high circulating calcitonin levels are associated with medullary thyroid carcinoma . however , several other neuroendocrine tumors ( nets ) can also release calcitonin , including pheochromocytomas , neuromas and lung , breast , prostate , and colorectal carcinomas . calcitonin - secreting pancreatic endocrine tumors ( ctspets ) have been described as extremely rare . we report 2 consecutive cases of ctspets found during the evaluation of patients with hypercalcitoninemia and thyroid nodules . these cases highlight the risk of underestimating calcitonin as a tumor marker for pancreatic net . written informed consent was obtained from both patients for the publication of this manuscript and accompanying images . a 53-year - old caucasian man was referred to our department for an elevated serum calcitonin level ( 253  pg / ml , reference range 010 ) discovered during an evaluation of thyroid nodules . the patient was asymptomatic and was not taking any medication ; his family history included only lung cancer , in his father . color doppler ultrasound ( cdus ) revealed 2 non - homogeneous thyroid nodules of 0.6 and 1.8  cm , with a medium elastography pattern ( 3b and 2 respectively ) . fine needle aspiration cytology ( fnac ) suggested benign hyperplastic nodules ( thy 2 , british thyroid association , bta - rcp 2007 ) ; calcitonin measurement in fine needle wash - out of both thyroid nodules was negative ( 1.24 and 1.68  pg / ml respectively ) . serum electrolytes , pthi , 24-h urinary metanephrines ( 144  mcg/24  h  <  345 ) and vanillylmandelic acid ( vma  =  8.0  mg/24  h < 13.6 ) were normal . hypercalcitoninemia was confirmed in 2 further samples ( 388 and 443  pg / ml ) . net markers were normal : neuron - specific enolase ( nse ) ( 5  ng / ml < 10 ) , gastrin ( 50  pg / ml < 120 ) , chromogranin a - cga ( 44  ng / ml < 90 ) , cea ( 1.5  ng / ml < 5 ) , vip ( 12  pmol / l < 30 ) , 5ht+5htp ( 4.0  mg/24  h < 5 ) , psa ( 0.65  ng / ml < 2.3 ) , and 24-h urinary 5hiaa ( 3.0  mg/24  h < 6 ) . abdominal computed tomography showed a pancreatic nodule ( 1.8  cm ) with moderate enhancement during arterial phase , confirmed on magnetic resonance imaging ( figure 1a ) as suggestive of net . an integrated nuclear medicine approach was undertaken ( a.b . ) : f - dopa pet / ct ( figure 1b - lower panel ) revealed mild pancreatic metabolization while f - fdg pet / ct ( figure 1b - upper panel ) and octreoscan + spect / ct were negative . mri , f - fdg pet / ct imaging , and immunostaining for calcitonin in case 1 . a , mri scan shows a solid 18-mm lesion in the pancreatic tail ( arrows ) , which appears hypointense on t1 and slightly hyperintense on t2 . contrast - enhanced sequences show hypervascularity in arterial phase with persistent enhancement in the subsequent phases . b , f - fdg pet / ct ( in the upper part of the panel ) and f - dopa pet / tc ( in the lower part of the panel ) both show no significant metabolic activity in the pancreatic lesion . the patient underwent a distal pancreatectomy ( p.c . ) that confirmed a well - differentiated net ( 2.3  cm , g1 , proliferation index 2% ) which was positive for calcitonin , ncam , cga , synaptophysin , nse immunostaining ( figure 1c ) and negative for insulin , glucagon , gastrin , somatostatin , and serotonin . calcitonin gradually normalized after surgery ( figure 2 ) ; prolonged follow - up ( 24 months ) showed repeatedly normal calcitonin levels , confirming disease eradication . genetic testing for men1 ( exons 2,3,4,5,6,7,8,9,10 ) and ret ( exons 10,11,13,14,15,16 ) mutations associated with ctspets were negative . time course of postsurgical calcitonin normalization ( solid : case 1 ; open : case 2 ) . a 78-year - old caucasian woman with a 5-month history of vague abdominal discomfort and constipation complained of a recent onset gastric pain and underwent a liver us , which found 2 suspect non - homogeneous lesions ( 1.6 and 0.6  cm ) in liver segment vii . before admission she had an abdominal computed tomography scan , which revealed a nodule ( 4.0  cm ) in the pancreatic tail , and a f - fdg pet / ct scan , that was negative . 010 ) , confirmed in 2 subsequent measurements ( 122 and 218  pg / ml ) , with normal nse ( 4  ng / ml < 10 ) , gastrin ( 64 pg / ml < 120 ) , cga ( 75  ng / ml < 90 ) , cea ( 1.79  ng / ml < 5 ) , vip ( 20  pmol / l < 30 ) , 5ht+5htp ( 4.0  mg/24  h < 5 ) , and 24-h urinary 5hiaa ( 4.0  mg/24  h < 6 ) . thyroid hormones and antibodies were normal . thyroid cdus confirmed 2 hypoechoic nodules ( 1.2 and 1.7  cm ) with a medium ( 3a ) elastography pattern . fnac showed benign hyperplastic nodules ( thy 2 ) with unremarkable calcitonin levels in needle wash - out . serum electrolytes , pthi , and 24-h urinary metanephrines ( 53.0  mcg/24  h ) and vma ( 6.0  mg/24 the patient underwent us - guided biopsy of the hepatic lesion that was consistent with metastasis from a well - differentiated net ( panckae1/ae3 + , ck8/18 + , ck7- , ck20- , synaptophysin+ , nse+/- , cga-/+ , heppar1- , alfafp- , ttf1- , cdx2- , calcitonin- ; ki67 staining < 3% ) . histopathology revealed a well - differentiated 5.0-cm pancreatic net with angioinvasion ( g1 , proliferation index 2% ) , with immunostaining positive for calcitonin , ncam , cga , synaptophysin and nse and negative for glucagon , gastrin , insulin , somatostatin , and serotonin . calcitonin levels normalized rapidly post - surgery ( + 24 h  =  101  pg / ml ; + 48 h  =  3.62  pg / ml ; + 21 days  =  1.31  pg / ml ) ( figure 2 ) . the patient is currently doing well and is followed up regularly in the outpatient clinic . a 53-year - old caucasian man was referred to our department for an elevated serum calcitonin level ( 253  pg / ml , reference range 010 ) discovered during an evaluation of thyroid nodules . the patient was asymptomatic and was not taking any medication ; his family history included only lung cancer , in his father . color doppler ultrasound ( cdus ) revealed 2 non - homogeneous thyroid nodules of 0.6 and 1.8  cm , with a medium elastography pattern ( 3b and 2 respectively ) . fine needle aspiration cytology ( fnac ) suggested benign hyperplastic nodules ( thy 2 , british thyroid association , bta - rcp 2007 ) ; calcitonin measurement in fine needle wash - out of both thyroid nodules was negative ( 1.24 and 1.68  pg / ml respectively ) . serum electrolytes , pthi , 24-h urinary metanephrines ( 144  mcg/24  h  <  345 ) and vanillylmandelic acid ( vma  =  8.0  mg/24  h < 13.6 ) were normal . hypercalcitoninemia was confirmed in 2 further samples ( 388 and 443  pg / ml ) . net markers were normal : neuron - specific enolase ( nse ) ( 5  ng / ml < 10 ) , gastrin ( 50  pg / ml < 120 ) , chromogranin a - cga ( 44  ng / ml < 90 ) , cea ( 1.5  ng / ml < 5 ) , vip ( 12  pmol / l < 30 ) , 5ht+5htp ( 4.0  mg/24  h < 5 ) , psa ( 0.65  ng / ml < 2.3 ) , and 24-h urinary 5hiaa ( 3.0  mg/24  h < 6 ) . abdominal computed tomography showed a pancreatic nodule ( 1.8  cm ) with moderate enhancement during arterial phase , confirmed on magnetic resonance imaging ( figure 1a ) as suggestive of net . an integrated nuclear medicine approach was undertaken ( a.b . ) : f - dopa pet / ct ( figure 1b - lower panel ) revealed mild pancreatic metabolization while f - fdg pet / ct ( figure 1b - upper panel ) and octreoscan + spect / ct were negative . mri , f - fdg pet / ct imaging , and immunostaining for calcitonin in case 1 . a , mri scan shows a solid 18-mm lesion in the pancreatic tail ( arrows ) , which appears hypointense on t1 and slightly hyperintense on t2 . contrast - enhanced sequences show hypervascularity in arterial phase with persistent enhancement in the subsequent phases . b , f - fdg pet / ct ( in the upper part of the panel ) and f - dopa pet / tc ( in the lower part of the panel ) both show no significant metabolic activity in the pancreatic lesion . the patient underwent a distal pancreatectomy ( p.c . ) that confirmed a well - differentiated net ( 2.3  cm , g1 , proliferation index 2% ) which was positive for calcitonin , ncam , cga , synaptophysin , nse immunostaining ( figure 1c ) and negative for insulin , glucagon , gastrin , somatostatin , and serotonin . calcitonin gradually normalized after surgery ( figure 2 ) ; prolonged follow - up ( 24 months ) showed repeatedly normal calcitonin levels , confirming disease eradication . genetic testing for men1 ( exons 2,3,4,5,6,7,8,9,10 ) and ret ( exons 10,11,13,14,15,16 ) mutations associated with ctspets were negative . time course of postsurgical calcitonin normalization ( solid : case 1 ; open : case 2 ) . a 78-year - old caucasian woman with a 5-month history of vague abdominal discomfort and constipation complained of a recent onset gastric pain and underwent a liver us , which found 2 suspect non - homogeneous lesions ( 1.6 and 0.6  cm ) in liver segment vii . before admission she had an abdominal computed tomography scan , which revealed a nodule ( 4.0  cm ) in the pancreatic tail , and a f - fdg pet / ct scan , that was negative . 010 ) , confirmed in 2 subsequent measurements ( 122 and 218  pg / ml ) , with normal nse ( 4  ng / ml < 10 ) , gastrin ( 64  pg / ml < 120 ) , cga ( 75  ng / ml < 90 ) , cea ( 1.79  ng / ml < 5 ) , vip ( 20  pmol / l < 30 ) , 5ht+5htp ( 4.0  mg/24  h < 5 ) , and 24-h urinary 5hiaa ( 4.0  mg/24  h < 6 ) . thyroid hormones and antibodies were normal . thyroid cdus confirmed 2 hypoechoic nodules ( 1.2 and 1.7  cm ) with a medium ( 3a ) elastography pattern . fnac showed benign hyperplastic nodules ( thy 2 ) with unremarkable calcitonin levels in needle wash - out . serum electrolytes , pthi , and 24-h urinary metanephrines ( 53.0  mcg/24  h ) and vma ( 6.0  mg/24  h ) were normal . the patient underwent us - guided biopsy of the hepatic lesion that was consistent with metastasis from a well - differentiated net ( panckae1/ae3 + , ck8/18 + , ck7- , ck20- , synaptophysin+ , nse+/- , cga-/+ , heppar1- , alfafp- , ttf1- , cdx2- , calcitonin- ; ki67 staining < 3% ) . histopathology revealed a well - differentiated 5.0-cm pancreatic net with angioinvasion ( g1 , proliferation index 2% ) , with immunostaining positive for calcitonin , ncam , cga , synaptophysin and nse and negative for glucagon , gastrin , insulin , somatostatin , and serotonin . calcitonin levels normalized rapidly post - surgery ( + 24 h  =  101  pg / ml ; + 48 h  =  3.62  pg / ml ; + 21 days  =  1.31  pg / ml ) ( figure 2 ) . the patient is currently doing well and is followed up regularly in the outpatient clinic . the discovery of 2 cases of ctspets within 11 months in our center suggests that extrathyroid calcitonin secretion by net could be more common than generally thought . the absence of specific symptoms ( except for a vague abdominal discomfort ) is problematic for both identification of the source and post - operative monitoring . several extrathyroidal tumors can produce ectopic calcitonin , including pheochromocytomas , pancreatic nets , adrenocortical carcinomas , nets of esophagus , acute leukemia , lung cancers , cervical tumors , prostatic carcinomas , breast cancers , renal carcinomas , gastrointestinal tract tumors . in all these tumors , the anatomic localization , rapid growth , and frequent cosecretion of other hormones ( including acth , gastrin , catecholamines , and somatostatin ) drive the clinical presentation and allow rapid localization of the source . symptoms of pancreatic net can include diarrhea , which has been associated with cosecretion of somatostatin or the histological nature of the tumor . however , neither of our patients complained of diarrhea . in contrast , isolated ectopic calcitonin secretion has not been associated with a specific clinical picture and can remain silent , meaning patients are unlikely to seek medical help . the lack of emphasis on differential diagnosis leads to general unawareness of ctspets and some cases probably remain undiagnosed . case 1 suggests that elevated calcitonin levels should be investigated with care even in the presence of thyroid nodules , and especially when the nodules have few suspicious features ; the pancreas should be screened first . in fact , if not promptly diagnosed , ctspets can metastasize , as in case 2 . calcitonin measurement should be included in the work - up of any neuroendocrine pancreatic lesion , with or without metastases , even if metastases can lose secretory activity , probably as they dedifferentiate ( case 2 ) . herein , we showed 2 cases with positive immunostaining for calcitonin in pets in which serum calcitonin decay ( 24  h , 48  h , and 21 days ) was helpful in postsurgical surveillance . nuclear medicine imaging supported the diagnosis and the combined morphological / functional imaging provided by hybrid pet / ct scan offered the best guide for surgery . in both cases , the absence of glucose metabolism in the pancreatic lesions supported the diagnosis of biologically nonaggressive ctspets . in case 1 , the lack of f - dopa fixation in the thyroid strengthened the suspicion of an extrathyroid calcitonin secretion , already suggested by the negative calcitonin measurement in fnac needle wash . of note was that the pancreatic nodule failed to metabolize f - dopa consistently , with low aromatic amino acid decarboxylase activity ( false negative ) . octreoscan was negative , suggesting low or negative sstr-2 expression ; unfortunately the more sensitive gallium - dotatoc - pet scan was not performed . the negative genetic tests suggest the sporadic nature of these pancreatic lesions . in conclusion , when calcitonin levels are elevated and thyroid examination is not clearly suggestive of medullary thyroid carcinoma or c - cell hyperplasia , general screening of extrathyroidal calcitonin secretion is recommended . ctspet should be suspected in the differential diagnosis , especially in view of the lack of specific symptoms , that may further delay diagnosis . routine serum calcitonin measurement may be a highly sensitive adjunct to identify a subset of ctsnets , and calcitonin monitoring may enable early detection and postoperative surveillance .