J Med Assoc Thai. 2010;93: 108–14. 16. Kubota R, Yamada Kubota K, Ishiwata K, Tamahashi N, Ido T. Intratumoal distribution of fluorine-18- fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissue studied by microautoradiography. J Nucl Med. 1992;33:1972–809.
Please cite this article in press as: Gedik GK, et al. Relationship between primary tumour 18 F-FDG uptake and immunohistochemical and clinical prognostic parameters in breast carcinoma. Rev Esp Med Nucl Imagen Mol. 2016. http://dx.doi.org/10.1016/j.remn.2016.09.006