To Evaluate the Role of Positron Emission Tomography-Computerized Tomography in Initial Staging of Carcinoma Breast.

BACKGROUND: Breast cancer is the most common cancer in urban and second common in rural Indian women. In India, in spite of the best treatment available being given to the patients they lose their lives because of paucity of diagnostic aids and lack of an organized breast cancer screening program. Early detection, accurate staging, and initiation of appropriate therapy are the key factors for improving the treatment outcome and prognosis of the disease for the patients. Traditional staging methods include clinical examination, blood tests, chest X-ray, ultrasound of the abdomen, and/or skeletal survey. As these tests lack sensitivity and specificity, these are being scaled down. The hybrid positron emission tomography-computerized tomography (PET-CT) is a unique tool in the field of imaging modalities that combines the effectiveness of PET and CT. This study was undertaken to assess the efficacy and accuracy of PET-CT as a single-session staging modality in the very initial stage itself and if it can replace the conventional means of staging.
METHODS: This was a cross-sectional study conducted in the Radiotherapy department at GGS Medical College and Hospital Faridkot from March 2014 to October 2015. 52 patients with newly diagnosed and histopathologically proven carcinoma breast were staged by conventional modalities (clinical examination, blood tests, X-ray chest, mammography, ultrasonography abdomen, skeletal survey) and by 18F-fluorodeoxyglucose (18F FDG) PET/CT. PET-CT images were used for the detection, localization, staging of tumors and detection, evaluation, and diagnosis of metastatic lesions, disease burden and organ function along with treatment planning and planning therapeutic procedures. Following the completion of initial study, the results of 18F FDG PET-CT staging in comparison with conventional staging method were assessed. Along with this, the accuracy, changes in staging of cases of carcinoma breast and cost-effectiveness of 18F-FDG PET-CT were also studied.
RESULTS: All the pathologic entities identified by conventional imaging were also perceived with 18F-FDG PET/CT. Therefore, we recommend the use of PET/CT as an important imaging modality for initial diagnosis of carcinoma breast. Copyright:

INTRODUCTION

The incidence rates of breast cancer in India begin to rise in the early thirties and peak at ages 50–64 years.[1] According to Globocan Report 2018 number of newly detected cases of breast cancer in 2018, worldwide, were 20,88,849 out of which 626,679 expired due to the disease (i.e., 1 female for every 3-4 cases detected) while in India number of new cases of breast cancer detected in 2012 was 162,468 of which 87,090 expired (1 female for almost every 2 cases detected).[23]

Breast cancer strikes women of all ages, races, ethnicities, socioeconomic status, and geographical locales.[4] Due to the lack of an organized breast cancer screening program, and paucity of diagnostic aids breast cancer cannot be diagnosed at an early stage. A multidisciplinary approach to breast cancer treatment, that is so vital, is available only at a few select regional centers. Therefore, in spite of the best treatment that is available being given to the patients they lose their lives. Accurate initial staging of patients with breast cancer is essential for precise prognostication and optimal therapy.[56]

The hybrid positron emission tomography-computerized tomography (PET-CT) imaging is a unique tool in the field of diagnostic imaging modalities.[7] PET alone can stage/restage a cancer with accuracies in excess of 90% so there should be more gains with PET and CT combined. PET-CT appears to add an approximate 10% improvement in diagnostic accuracy.[8] The main advantage of PET-CT is its ability to measure not only morphological but also metabolical and biological behavior of the tissue.[7]

Lymph node involvement (axillary, supraclavicular, internal mammary) is the most important prognostic factor affecting local control, disease-free survival and overall survival.[9] Patients with multiple positive axillary lymph nodes show poor local control and require aggressive treatment like adjuvant chemotherapy.[10]

Fluorodeoxyglucose (FDG)-PET-CT is a noninvasive and accurate technique to predict axillary node status and prevent unnecessary axillary lymph node dissection/sentinel lymph node biopsy (SLNB) procedure.[1112] In patients with tumor size >2 cm the sensitivity of this procedure has been found to approach 97% and specificity 100% such that PET-CT positive axilla indicates complete axillary lymphnode dissection instead of SLNB.[1013] Sensitivity and specificity in detecting axillary lymph nodes were 41% and 92% by clinical evaluation.[14] SLNB cannot detect the status of the extra axillary lymph nodes (internal mammary and supraclavicular).[1516] However, PET-CT was found to detect all the extra axillary lymph nodes resulting in up gradation of the TNM stage and change in treatment modality.[171819]

The sensitivity and specificity of PET-CT to detect metastasis in lungs, liver, bone etc., have been found to be 100% and 98%, respectively, whereas, it was 60% and 83% with conventional imaging techniques (such as chest X-ray, ultrasonography [USG], mammography etc.,) which led to change in initial staging in 42% of patients in one of the studies.[17181920] FDG PET-CT is known to detect osteoblastic and osteolytic bone metastases which have been missed even by bone scintigraphy due to superior spatial resolution and improvised sensitivity.[2122] Detection of multi focal and multicentric disease, detection, and evaluation of proliferative activity (aggressiveness of primary breast tumors) by studying the rate of FDG uptake also has an important role in assessment of T, N and M staging of carcinoma breast. The detection of distant metastasis upstages the disease and therefore changes the treatment modality and has poorer prognosis.[21]

Therefore, we propose to study in our thesis the efficacy, cost-effectiveness, reliability, sensitivity, and specificity of PET-CT for staging of carcinoma breast in a single step at the very initial stage as compared to the conventional multiple modalities of staging based on clinical examination and imaging.

MATERIALS AND METHODS

A total of 52 patients with newly diagnosed and histopathologically proven carcinoma breast were staged by conventional modalities and by 18-F FDGPET/CT. All patients had a conventional work up which included (clinical examination, blood tests, X-ray chest, mammography, USG abdomen, skeletal survey) as is the norm followed in our institution. The patients were then assessed by 18F-FDG PET/CT. PET-CT is available at the Department of Nuclear Medicine G. G. S. Medical College and Hospital, Faridkot. The images are used in:

The detection, localization, and staging of tumors.

The, detection evaluation, and diagnosis of metastatic lesions, disease burden, and organ function.

Treatment planning and planning therapeutic procedures.

18-F FDG PET/CT scans were interpreted by 2 nuclear medicine specialists independent of the results of conventional imaging.

The patients were assessed for size of primary tumor, multifocality, axillary and extra axillary lymph nodes and distant metastasis. In bone lesions, CT findings (location [cortex, medulla, or both], morphologic changes [none, nonspecific, osteolytic, osteoblastic], and the presence of an osteosclerotic rim, associated soft-tissue mass, and/or bone destruction) were documented.

Any pulmonary nodule with increased 18F-FDG uptake or increased mitotic activity nodules was considered as suggestive. All the findings considered suggestive of malignancy were confirmed with biopsy, further work up or follow-up. For bone foci, skeletal X-ray/follow-up CT was performed instead of biopsy.

Following the completion of initial study, the results of 18F FDG PET-CT staging in comparison with conventional staging method were assessed. Along with this the accuracy, changes in staging of cases of carcinoma breast and cost effectiveness of 18F-FDG PET-CT were also studied. The statistical analysis was done using an appropriate statistical analysis package and P < 0.5% was considered significant.

RESULTS

The patient characteristics are shown in Table.

Conventional methods detected lung metastasis, liver metastasis, bone metastasis, ovarian metastasis, skin metastasis in two (3.8%), two (3.8%), three (5.8%), one (1.9%), and twenty seven (52%) patients, respectively. Whereas PET CT detected lung metastasis, liver metastasis, bone metastasis, ovarian metastasis, skin metastasis in six (11.5%), six (11.5%), fourteen (26.9%), three (5.8%) and thirty one (59.6%) patients, respectively. Figure 1 shows the Graphical presentation of satellite nodule. Figure 2 shows the Graphic representation of performance of conventional imaging versus positron emission tomography-computerised tomography in detecting nodal metastasis in overall series of 52 patients compared with confirmatory methods. Figure 3 shows the graphical representation of distribution of patients according to the change of stage. Table 1 shows demographic and clinical data and Table 2 shows the distribution of patients according to multifocality.

Figure 1

Graphical presentation of satellite nodule

Figure 2

Graphic representation of performance of conventional imaging versus positron emission tomography-computerised tomography in detecting nodal metastasis in overall series of 52 patients compared with confirmatory methods

Figure 3

Graphical representation of distribution of patients according to the change of stage

Table 1

Demographic and clinical data

Characteristic	n (%)
Age
20-40	17 (32.7)
41-60	27 (51.9)
>60	8 (15.4)
Breast feeding
Yes	51 (98.1)
No	1 (1.9)
Laterality
Right	23 (44.2)
Left	29 (55.8)
Quadrant involved
Upper outer	24 (46.2)
Upper inner	7 (13.5)
Lower outer	8 (15.4)
Lower inner	5 (9.6)
Central	8 (15.4)
Menstrual status
Nonmenstruating	1 (1.9)
Premenopausal	18 (34.6)
Postmenopausal	33 (63.5)
Histology
Infiltrating ductal carcinoma	34 (65.4)
Infiltrating lobular carcinoma	1 (1.9)
Mucinous carcinoma	2 (3.8)
Others	15 (28.8)

Table 2

Distribution of patients according to multifocality

Characteristics	Conventional		PET-CT
	Yes, n (%)	No, n (%)	Yes, n (%)	No, n (%)
Total number of patients detected	1 (1.19)	51 (98.10)	13 (25)	39 (75)
Sensitivity (%)	7.14		92.86
Specificity (%)	100.0		100.0
PPV (%)	100.0		100.0
NPV (%)	74.51		97.44
Accuracy (%)	75.0		98.1

PET-CT: Positron emission tomography-computerised tomography, PPV: Positive predictive value, NPV: Negative predictive value

DISCUSSION

18F-FDG PET/CT a dual modality imaging technique combining the anatomical advantage of CT with morphological assessment by PET can be of immense use in accurate staging of carcinoma breast. Though NCCN guidelines currently do not recommend the routine use of PET/CT for early-stage breast cancer but in a study of 60 breast cancer patients, found a sensitivity of 100% for FDG-PET-CT versus 60% for conventional imaging; for specificity, these values were 98% versus 83%.[22] Up to 42% of patients have been reported to be up staged or down staged with FDG-PET(-CT), with change of treatment in 10%–30% of the patients.[222324252627] FDG-PET/CT is also much more convenient with respect to logistics. It requires only one examination, while conventional staging takes at least three examinations Furthermore, due to the relatively poor specificity of conventional staging, additional diagnostic procedures are often needed to deny or confirm metastasis, causing distress and delay of the start of treatment.

Multifocal disease was identified in 13 out of 52 patients (25%). Groves et al.[28] in their study on defining role of PET-CT for early-stage breast cancer also reported PET-CT identifying 7 cases of multifocal disease out of a total of 70 patients. These lesions were missed by mammography. Multifocal disease was confirmed by histopathology. Therefore, our study correlates well with studies conducted by others worldwide. They also reported that identification of multifocal disease impacted patient management as these patients had to undergo mastectomy instead of wide local excision.

Skin involvement was identified in 31 out of 52 patients (59.6%) whereas conventional methods identified skin involvement in 21 patients (51.9%) and were false-negative in 10 patients.

Axillary nodal metastasis was identified in 39 (75%) patients by PET-CT and in 38 (73.1%) patients by conventional methods and confirmed by subsequent histopathology. PET CT sensitivity was 100% and specificity was 86.7% with an accuracy of 96.2% and conventional methods had sensitivity of 89.19% and specificity of 66.7% and accuracy of 82.7%. Marco Greco and Flavio Crippa[17] in their study reported an overall sensitivity of 94.4% and accuracy of 89.9%. NPV was found to be 95.3%. They concluded that FDG PET can safely predict axillary nodal status and is a reliable and accurate noninvasive method. Fuster et al.[22] have also reported a sensitivity and specificity of 70% and 100% for detection of axillary lymph nodes by PET/CT. The reason for high sensitivity and specificity for conventional methods in our study could be due to 42.3% patients (22/52) presenting in locally advanced stage III, when there are increased chances of palpable axillary nodal metastasis.[29] Similarly, supraclavicular lymph nodes were identified in 3 (5.76%) patients by conventional methods but only one was true positive and the other two (3.84%) were false positive and PET/CT identified supraclavicular lymph nodes in 5/52 (9.6%) patients, and all were true positive.

In our study, conventional methods identified no infraclavicular or internal mammary whereas PET/CT identified infraclavicular nodes in 5/52 (9.6%). Jager et al.[30] have also stated in their study that infraclavicular and internal mammary lymph nodes are only detected by PET/CT compared to conventional methods which compares well with our results. Moreover, it has been suggested that metastases to the IMC might be associated with a two-fold risk of relapse and breast cancer death,[31] which might indicate a potential impact for PET/CT on adequate therapy.

Therefore, FDG PET/CT had a higher yield as compared to conventional methods in detecting nodal metastasis, both axillary and extra axillary.

Distant metastasis was identified in 21 out of 52 patients (40.38%) by PET-CT whereas conventional methods detected distant metastasis in only 6 cases (6.5%). Fuster et al.[22] have reported an overall sensitivity and specificity of 100% AND 98% for PET/CT for the detection of distant metastasis while sensitivity and specificity for conventional methods was 60% and 83%, respectively, and similarly other studies[323334] have favored PET-CT over conventional methods for detecting distant metastasis.

We found 27 (51.9%) patients were upstaged and 7 (13.46%) patients were down staged and 18 (34.61%) patients had no change of stage. Maximum upstaging was seen in patients presenting in stage IIIB (60.86%). Total patients who had a change of stage were 34 (65.38%) which is approximately equal to 42% reported by Fuster et al.[22] in 2008. However, Manohar et al.[34] have shown a change of stage in only 39.5% of patients. The reason could be attributed to the late presentation of patients in locally advanced stages and false-positive detection of primary tumor by PET/CT in two patients.

In our study, 12 (23.07%) patients had a change of treatment modality due to upstaging of tumor which is consistent with the findings of Jager et al.[30] and Groheux et al.[24] who reported a change of treatment modality in 13%–31% of patients. In our study, no correlation was found between age of the patient and change of stage of disease.

CONCLUSION

Our study substantiates the use of PET/CT as an important diagnostic and staging modality for patients of carcinoma breast especially for the diagnosis of extra-axillary nodal metastasis and distant metastasis. Bones were found to be the most common site of distant metastasis. PET/CT helps to accurately stage the disease so that appropriate therapeutic modality can be given to the patient at the right time and save the patient from undue stress and anxiety. It also helps to confirm the diagnosis made by conventional methods as it combines anatomical details with the morphological details.

PET/CT also obviates the need for multimodality examination as it can image all the viscera at one time. Moreover, it is a noninvasive procedure with a high sensitivity and specificity.

The limitations of our study were that all the sites of distant metastasis identified by PET/CT could not be confirmed histopathologically. The identification of metastasis in mediastinal lymph nodes, especially is a grey zone. It is difficult to confirm mediastinal lymphadenopathy as benign due to infective or inflammatory disease or malignant due to metastasis due to high prevalence of tuberculosis and other infective diseases in this region. However, the use of dual time point PET/CT and newer advances over time may help to overcome this dilemma to a great extent.

Therefore, we recommend the use of PET/CT as an important imaging modality for initial diagnosis of carcinoma breast.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.