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Interpreting discordance on dual-tracer positron emission tomography–computed tomography in the setting of metastatic neuroendocrine tumor: Detection of metachronous triple-negative breast carcinoma

Second primary malignancies (SPMs) are known to be associated with neuroendocrine tumors (NETs). The association necessitates a careful assessment of the dual‐tracer positron emission tomography–computed tomography (PET‐CT) imaging findings to identify these malignancies earlier. Such early diagnosis can provide incremental benefit for screening these SPMs apart from their known applications in the management of NETs. A case of incidentally detected metachronous triple-negative breast carcinoma on dual-tracer PET-CT imaging is presented using 18fluoro-2-deoxy-D-glucose (FDG) and 68Ga-DOTATATE that showed a high uptake on FDG but no uptake on somatostatin receptor-based imaging.


INTRODUCTION
Second primary malignancies (SPMs) have been reported in the literature in association with neuroendocrine tumors (NETs). In one of the reports, metachronous breast cancer was found in 13% of patients suffering from NETs. [1] With an increasing number of somatostatin receptor (SSTR)-targeted imaging studies being performed, there is a rising incidence of NETs being reported. Dual-tracer positron emission tomography-computed tomography (PET-CT) ( 68 Ga-DOTATATE and 18 fluoro-2-deoxy-D-glucose [FDG]) is frequently undertaken in the evaluation and management of NETs. There has been also report of SSTR 2-based inhibitory signalling in breast cancer cells. [2] We herein present a case of metastatic NET who developed a metachronous breast malignancy that was indicated by finding of discordance on dual-tracer PET-CT and hence was diagnosed despite being very small in size.

CASE REPORT
A 53-year-old woman with metastatic NET from jejunal primary underwent surgery in the form of jejunal resection-anastomosis and adhesiolysis 3½ years previously. The histopathology was suggestive of well-differentiated NET, Grade II with MIB-1 labeling index of 1%. She presented with hepatic and mesenteric nodal metastases 2 years subsequent to her surgery. She was initially treated with long-acting octreotide for flushing and abdominal pain but had poor control of functioning symptoms. Hence, in view of biochemical and symptomatic poor control and Ga-DOTATATE avid [ Figure 1]. In view of this finding, she was advised mammogram which showed a BIRADS category 4C lesion in the inner central region of the left breast [ Figure 2]. Biopsy from the lesion was suggestive of triple-negative infiltrating ductal carcinoma, Grade III. Subsequently, she underwent left modified radical mastectomy and is now being planned for chemoradiation. The findings of discordance on dual-tracer PET-CT compared to other metastatic lesions in the patient in the present case were noteworthy that warranted clinical suspicion and further radiological and pathological evaluation.

DISCUSSION
The present case study underscores the importance of appropriate interpretation of dual-tracer noninvasive molecular imaging methods for in vivo characterization of lesions in patients of metastatic NET. The role of dualtracer PETCT in the setting of evaluation of NETs has been reported in the literature earlier including detection of breast metastasis, [3] and incidental detection of SPMs, including breast cancer; [4] there has been report of SSTRbased signalling and imaging in breast cancer. [2,5]  In this particular case, the absence of SSTR expression in a FDG-avid breast lesion raised a high suspicion of metachronous breast malignancy. Another point which needs to be highlighted is that as we performed dual-tracer PET-CT imaging as part of selective NET work-up, a subcentimeter-sized lesion was picked up earlier giving this patient access to early diagnosis and treatment before she would even become symptomatic. Appropriate interpretation of FDG PET-CT in conjunction with SSTR-based PET-CT thus would be of importance for some patients with NETs showing an inherent predisposition to SPMs. A larger study to critically look at the sensitivity and diagnostic values of such imaging in these patients is necessary to further clarify its role in the management.
A futuristic but relevant aspect that would be worth discussing is the biology of the lesion and the findings on SSTR-based PET imaging. A study by Chereau et al. [6] suggested that SSTR expression and SSTR-mediated imaging can differentiate low-grade breast cancer from high-grade ones. In our case of triple-negative breast carcinoma, the absence of uptake on SSTR-based 68 Ga-DOTATATE PET and the high uptake on 18 FDG was commensurate with the known aggressive biology of the disease. If the SSTR and glucose transporter receptor mismatch could be clinically explored in the future, it may open a new horizon of in vivo characterization of primary breast malignancies.

CONCLUSION
The appropriate interpretation of dual-tracer PET-CT with somatostatin analogs ( 68 Ga-DOTA-NOC/TATE and FDG) can lead to early identification of developing SPMs in patients with NETs and initiation of treatment for the second malignancy.

Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship
Nil.