Are Pancreatic Endocrine Neoplasms in Tuberous Sclerosis Complex a Syndrome Associated Lesion?
Tze S Khor, Long P Le, Anthony J Iafrate, Gregory Y Lauwers, Vikram Deshpande. Massachusetts General Hospital, Boston, MA
Background: Pancreatic endocrine tumors (PanNET) occur either sporadically or associated with a genetic syndrome, principally MEN-1, VHL and NF-1. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder due to germline mutations in TSC1/TSC2. Loss of TSC1/2 in vitro and in vivo leads to mTOR cascade activation. Rare reports of PanNET in TSC exist, however, the association of PanNET in TSC has not been systematically studied and it is debated whether these are syndrome associated tumors. To better understand the nature of PanNET in TSC, we studied the clinicopathologic features of 5 PanNET in TSC with immunohistochemical (IHC) staining for S6K and 4E-BP1, surrogate markers for activation of the mTOR pathway, and array CGH analysis in 2 tumors.
Design: A retrospective search of records at this institution was performed for patients with pancreatic lesions detected on abdominal imaging. Of 219 patients with tuberous sclerosis who underwent abdominal imaging, 8 pancreatic lesions were initially identified. Of these, 3 patients underwent resections. A retrospective review of the pathology records identified 2 additional TSC patients with PanNET. Representative sections of tumor were stained for S6K and 4E-BP1. Demographic and clinical data were collected from patient files. Array CGH was performed in two cases in which snap frozen tissue was available.
Results: The 5 cases comprised 3 males and 2 females with a mean age of 37.4 yrs (range 20-54 yrs). Germline mutation was known in 3 of 5 patients, all with TSC2 mutations. The lesions were asymptomatic and incidentally detected on abdominal MRI (n=3), during laparoscopic appendectomy (n=1) and at autopsy (n=1). Of 4 surgically resected tumors, 3 were cystic and 1 solid, with mean tumor size of 37.4mm (range 7-48mm) and locations in the tail (n=2) and body (n=2) of the pancreas. The 5th case was a microscopic finding at autopsy with no visible macroscopic tumor. IHC staining of all 5 tumors showed positive staining for S6K and 4E-BP1. Array CGH did not demonstrate copy number variation in TSC1/2 gene loci in one case but demonstrated gains in TSC2 in the other case.
Conclusions: The uniform finding of mTOR activation in TSC associated PanNET contrasts with sporadic PanNET, 14% of which have been reported with mutations in mTOR pathway genes. This feature, together with the relative young age of onset, suggests that PanNET in TSC may be syndrome related lesions. These findings may also have implications for both surveillance and therapy.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 274, Monday Morning