thymic neuroendocrine ( ne ) tumors associated with multiple endocrine neoplasia type 1 ( men-1 ) are rare , variably documented in 1 - 8% cases .
thymic ne tumors are usually detected about 7 - 29 years following surgical treatment of primary hyperparathyroidism ( phpt ) in men-1 .
transcervical thymectomy ( tct ) at the time of parathyroid surgery for phpt usually prevents thymic ne tumors .
the occurrence of thymic ne tumors is very rare after tct as part of the parathyroidectomy procedure for phpt .
here we report a case of thymic ne carcinoma developing within a span of 8 months after subtotal parathyroidectomy and tct for phpt in a men-1 patient .
a 56-year - old non - smoker male presented with generalized bodyaches , low back pain , and proximal myopathy of 1-year duration without any fragility fractures .
examination revealed bony tenderness over the sternum and proximal muscle weakness of the lower limbs .
laboratory evaluation revealed hypercalcemia ( serum total calcium 12.8 mg / dl , normal 8.5 - 10.5 mg / dl ) , hypophosphatemia ( serum phosphorus 2.1 mg / dl , normal 2.5 - 4.5 mg / dl ) , normal serum albumin ( 3.8 g / dl ) , normal serum alkaline phosphatase ( 136 iu / l , normal 50 - 150 iu / l ) , vitamin d sufficiency ( serum 25oh vitamin d 31 ng / ml ) , and normal renal function ( serum creatinine 1.2 mg / dl ) . hypercalcemia was pth dependent ( serum calcium 12.8 mg / dl with high serum intact pth 215 pg / ml , normal 15 - 70 pg / ml ) . his hemogram and esr were unremarkable ( hb 13.4 g / dl , tlc 6700/mm , platelet count 2.8 lakhs / mm , and peripheral smear showed normocytic , normochromic rbcs , esr 20 mm at end of the first hour ) .
bone mineral density by dual energy x - ray absorptiometry showed osteoporosis ( t - score 2.7 at lumbar spine , 2.0 at total hip , and 3.4 at distal forearm ) .
ultrasound neck revealed multiglandular parathyroid enlargement , while a tc tetrofosmin parathyroid scan showed a right inferior parathyroid tumor .
the patient was advised surgery as he had serum calcium > 12 mg / dl and osteoporosis .
the patient was subjected to bilateral neck exploration , where asymmetrical parathyroid hyperplasia was found .
histopathology showed multiglandular parathyroid hyperplasia and a normal thymus . on follow - up , 8 months after parathyroidectomy , he presented with heaviness in the left side of the chest , dry cough , and exertional dyspnea of 3 months duration .
chest radiograph revealed mediastinal widening with an oval well - circumscribed homogenous opacity ( figure 1b - dark arrow ) in left hemi - thorax .
contrast - enhanced computed tomography ( ct ) of thorax showed a 10  6.7 cm inhomogenously enhancing anterior mediastinal soft tissue mass in the prevascular space on the left side , in close proximity to the ascending aorta and arch of aorta [ figure 2 ] . chest radiograph done 9 months earlier [ figure 1a ] did not show any mediastinal widening .
chest radiographs done 9 months apart  radio - opacity in the left hemi - thorax in july 2009 radiograph ( marked with arrow ) was not present in september 2008 radiograph contrast - enhanced computed tomogram of the thorax showing large solid anterior mediastinal mass ( marked with arrow ) to the left of mid - line tc methylene diphosphonate ( mdp ) whole - body skeletal scan showed increased tracer uptake at thoraco - lumbar vertebrae and multiple ribs suggestive of skeletal metastases .
the anterior mediastinal mass was excised in toto via trans - sternal approach . on surgery , the tumor was not found to invade any of the adjacent structures . the excised tumor measured 12  7  5 cm and weighed 264 g [ figure 3 ] . on microscopy
[ figure 4a and b ] , the tumor was partially encapsulated , and was composed of rosettes of tumor cells traversed by thin fibro - vascular septae .
the tumor cells displayed round to oval nuclei , granular chromatin , occasional nucleoli , and moderate amount of granular to pale cytoplasm with areas of punctate necrosis and lympho - vascular emboli suggestive of thymic ne carcinoma .
immuno - histochemical studies were suggestive of positive staining for chromogranin and synaptophysin , but absence of staining for nse and vimentin [ figure 4c and d ] , consistent with thymic ne carcinoma .
lobulated solid tumor which was homogenous grayish white and fleshy on the cut surface histopathology and immuno - histochemistry . ( a ) tumor with adjacent thymus , h and e , 100 .
( b ) tumor cells displaying rosette formation and necrosis , h and e , 400 . ( c )
( d ) cytokeratin immuno - positivity 200 with strong suspicion of sporadic men-1 , in view of coexistence of phpt with metastatic thymic ne carcinoma , work up for men-1 was done , which revealed raised fasting serum gastrin ( 18,000 pg / ml , normal < 200 ) suggestive of gastrinoma . his serum prolactin ( 12 ng / ml , normal 2.1 - 17.7 ng / ml ) and serum igf-1 ( 131 ng / ml ) were within normal range , thereby ruling out any functioning pituitary tumors .
there was no family history of disorders suggestive of men-1 ( family pedigree chart , figure 5 ) .
somatostatin - receptor scintigraphy with ga - dotanoc pet / ct revealed somatostatin receptor expressing tumors involving second part of duodenum , head , body , and tail of pancreas , suggestive of gastrinomas .
there was no evidence of somatostatin receptor expression in the mediastinum or vertebrae , suggesting that the vertebral metastasis were from the thymic ne carcinoma and not from the gastrinomas .
family pedigree chart showing index case of men-1 and unaffected family members the diagnosis of sporadic men-1 , with two major endocrine gland involvement ( phpt due to parathyroid hyperplasia and gastrinomas ) along with a rare occurrence of thymic ne carcinoma was apparent .
the thymic ne carcinoma had evolved rapidly within a span of 8 months after parathyroidectomy and tct , and presented with bony metastases . with wide - spread metastatic disease ,
the patient was managed palliatively ( pantoprazole , zoledronic acid 4 mg intravenous infusion 4 weekly and lanreotide 20 mg intramuscular 4 weekly ) .
the patient has been followed up with serum alkaline phosphatase , calcium , chromogranin and gastrin estimations ; and ga - dotanoc pet / ct and tc mdp bone scans at 6 monthly intervals , and other appropriate imaging such as abdomnal and thoracic ce - ct scans .
he has been treated with external beam radiotherapy as well as sm samarium therapy for palliation of painful spinal lesions .
sunitinib maleate- a multi - target tyrosine kinase inhibitor- 37.5 mg per orally , once daily was initiated in view of progressive metastatic disease , including liver , lungs and skeletal metastases , which he has received for 18 months with effective symptom palliation , and manageable toxicity .
he suffered osteo - necrosis of the jaw- a known complication of long - term zoledronic acid usage , which has been managed by discontinuation of inj zoledronic acid and other supportive care .
four years since being operated upon for the thymic n - e carcinoma , the patient is alive , ambulatory , is reasonably symptom free with good quality of life , and is normocalcemic , with no loco - regional recurrence of the thymic tumor .
thymic ne tumors have been variably reported in men-1 from 1% to 8% of cases . in recent studies ,
thymic ne carcinoma has emerged as a major cause of mortality in men-1 along with gastro - entero pancreatic tumors .
thymic ne tumors in men-1 are commoner in males and smokers and are almost always hormonally inactive and diagnosed incidentally .
they are malignant , aggressive tumors and are widely invasive and metastatic at presentation ( usually to bone ) .
thymic ne tumors are never the presenting feature of men-1 and almost always occur after phpt , providing an opportunity for prophylaxis for these tumors with tct at the time of parathyroid surgery .
while operating a phpt patient with multigland parathyroid disease , routine tct is usually performed to take care of the supernumerary parathyroid glands that can be found within the thymus gland in 15 - 20% patients .
the utility of tct in preventing the thymic ne tumors in men-1 patients is a matter of debate .
our patient developed thymic ne carcinoma despite tct being performed as part of his first operation ( sub - total parathyroidectomy ) .
tct could not prevent thymic ne carcinoma in our patient , as also reported by others .
this may be because tct results in removal of only 40 - 50% of thymic tissue . in our patient ,
the thymic ne tumor was arising from thymic limb low down in the left pulmonary hilar region , which could not have been removed by tct .
more radical thymectomy procedures like the trans - sternal thymectomy or video - assisted thoracoscopic surgical thymectomy have not been reported as a prophylactic procedure in men-1 patients .
usually , phpt is the first component of men-1 manifesting in the third to fourth decade .
in contrast , our patient had a rapid presentation of thymic ne carcinoma , which was not evident on the chest radiograph done about 9 months earlier during management of phpt .
the rapid pace of development of thymic ne carcinoma with bone metastases in our patient underscores its aggressiveness and metastatic potential .
current guidelines for surveillance of men-1 recommend screening for thymic ne tumors once every 1 to 2 years with ct or mri of thorax , although currently annual screening is advised by newer studies .
as men-1 patients undergo parathyroid surgery almost universally , tct is recommended for prevention of thymic ne tumors .
a complete surgical excision through a trans - sternal route is the only curative treatment for thymic ne tumors .
our patient did not have any direct invasion of adjacent structures inspite of its large size and the histological margins were reported uninfiltrated . in view of the multiple bone metastases ,
we report a sporadic men-1 patient cured of phpt , presenting with gastrinoma and aggressive metastatic thymic ne tumor that developed within a year after subtotal parathyroidectomy along with tct .
men-1 patients need to be screened for thymic ne tumors by routine annual ct or mri of the thorax even after tct at the time of parathyroid surgery .
 thymic neuroendocrine ( ne ) tumors are a rare manifestation of multiple endocrine neoplasia syndrome type 1 ( men-1 ) . 
 they are malignant and aggressive tumors and form a major cause of mortality in men-1 . 
 transcervical thymectomy ( tct ) at the time of parathyroid surgery for primary hyperparathyroidism ( phpt ) in men-1 usually prevents thymic ne tumors . 
 we report a 56-year - old nonsmoker male with sporadic men-1 who presented with thymic ne carcinoma developing rapidly within a span of 8 months after subtotal parathyroidectomy and tct for phpt . 
 we present a brief review of literature on this rare ne malignancy , focusing on its occurrence despite tct . 
 this case highlights the fact that thymic ne carcinoma may develop even after tct in men-1 . 
 regular surveillance for these aggressive thymic ne tumors is mandatory even after tct in men-1 setting . 
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