ª Springer Science+Business Media New York 2014

Abdominal Imaging

Abdom Imaging (2014) DOI: 10.1007/s00261-014-0266-y

Metabolic signatures of malignant and non-malignant mass-forming lesions in the periampulla and pancreas in FDG PET/CT scan: an atlas with pathologic correlation Sampath Santhosh,1,5 Bhagwant Rai Mittal,1 Surinder Singh Rana,2 Radhika Srinivasan,3 Anish Bhattacharya,1 Ashim Das,4 Deepak Bhasin2 1

Department of Nuclear Medicine and PET, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India 3 Department of Cytology and Gynaecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India 4 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India 5 Institute of Nuclear Imaging and Molecular Medicine, Tamil Nadu Government Multi Super Specialty Hospital, Omandurar Government Estate, Chennai 600002, Tamil Nadu, India 2

Abstract Positron emission tomography (PET) has been used for the characterization of pancreatic and periampullary lesions. Pancreatitis-associated inflammation affecting only a portion of the pancreas gives the appearance of a mass lesion on imaging. Consequently, the differential diagnosis between cancer and pancreatitis becomes a commonly encountered problem. Traditionally, PET was interpreted as positive (to denote malignancy) if fluorodeoxyglucose (FDG) activity in the pancreas exceeded background activity and as negative (to denote benign) if activity was less than or equal to background activity. However, the specificity was limited with this method of interpretation. A relatively wide overlap has been reported between semiquantitative uptake values obtained in cancers and those in inflammatory lesions. Also, the qualitative (metabolic patterns) and quantitative variables (standardized uptake values) have been complementary and at sometimes controversial to each other in various clinical situations. There is paucity of data in the literature highlighting the role of FDG PET/CT in

The data and work originated from the Postgraduate Institute of Medical Education and Research, Chandigarh (India). However, the corresponding author is currently working in the Tamil Nadu Government Multi Super Specialty Hospital, Chennai (India). Correspondence to: Sampath Santhosh; email: santhosh610@yahoo. com

characterization of such mass lesions. The primary aim of this pictorial review is to list the various pathologic processes of pancreas and periampulla that could be studied with FDG PET/CT and recognize the different FDG uptake patterns and apply this information to characterize the different lesions affecting the pancreas and periampulla. We have also discussed the limitations of conventional imaging and advantages of FDG PET/ CT for the evaluation mass-forming lesions of the pancreas and periampulla. Key words: Pancreatic adenocarcinoma—Periampullary adenocarcinoma—Maltoma—Autoimmune pancreatitis—Lymphoma—FDG PET/CT

Pancreatic adenocarcinoma is the most common type of pancreatic cancer [1, 2]. Carcinoma of the ampulla may be difficult to differentiate from those arising from the head of the pancreas. Pancreatitis-associated inflammation affecting only a portion of the pancreas gives the appearance of a mass lesion on imaging. As chronic pancreatitis (CP) is a risk factor for pancreatic cancer, mass-forming pancreatitis is highly suspicious of pancreatic cancer. Consequently, the differential diagnosis between cancer and pancreatitis becomes a commonly encountered problem. The diagnostic issues include early detection, differentiation of malignant from benign tu-

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 1. F-18 FDG PET/CT images in a 60-year-old male presenting with 2 months history of abdominal pain. MIP image (A) shows focal FDG-avid lesion in the epigastrium (arrow, SUVmax 7.2), abdominal lymph nodes (curved arrow head), and a metastatic lesion in the liver (arrow head). Axial CT (B) and fused PET/CT (C) images show the lesion pan-

creatic head (arrow) with portal vein invasion; the rest of the pancreas was completely atrophic. Fused PET/CT (D) showing FDG avidity in the necrotic liver lesion (arrow head). FNA smear (E) from the pancreatic lesion shows malignant cells in a hemorrhagic background [H–E stain; O.M 9 400].

mors, and staging for resection [3]. Of the various imaging modalities, ultrasonography (USG), computed tomography (CT), and magnetic resonance imaging (MRI) are the mainstay of investigations for initial diagnostic work-up [4]. F-18 fluorodeoxy glucose (FDG) positron emission tomography (PET) has a good role in the evaluation of pancreatic mass when (i) CT is non-diagnostic, (ii) biopsy is equivocal or non-diagnostic, (iii) there is concurrent CP, and (iv) the lesion is cystic in nature. Traditionally, PET was interpreted as positive (to denote malignancy) if FDG activity in the pancreas exceeded background activity and as negative (to denote benignity) if activity was less than or equal to background activity [5]. A relatively wide overlap has been reported between semiquantitative uptake values obtained in cancers and those in inflammatory lesions. As for false-positive cases, active and chronic pancreatitis and autoimmune pancreatitis sometimes show high FDG accumulation and mimic pancreatic cancer [6]. In earlier days, standalone PET was used for studying metabolism of FDG in pancreatic lesions [5, 7–10]. A study published in 2001 analyzing data of various studies

reported average sensitivity and specificity of 94% and 90%, respectively, for the diagnosis of pancreatic cancer by FDG PET [11]. PET/CT is a technologic advancement of fusion imaging, aiming at precise anatomic localization of the FDG-avid lesions, which helps improve overall image interpretation, accuracy, and confidence. In addition, the CT component helps in identifying lesions that do not demonstrate FDG uptake [12]. There are limited data in the literature highlighting the role of FDG PET/CT in characterization of such lesions [13–15]. In this atlas article, we have tried to describe the metabolic signatures of different malignant and non-malignant mass-forming lesions in the periampullary region and pancreas in FDG PET/CT with pathologic correlation.

PET/CT imaging PET/CT imaging was done using a hybrid scanner (Discovery STE-16, GE healthcare, Milwaukee, USA). All patients were instructed to fast for a minimum period of 6 h before the study. Blood glucose level was checked before intravenous injection of FDG, and no patient

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 2. 42-year-old male presenting with 3 months history of jaundice and abdominal pain. MIP image (A) shows focal FDG uptake in the epigastrium (arrow). Axial CT (B) shows heterogeneously enhancing lesion (measuring 4.6 cm 9 3.9 cm) in the head of pancreas (arrow) and enlarged retroperitoneal nodes (black arrow); biliary stent in situ (C) is seen with dilated

proximal pancreatic duct. Fused PET/CT (D) image shows focal FDG uptake (arrow, SUVmax 14.9) in the pancreatic head, with physiologic uptake in the rest of the pancreas (E). Multiple foci of uptake are seen in the liver (A, E), suggesting liver metastasis. Pathologic specimen from the head of pancreas revealed poorly differentiated adenocarcinoma.

having glucose level >150 mg/dL was subjected to PET/ CT procedure. Approximately, 370 MBq of F-18 FDG was injected intravenously and at 60 min after injection, PET/CT imaging covering the upper torso from eyebrows to mid thighs was started. To distend bowel loops, a commercially available product PEGLEC, containing polyethylene glycol and electrolytes, diluted in 1–2 L of water was used as neutral oral contrast agent. Non-ionic iodinated contrast material was intravenously administered in all patients, unless it was contraindicated. An initial scout scan was acquired with 10 mA current. On the basis of patient’s body weight, 60–90 mL low osmolar non-ionic intravenous contrast material (Omnipaque, Iohexol injection 300 mgI/mL; GE Healthcare) was administered at a rate of 3.0 mL/s, and 20 mL saline flush was administered at a similar rate through a power injector. Whole-body venous-phase multidetector CT (from the skull to the mid thigh) was performed at a delay of 55–65 s. CT scan acquisition was done, with patient in shallow respiration using tube voltage of 120 kV and an automatically modulated current mode with section thickness of 3.75 mm, section interval of 3.75 mm, and pitch 1.375. An arterial phase image of the upper abdomen was obtained through bolus-tracking mechanism, especially for staging purposes and if there was any suspicion of neuroendocrine tumor.

After transmission scan, 3-D PET acquisition was done in 6–8 bed positions at 2 min per bed position, in the caudocranial direction. The axial PET images were reconstructed at slice thickness of 3.3 mm. Data obtained from CT acquisition were used for low-noise attenuation correction of PET emission data and for fusion of attenuation-corrected PET images with corresponding CT images. Transaxial, coronal, and sagittal images for visual and semiquantitative analysis of the data were corrected for dead time, decay, and photon attenuation, and reconstructed in a 128 9 128 matrix. Image reconstruction was done using iterative reconstruction (Ordered Subset Expectation Maximum) algorithm.

Interpretation of F-18 FDG PET/CT The reconstructed PET images in the standardized display intensity were analyzed visually. A lesion showing focally increased FDG uptake compared to the rest of the pancreas was considered to be neoplastic. Diffusely increased FDG uptake in more than one segment of the pancreas (e.g., head and body, or head and tail, or body and tail, or throughout the pancreas) in addition to the site of suspicion was considered to be benign. Focal or diffuse uptake was always visualized with good contrast in the maximum intensity projection (MIP) images. The

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 3. 61-year-old male presenting with 12 months history of loss of appetite and abdominal pain; CA 19.9–3562.4 U/ mL. MIP image (A) showing a solitary FDG-avid focus in the epigastrium (arrow) along with multiple FDG-avid foci (surface deposits) in the liver (arrow heads), suggestive of liver metastases. Axial CT (B) shows heterogeneous enhancing

mixed solid–cystic lesion (measuring 4.0 9 5.4 9 4.4 cm) in the tail of pancreas with focal FDG uptake (SUVmax 8.3) in fused PET/CT (C). Axial fused PET/CT (D) at a cranial section showing FDG avidity in the periphery of the lesion (arrow) and FNA (E) from this location showed cluster of malignant cells. [May-Grt‹ nwald-Giemsa stain; O.M 9 400].

lesion was also considered to be benign, if it showed no FDG avidity. Semiquantitative measurement was done by calculating maximum standardized uptake value (SUVmax), corrected by patient’s body weight. The volume of interest (VOI) was placed on the lesion with the highest FDG uptake to measure SUVmax.

Pancreatic lesions Tumors These are described as per the World Health Organization (WHO) classification of pancreatic tumors (Table 1) [16].

Pathological diagnosis Pathological diagnosis of suspected lesions was established by fine-needle aspiration (FNA) cytology and/or biopsy guided by endoscopic ultrasound (EUS), USG, or CT. Pathological examination of the resected surgical specimen was done for characterization and proper staging of lesions. The MIP, axial venous-phase CT, and axial fused PET/CT images were reviewed in all patients. One representative pathologic image (Figs. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) has been depicted for each category of lesions for pathologic correlation.

(1) Epithelial tumors (a) Malignant lesions: Intense focal activity in one segment of the pancreas is suggestive of malignancy and has been reported by many authors for differentiating from CP [17, 18]. Pancreatic adenocarcinoma shows focal hypermetabolism (Fig. 1, 2, 3, and 4). Based upon these criteria, a sensitivity of 93% and specificity of 90% of PET/CT for characterizing both pancreatic and periampullary lesions had been reported [19]. In comparison with the FDG uptake pattern, SUVmax has a lower sensitivity and specificity of 87.5% and 45%, respectively

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 4. 71-year-old male presenting with abdominal pain for 4 months; CA19.9–46,200 U/mL. MIP image (A) shows multiple FDG-avid foci that were localized to multiple hypodense liver lesions (curved arrows), multiple bones with sclerotic changes (arrow heads) and the epigastrium (arrow). Axial CT (B) showing heterogeneous lesion in the tail of pancreas (arrow). Axial fused PET/CT (C–E) showing intense FDG

uptake (SUVmax 8.1) in the tail (arrow in c), physiologic uptake in the rest of pancreas (D) and metastasis in the marrow of shaft of left femur (arrow in E). FNA from a liver lesion was consistent with metastatic adenocarcinoma. The patient was treated with palliative radiotherapy; however, the lesions progressed in a follow up PET/CT scan after 4 months (not shown).

[19]. About 40% of patients with pancreatic cancer diagnosed as resectable by preoperative imaging modalities turned out to be unresectable at the time of operation [20]. Accurate staging is possible with PET/CT, with the CT part helping in assessment of vascular invasion (Fig. 1) and PET in the assessment of distant metastasis to liver (Figs. 1, 2), peritoneum (Fig. 3), bone (Fig. 4), and other sites. Inflammatory changes in CP may result in local lymphadenopathy and vessel involvement, raising further concern for malignancy. This problem is compounded by the fact that adenocarcinoma often develops in the setting of CP, so that the two conditions may co-exist. When enlargement is focal with parenchymal changes due to chronic inflammation, it may be virtually indistinguishable from adenocarcinoma on the basis of morphologic features or enhancement pattern at MR imaging and CT [21]. But FDG PET/CT has a definite role in the evaluation of malignancy in patients with long-standing CP (Figs. 5, 6). In a study of 83 patients with long-standing CP, FDG PET was positive in

all the six (8%) patients who developed carcinoma [22]. Adenosquamous carcinoma of the pancreas also shows focal intense FDG uptake [19]. Pancreatoblastoma is an extremely rare primary pancreatic neoplasm of adolescence [23] and shows mild focal FDG uptake. An initial CT abdomen of an adolescent boy having abdominal pain showed bulky pancreatic head. FNAC from the pancreatic mass suggested a possibility of pancreatoblastoma, following which the patient was referred for PET/CT (Fig. 7). The metastatic lymph nodes in this condition also show mild FDG uptake, and FDG PET/ CT may be used for staging of pancreatoblastoma. (b) Premalignant lesions: FDG PET/CT is more accurate than conventional imaging techniques in distinguishing invasive from non-invasive intra-papillary mucinous neoplasm (IPMN), with sensitivity of 95% [24]. Although in our experience, one invasive IPMN did not show FDG uptake (Fig. 8); it is likely due to the high mucin content in this variety. In another study, malignant IPMNs showed significantly higher SUVmax

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 5. 48-year-old female with history of DM and CP presenting with abdominal pain for 3 months; CA 19.9–2659.0 U/ mL. MIP image (A) showing focal FDG uptake in the epigastrium (arrow). Axial CT (B) showing macro-calcification in the head of pancreas (arrow). Axial fused PET/CT (C) showing focal FDG uptake (SUVmax 6.0) in the head of

pancreas (arrow) in this patient with history of chronic calcific pancreatitis; rest of the pancreas (D) with calcification and dilated MPD shows physiological FDG uptake. Section of surgical specimen (E) shows infiltrating tumor arranged in glandular pattern [H–E stain; O.M 9 10].

(6.7 ± 3.6) than benign IPMNs (2.1 ± 1.0) (P < 0.001) [25]. These authors reported that PET/CT improves the limited efficacy of MDCT in determining malignant potential of pancreatic IPMN and may help determine the optimal treatment strategy [25]. IPMNs are classified into four subtypes based on their histomorphology and mucin phenotype, and varied degrees of malignant nature and prognosis among these subtypes have been shown [26]. Thus, there is a need for a larger prospective study with histologic correlation for accurate characterization of IPMN with FDG PET/CT. (c) Benign lesion: In a study of cystic lesions of pancreas with FDG PET, 31 of the 33 benign lesions (94%) showed no FDG uptake [27]. Simple cysts usually contain mucinous material and are metabolically inert (Fig. 9). The sensitivity and specificity of combined PET and CT images is comparable with or superior to either CT or PET alone in determining malignancy in cystic pancreatic lesions [28]. (d) Neuroendocrine neoplasm: These tumors account for only 1–2% of all neoplasms of the pancreas [29]. The WHO classifies neuroendocrine neoplasms into three categories as neuroendocrine tumor (NET), neuroendo-

crine carcinoma, and mixed adenoneuroendocrine carcinoma [30]. The neuroendocrine carcinomas are more aggressive and usually show intense FDG uptake (Fig. 10). FDG PET/CT has limited role in the evaluation of well-differentiated NET subtypes and is best achieved by Gallium-68 based tracers targeting the somatostatin receptor. (2) Mesenchymal tumor: Pleomorphic sarcoma of the pancreas has been rarely reported [31]. Patients with this tumor usually have poor survival [32], and this type of lesion shows focal intense activity (Fig. 11), suggesting a highly mitotic pathology. (3) Lymphoma: The pancreas is involved in 0.6% of cases of gastrointestinal tract NHL [33]. Primary pancreatic lymphoma is even rare, with a reported prevalence of 0.4% in a study of 1212 patients with NHL [34]. Focally increased FDG uptake in primary pancreatic lymphoma has previously been reported by Yoon et al. [35]. Pancreatic lymphoma can show focal (Fig. 12) or diffuse (Fig. 13) increased uptake depending upon the extent of involvement; these would be labeled as secondary and tertiary pancreatic lymphoma, respectively, based on the nomenclature proposed by Salvatore et al.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 6. 50-year-old male having chronic pancreatitis presenting with 4 months history of jaundice and abdominal pain. MIP image (A) shows focal FDG uptake in the epigastrium. Axial CT (B, C) shows heterogeneously enhancing lesion in the head of pancreas (arrow in B) and dilated pancreatic duct (arrow in C), with no definite calcific focus. Axial fused PET/

CT (D, E) showing focal FDG uptake (SUVmax 3.5) in the pancreatic head (arrow in D), with physiologic uptake in the rest of the pancreas (E). Surgical specimen revealed moderately differentiated adenocarcinoma in a background of chronic pancreatitis and negative nodes.

[36]. Conventional imaging modalities cannot differentiate between adenocarcinoma and lymphoma accurately. However, extra-nodal lymphomatous involvement, with secondary involvement of the pancreas, a characteristic pattern in whole-body PET/CT, and very high SUVmax values help in the diagnosis of lymphoma.

ductal dilatation. CP often manifests, as mass-forming pancreatitis and different patterns of FDG uptake will help arrive at a diagnosis non-invasively. Non-active pancreatitis hardly shows any FDG uptake (Fig. 15) or no FDG uptake at all (Fig. 16). A negative PET in a patient with elevated C-reactive protein (CRP) levels excludes both a pancreatic malignancy and localized active inflammatory disease [8]. Whenever there is acute on chronic pancreatitis, diffusely increased FDG uptake is seen throughout the pancreas (Fig. 17). In such situations, a co-existing adenocarcinoma can be missed because of the diffuse FDG uptake. Peripancreatic inflammatory cystic collection, a complication of pancreatitis, also show intense FDG uptake (Fig. 18); in this instance, extreme caution is needed in differentiating it from a metastatic necrotic lymph node in pancreatic carcinoma. In the above two examples, inflammatory markers like CRP, total leucocyte count, and erythrocyte sedimentation rate can assist in the diagnosis of pancreatitis. PET/CT has a negative predictive value of 100% in ruling out malignancy [19]. (iii) Pseudocyst: It shows a characteristic picture (Fig. 19) of peripheral uptake (corresponding to the thin inflammatory wall) with a central area of absent tracer

B) Pseudotumors/Inflammatory lesions. (i) Autoimmune pancreatitis (AIP): Patients with AIP and pancreatic cancer share many clinical features [37], with a substantial proportion of the former undergoing unnecessary major surgery [38]. Kamisawa et al. [39] suggested that AIP is a pancreatic lesion involved in IgG4-related systemic disease. Patients with AIP frequently have extra-pancreatic lesions; diffuse uptake of FDG (Fig. 14) by the pancreas alongwith concomitant extra-pancreatic uptake by the salivary glands help to differentiate AIP from pancreatic cancer [40]. FDG PET/CT has a role both in diagnosis and response assessment to steroid therapy in AIP associated with extra-pancreatic autoimmune disease [41]. (ii) Chronic pancreatitis (CP): CP can be associated with a range of anatomic abnormalities of the pancreas, including atrophy or enlargement of the organ and

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 7. 15-year-old male presented with 1 month history of jaundice. MIP image (A) shows mild focal uptake of SUVmax 2.4 in the epigastrium (arrow). Axial CT (B, C) shows heterogeneously enhancing lesion in the bulky pancreatic head (arrow in B) with vascular invasion and enlarged abdominal

nodes (arrow in C). Axial fused PET/CT (D, E) shows focal FDG uptake (SUVmax 2.4) in the pancreatic head (arrow in D) and the nodes (arrow in E). Surgical specimen revealed pancreatoblastoma and metastatic nodes.

concentration (corresponding to the cyst). This pattern has been consistently reported across many studies [27, 28]. Pseudocyst being a complication of pancreatitis, the FDG uptake often extends into the adjacent segment of pancreas suggesting an inflammatory etiology. (iv) Tuberculosis (TB): TB lesion in pancreas also shows increased FDG uptake and is a great mimic of cancer. Sanabe et al. have reported a case of pancreatic TB operated, mistaking it to be a neoplastic lesion based upon FDG PET finding [42]. However, in our experience, EUS-guided FNA was done from all the suspicious lesions on FDG PET and were confirmed to be due to TB and subsequently started on anti-tubercular treatment. There were two cases of primary pancreatic TB (Fig. 20, including one with history of calcific CP (Fig. 21) in our experience, correctly identified as benign because of the diffuse FDG uptake pattern. TB should also be considered as a differential diagnosis for pancreatic masses with diffuse FDG uptake in TB endemic zones. Majority of pancreatic TB cases show multifocal lesions in the pancreas [43]. In endemic countries, nodal or pulmonary TB can co-exist with pancreatic cancer

(Fig. 10). Hence, any suspicious FDG-avid hilar nodes or pulmonary lesions should be first subjected to FNA/ biopsy to rule out TB before proper treatment.

Periampullary region Malignant lesions: Periampullary tumors (of the ampulla, lower common bile duct, or duodenum) present with similar symptoms and signs to pancreatic cancer; without careful histological evaluation, the differential diagnosis of tumor type may be impossible. The periampullary cancers are more often resectable, than pancreatic cancers [44]. Thus, early diagnosis with proper staging and timely intervention increases the survival of these patients. Ampullary carcinomas comprise four clinicopathologic subtypes that are prognostically distinct [45]. FDG PET/CT helps in accurate characterization (Figs. 22, 23) and staging (Fig. 24) of these lesions. Similar to pancreatic adenocarcinoma, periampullary adenocarcinoma can also present alongwith CP (Fig. 25). In the study by Kalady et al., FDG PET failed to identify the 12% (5 out of 41) of malignant

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 8. 65-year-old male presenting with 2 months history of loss of appetite, jaundice, and abdominal pain; BG–88 mg/dL. No abnormality is seen in the MIP image (A) except for the bowel uptake (arrow heads). Axial CT (B) showing a mixed solid– cystic lesion in the head of pancreas (arrow). Axial fused PET/CT image (C) shows no significant FDG uptake in this region (arrow). The patient underwent Whipple’s surgery for persistent jaundice and the specimen revealed IPMN.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 9. 72-year-old female presenting with loss of appetite for 1 month. MIP image (A) shows no abnormal FDG uptake in the abdomen apart from the physiological colonic activity. Axial CT (B) shows a cystic lesion in the body of pancreas.

Axial fused PET/CT (C) shows no increased FDG uptake (arrow) in this lesion. FNA smear showing mucinous material (D) with a few areas showing benign pancreatic ductal epithelial cells (E) [H–E stain; O.M 9 400].

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 10. 53-year-old female presenting with 12 months history abdominal pain; CA19.9-62 U/mL. MIP image (A) showing focal FDG uptake in the epigastrium, abdominal nodes (arrow heads), and multiple mediastinal nodes (curved arrows). Axial CT (B, C) showing heterogeneously enhancing lesion in the head of pancreas (arrow in B) and double-duct

sign (arrow in C). Axial fused PET/CT (D, E) showing focal FDG uptake (SUVmax 12.7) in the pancreatic head (arrow in D), with physiologic uptake in the rest of the pancreas (E). Surgical specimen revealed neuroendocrine carcinoma with metastatic abdominal nodes; the mediastinal nodes were found out to be due to granulomatous etiology.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 11. 65-year-old female presenting with 2 months history of loss of appetite and abdominal pain. MIP image (A) showing focal FDG avidity in the epigastrium (arrow), FDGavid abdominal lymph nodes (open arrow heads), and peritoneal metastases (arrow heads). Enlarged mediastinal lymph nodes showing symmetric FDG uptake (curved arrow heads) were also noted, a pattern consistent with granulomatous etiology. Axial CT (B) shows a large heterogeneous enhancing lesion, measuring 11 9 7.5 cm in the head of

pancreas (arrow). Axial fused PET/CT (C) shows focally increased FDG uptake (SUVmax 27.7) in this lesion (arrow), and large hypodense photopenic areas (arrow heads) within the mass suggestive of necrosis. Axial fused PET/CT (D) showing physiological FDG uptake in the rest of the pancreas and FDG-avid nodes (open arrow head). FNA smear (E) showing scattered pleomorphic spindle-shaped sarcomatous cells [May-Grt‹ nwald-Giemsa stain; O.M 9 400].

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 12. 65-year-old male presenting with 2 months history of loss of appetite; CA 19.9–23.57 U/mL. MIP image (A) shows intense FDG uptake in the entire epigastrium (arrow) and left inguinal node (arrow head). Axial CT (B, C) showing homogeneously enhancing lesion in the head of pancreas (B) and enlarged retroperitoneal nodes (arrows in C) displacing the renal vessel anteriorly. Axial fused PET/CT (D, E) showing

focal FDG uptake (SUVmax 10.9) in the head of pancreas (arrow in D) and retroperitoneal nodes (arrows in E); rest of the pancreas shows normal architecture with physiological FDG uptake (curved arrow in B, D). USG-guided FNA from the retroperitoneal nodes indicated DLBCL, and the patient was treated as stage II NHL.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 13. 52-year-old male presenting with abdominal pain for 4 months. MIP image (A) showing multiple FDG-avid foci in the mediastinum and abdomen. These foci were localized to the left lobe of thyroid gland (curved arrow), a 10-cm-sized soft tissue mass in the anterior mediastinum (curved arrow head), mediastinal lymph nodes, multiple lung nodules (open arrow heads), hypodense lesion in segment IVb of the liver (curved arrow), pancreas (arrow), multiple hypodense lesions in the cortex of both kidneys (arrow heads), and a few

abdominal lymph nodes. Axial CT (B, D) showing homogeneously enhancing bulky pancreas (arrows) and hypodense lesions in both kidneys (arrow heads). Axial fused PET/CT (C, E) showing multiple foci of increased FDG uptake (SUVmax 10.8) in the pancreas (arrows) and both kidneys (arrow heads). CT-guided FNA from the mediastinal mass was consistent with high-grade B cell NHL, and the patient was treated as stage-IV NHL.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 14. 68-year-old male having history of DM and CP presenting with 3 months history of abdominal pain; CA 19.9– 4.18 U/mL. MIP image (A) showing faintly FDG-avid salivary glands (curved arrow head), intensely avid multiple mediastinal nodes (closed arrow heads), FDG uptake in right lung (curved arrows), left lobe of liver (open arrow head), and diffuse FDG uptake in the pancreas (arrow), suggesting a systemic involvement. Axial CT (B, C) showing mild diffuse

enlargement of the pancreas (arrows) with minimal peripancreatic stranding; the pancreas appears featureless with effacement of the normal lobular appearance. Axial fused PET/CT (D, E) shows diffuse FDG uptake, SUVmax 4.2 in the pancreas (arrows). FDG-avid perigastric, enlarged periportal, aortocaval, and mesenteric lymph nodes were also seen. Pathologic analysis revealed lymphoplasmacytic infiltration of the ampulla of vater.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 15. 60-year-old female having type II DM presenting with one month history of jaundice, BG–105 mg/dL. MIP image (A) showing mild FDG uptake in the epigastrium (arrow), equal to that of liver. Axial CT (B) showing homogeneous enhancement with smooth effacement of the head of pancreas (arrow). Axial fused PET/CT (C–E) showing mild FDG

uptake (SUVmax 2.7) in the head (arrow in D) extending to the body of pancreas (arrow in C) with smooth dilated pancreatic duct and atrophic tail (arrow in E). Subsequently, Whipple’s procedure was done showing chronic inflammatory cells with foci of IgG4 positivity, suspicious for an underlying autoimmune component.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 16. 59-year-old female having history of CP presenting with loss of appetite for 8 months. MIP image (A) shows no abnormal FDG uptake in the epigastrium. Apart from bowel uptake. Axial CT (B) shows a heterogeneous lesion in the head of pancreas (arrow). Axial fused PET/CT (C–E) shows

no significant FDG uptake in the head of pancreas (arrow in D); rest of the pancreas (C, E) shows physiological FDG uptake with calcific foci in the tail of pancreas (arrow in E). Biopsy from the head of pancreas showed normal cells with no evidence of malignancy.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 17. 41-year-old male presenting with 6 months history of loss of appetite and abdominal pain; CA 19.9–44.0 U/mL. MIP image (A) showing diffuse FDG uptake (SUVmax 5.1) in the pancreas (arrow). Axial CT (B, C) showing heterogeneously enhancing lesion in the head (arrow in B) and a cystic

lesion in the tail of pancreas (arrow in C). Axial fused PET/CT showing diffuse FDG uptake in the head (arrow in D) and body of pancreas with a non FDG-avid pseudocyst in the tail (arrow in E). Endoscopic biopsy from the head of pancreas showed only inflammatory cells.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 18. 48-year-old male presenting with 6 months history of abdominal pain; CA 19.9–44.0 U/mL. MIP image (A) showing two foci of FDG uptake in the abdomen. Axial CT (B) showing heterogeneous enhancing lesion in the body of pancreas. Axial fused PET/CT (C, D) showing focal FDG

uptake (SUVmax 6.1) in the pancreatic lesion (arrow in C) and the necrotic collection near the greater curvature of stomach (arrow head in D). FNA smear (E) from the pancreatic lesion showing benign pancreatic ductal epithelial cells with scattered inflammatory cells [H–E stain; O.M 9 100].

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 19. 50-year-old male presenting with 3 months history of jaundice and abdominal pain. MIP image (A) shows faint diffuse FDG uptake in the epigastrium, equal that of liver. Axial CT (B) showing a large cystic lesion with multiple septae and enhancing wall in the head of the pancreas (arrow). Significant peripheral stranding around the lesion is noted; adjacent duodenal wall appear thickened (arrow head). Axial

fused PET/CT (C–E) showing mild FDG uptake (SUVmax 3.6) in the wall of the cyst (arrow in D), body and tail (arrows in C, E) of the pancreas and dilated MPD (arrow heads in C, E). These findings are suggestive of an inflammatory pseudocyst in the head of pancreas, following pancreatitis, which was later confirmed by FNA cytology.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 20. 28-year-old female presenting with 6 months history of jaundice and abdominal pain. MIP image (A) showing multiple FDG-avid foci in the epigastrium. Axial fused PET/CT (B–D) localized these foci of FDG uptake in the head (SUVmax 5.2), body, and tail of pancreas (arrows in B–D,

respectively). However, CT showed a mass-forming lesion only in the head of pancreas with rest of the pancreas appearing normal (not shown separately). FNA smear (E) showing numerous epithelioid cell granulomas with inflammatory cells [H–E stain; O.M 9 200].

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 21. 45-year-old female having 10 years history of CP and DM presenting with recent onset of abdominal pain; CA19.9—177.81 U/mL. MIP image (A) showing multifocal FDG uptake in the epigastrium (arrows). Axial CT (B, C) showing heterogeneous mass-forming lesion in the head measuring 1.7 9 2.4 cm (arrow in B) and chunky calcification

in the pancreas (arrow heads in B, C). Axial fused PET/CT (D, E) showing multiple foci of FDG uptake (SUVmax 12.8) in the head (arrow in D) and body of pancreas (arrow in E). Ziehl Nielson staining of the FNA smear from the head of pancreas showed acid-fast bacilli.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 22. 37-year-old male presenting with 3 months history of jaundice, loss of appetite, and abdominal pain; CA 19.9– 44.0 U/mL. MIP image (A) shows focal FDG uptake in the right hypochondrium (arrow). Axial CT (B, C) shows an asymmetric polypoidal mural thickening in the duodenal ampulla (arrow in B) and normal appearing pancreas (C); CBD

stent in situ is also visualized in b and c. Axial fused PET/CT (D, E) showing focal FDG uptake, SUVmax 9.2 in the ampulla (arrow in D) and physiological uptake in the pancreas (E). The surgical specimen revealed moderately differentiated periampullary adenocarcinoma, with the sampled nodes negative for malignancy.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 23. A 69-year-old female patient presenting with 2 months history of abdominal pain. MIP image (A) shows focal FDG uptake in the right hypochondrium (arrow). Axial CT (B) shows thickened duodenal ampulla; CBD stent in situ is also visualized. Axial fused PET/CT (C) showing focal FDG uptake (SUVmax 7.0) in the ampulla (arrow) and physiological uptake in the pancreas. Pathologic analysis revealed papillary variant of periampullary adenocarcinoma.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 24. 58-year-old female presenting with one month history of jaundice and loss of appetite. MIP image (A) shows focal FDG uptake in the right hypochondrium (arrow). Axial CT (B) shows heterogeneously enhancing lesion, measuring 2.6 cm 9 2.5 cm around the biliary stent in situ (arrow). Axial fused PET/CT (C) showing focal FDG uptake (SUVmax 10.6)

in the ampullary lesion (arrow). Axial CT (D) showing 0.8-cmsized left supraclavicular node (arrow) with FDG avidity in the fused PET/CT (arrow in E). Biopsy from the periampullary region revealed poorly differentiated adenocarcinoma and FNA from the left supraclavicular node showed metastatic adenocarcinoma.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 25. 63-year-old male having history of type II diabetes and CP presented with on and off episodes abdominal pain and periampullary mass; CA 19.9—1846.0 U/mL, BG—219 mg/dL. MIP image (A) of second PET/CT shows mild focal FDG uptake in the epigastrium. Axial fused PET/CT done one year ago (B, C) showed no abnormal FDG uptake in the periampullary region (arrow in B) and rest of pancreas (C).

Axial fused PET/CT done one year later (D, E) showed FDGavid mass in the periampullary region, SUVmax 2.7 (arrow in D); the rest of pancreas appear atrophied (E) compared to the initial study (C). Subsequently, Whipple’s procedure was done confirming moderately differentiated adenocarcinoma of the periampullary region and chronic fibrosing pancreatitis in the resected margin.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 26. 70-year-old male having history of type II diabetes presenting with 2 months history of jaundice and abdominal pain; CA 19.9–26.0 U/mL, BG–94 mg/dL. MIP image (A) showing no abnormal FDG uptake in the abdomen. Axial CT (B) showing a mass-forming lesion (arrow), measuring 2.0 9 1.0 9 0.5 cm in the periampullary region. Axial fused

PET/CT (C, D) showing no significant FDG uptake (SUVmax 1.3) in the periampullary lesion (arrow in C) and pancreas (D). Surgical specimen (E) showing tumor arranged in varying sized glands at terminal part of bile duct and surrounding pancreas showing changes of chronic pancreatitis [H–E stain; O.M 9 10].

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Fig. 27. 45-year-old male presenting with 12 months history of jaundice. MIP image (A) shows multiple FDG-avid regions in the thorax that were localized to consolidative lesions in both lungs (curved arrow) and mediastinal lymph nodes (curved arrow head), and diffuse FDG uptake the epigastrium. Axial CT (B) showing a 2.5 9 1.5-cm-sized lesion at the periampullary region (arrow, SUVmax 4.2) showing FDG uptake

in fused PET/CT (C). Axial fused PET/CT (D) showing another FDG-avid heterogeneous lesion in the body of pancreas (arrow head) causing dilatation of the proximal MPD; biliary stent in situ is also visualized in B–D. Immunohistochemistry (E) of the biopsy specimen from the periampullary lesion showing CD 20+ve lymphoid cells [O.M 9 10].

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

Table 1. The uptake intensity and pattern of FDG avidity of different pancreatic and periampullary lesions Lesion type Pancreatic lesions A) Tumors 1) Epithelial tumors (a) Malignant lesions Adenocarcinoma Adenosquamous carcinoma Pancreatoblastoma (b) Premalignant lesions (IPMN) Invasive Non-invasive (c) Benign lesion Simple cyst (d) Neuroendocrine neoplasm Well-differentiated Poorly differentiated 2) Mesenchymal tumor Pleomorphic sarcoma 3) Lymphoma Primary Secondary Tertiary B) Pseudotumors/Inflammatory lesions (i) Autoimmune pancreatitis (ii) Chronic pancreatitis Non-active Acute on chronic (iii) Pseudocyst (iv) Tuberculosis Periampullary lesions (a) Malignant lesions Adenocarcinoma Lymphoma (MALToma) (b) Benign lesion

FDG uptake intensity

FDG uptake pattern

High High Low

Focal Focal Focal

High/low Physiological Nil

Focal Physiological Nil

Low High

Focal Focal

High

Focal

High High High

Focal Usually diffuse Diffuse

High

Diffuse

Physiological High Rim uptake with central photopenia High

Physiological Diffuse Diffuse Usually diffuse

High High Physiological

Focal Variable Physiological

Fig. 28. 65-year-old female presenting with 3 months history of jaundice and abdominal pain. MIP image (A) shows no abnormal FDG uptake in the abdomen. Axial CT (B) shows narrowing at the terminal CBD in the ampulla with asymmetric thickening around the biliary stent in situ (arrow). Axial fused PET/CT (C–E) shows no

significant FDG uptake in the periampullary region (arrow in D) and the pancreas (C, E). The biliary stent in situ (B–E) did not pose any problem for interpretation of PET images. The patient underwent Whipple’s surgery for persistent jaundice, and the specimen was negative for malignancy.

S. Santhosh et al.: Metabolic signatures of malignant and non-malignant mass-forming lesions

periampullary lesions [46]. The sensitivity for detection of primary malignancy by visual inspection in our study was 92% [19] missing one case of well-differentiated periampullary adenocarcinoma (Fig. 26). An extremely rare case of periampullary MALToma was also seen in our experience. Diffuse FDG uptake was also seen in the pancreas in addition to focal FDG uptake in this periampullary lesion, the confirmation of which could only be obtained with tissue diagnosis (Fig. 27). Benign lesion: Non-inflammatory, radiologically equivocal lesions can present as pseudotumors at the periampullary region. Endoscopic biliary stents are usually placed for relieving jaundice in these cases; in this scenario, FDG PET/CT can certainly rule out malignancy even in the presence of stent in situ (Fig. 28).

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