Pancreatic Metastasis Arising from a BRAF V600E -Positive Papillary Thyroid Cancer: The Role of Endoscopic Ultrasound-Guided Biopsy and Response to Sorafenib Therapy

Abstract

Background:

Lungs and bones are the most common sites for distant metastases from papillary thyroid cancer (PTC). Metastases to the pancreas are extremely rare. Here we present a man with pancreatic metastases from PTC, report our experience with sorafenib therapy, and discuss the role of endoscopic ultrasound (EUS)-guided biopsy in its diagnosis.

Patient Findings:

A 56-year-old man underwent total thyroidectomy, right-modified neck dissection, and radioactive iodine (RAI) remnant ablation for PTC at age 47 years (in 2002). Between 2002 and 2007, he had three more neck surgeries, two RAI therapies, and external beam radiotherapy for persistent and subsequently metastatic PTC. In 2008, a computed tomography/positron emission tomography (CT/PET) scan showed an 18F-fluorodeoxyglucose (FDG)-avid pancreatic focus. Magnetic resonance imaging (MRI) revealed a pancreatic nodule at the same location. An EUS-guided biopsy confirmed the diagnosis of pancreatic metastasis from PTC, and molecular studies showed positive BRAF ^V600E mutation. He was treated with sorafenib for 6 months. Although a lung CT scan done 2 months after initiation of sorafenib suggested stability of the disease, MRI studies done at 3 and 6 months showed clear progression with an increase in the size of the lung and pancreatic metastases. Subsequently, he developed liver, bone, and omental metastases. He died in July 2011, 9 years and 8 months after the initial diagnosis of PTC and 20 months after discovery of the pancreatic metastasis.

Summary:

A middle-aged man with PTC developed lung metastases despite multiple surgeries and RAI therapies. Seven years after the initial diagnosis, a pancreatic metastasis was accidentally discovered. Both the metastasis and the primary thyroid tumor are positive for BRAF ^V600E mutation. The lung and pancreatic metastases progressed while the patient was receiving sorafenib for 6 months, and the patient died 20 months after diagnosis of pancreatic metastasis.

Conclusion:

PTC rarely metastasizes to the pancreas. In this patient, an FDG PET scan and EUS-guided biopsy played important roles in the diagnosis. PTC metastases to the pancreas usually occur in otherwise advanced disease. In the patient presented here, sorafenib may have slowed disease progression but the overall utility of tyrosine kinase inhibitors in pancreatic metastases from PTC is not clear.

Introduction

P apillary thyroid cancer (PTC) is the most common endocrine malignancy (1). Its incidence is increasing in many parts of the world (1). Locoregional metastases are common, but distant metastases are rare (2). Age, tumor size, extrathyroidal invasion, and certain histopathological types are associated with a high risk for recurrence and mortality (2,3). However, distant metastases are probably the most important prognostic factor for increased mortality (3 –5). The 10-year survival for patients with distant metastases is only 40% (3,6). The most common sites for metastases are lungs, bones, and, rarely, the brain (4,5). For unclear reasons, other body organs are rarely involved. Metastases to the pancreas are extremely rare (7). So far, only seven cases have been reported in the literature (8 –13). The presence of pancreatic metastases is usually accompanied by widespread metastases to other organs and reflects an advanced stage of the disease (7). In this report, we describe a patient with PTC who had radioinsensitive lung metastases for 6 years before he developed a pancreatic metastasis that was detected on a merged computed tomography (CT)/18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan, localized by magnetic resonance imaging (MRI) and confirmed by endoscopic ultrasound (EUS)-guided biopsy. The biopsy specimen and the original thyroid specimen were also examined for a BRAF mutation and revealed the typical BRAF ^V600E mutation. Due to the radioinsensitivity and progression of his disease, he was treated with sorafenib. The objective of this report is to highlight the unusual site of metastases, the method of its diagnosis, and the response to the relatively newly introduced tyrosine kinase inhibitor sorafenib.

Patient

A previously healthy 47-year-old man was referred to our hospital in December 2001 with a right neck mass of 2-month duration. An ultrasound (US) of the neck revealed a 3.5-cm right thyroid nodule and multiple abnormal right cervical lymph nodes. A US-guided fine-needle aspiration biopsy (FNA) confirmed the diagnosis of PTC. The patient underwent total thyroidectomy with right central and lateral-modified neck dissection in February 2002. The tumor was adherent to the trachea and strap muscles, but there was no evidence of tracheal invasion. The histopathological examination confirmed the diagnosis of a 2-cm classic type of PTC in the right thyroid lobe with extrathyroidal extension and multiple lymph node metastases. The Tumor–Node–Metastases (TNM) stage was IVA (T4aN1bM0). There was no evidence of poor differentiation. In April 2002, the patient received 148 mCi for thyroid remnant ablation after withdrawal of thyroid hormones for 5 weeks. At that time, serum thyroglobulin (Tg) was 300 ng/mL with Tg autoantibodies <20 IU/L and thyroid-stimulating hormone (TSH) was 51 mIU/L, and preablation diagnostic radioactive iodine (RAI) whole-body scan (DxWBS) showed 0.2% uptake in the thyroid bed only. Postablation DxWBS showed similar findings without evidence of distant metastases. In October 2002, serum Tg while on l-thyroxine was still elevated at 89 ng/mL. CT scan of the chest revealed no evidence of metastases, and FDG PET whole-body scan showed an uptake in the superior mediastinum/lower neck region. In February 2003, a neck US showed multiple abnormally looking central and right lateral cervical lymph nodes. FNA of a lymph node in the right central region was positive for persistent PTC. In March 2003, the patient underwent limited right central and lateral neck dissection. The histopathological examination was negative for malignancy. In September 2003, withdrawal DxWBS was negative, but serum Tg was quite elevated at 3121 ng/mL with negative Tg autoantibodies and TSH of 156 mIU/L. The patient was treated with 150 mCi ¹³¹I for Tg-positive, scan-negative disease. Posttherapy DxWBS revealed a small focus of uptake in the superior mediastinum. In May 2004, serum Tg was elevated at 394 ng/mL while on l-thyroxine with TSH of 0.1 mIU/L. A neck US revealed multiple bilateral lymph nodes, and an FNA from a right jugular lymph node was positive for persistent PTC. He underwent bilateral jugular and central lymph node dissection (areas II and VI). Seven (from the right central and right jugular areas) out of 16 lymph nodes dissected were positive for metastatic PTC. The serum Tg while on l-thyroxine declined to 270 ng/mL. In May 2005, computed tomography (CT) scan of the chest revealed a 4.9-cm superior mediastinal mass and a few tiny nodes, <3 mm in size involving the lower regions of the lungs, consistent with early lung metastases. Due to the large size of the mediastinal mass and concern about tracheal invasion, the patient underwent central and bilateral cervical lymph node resection, sternal splitting, and resection of a large mediastinal mass that was adherent to the surrounding soft tissue. The histopathological examination was positive for PTC. A follow-up CT scan of the chest done 4 months later showed significant increase in the size of the lung lesions confirming that there were lung metastases.

In July–August 2005, the patient received 6000 cGy of external beam radiotherapy to the lower neck and mediastinum. Following the fourth surgery and external beam radiotherapy, serum Tg while on l-thyroxine declined to reach its nadir of 18.6 ng/mL in April 2006 but gradually increased to 81.7 ng/mL in March 2007. In November 2007, however, a repeat CT scan of the chest and CT/PET whole-body scan revealed an increase in the size and number of lung metastases. Due to progression of the lung metastases, the patient received 201 mCi activity of ¹³¹I in April 2008. At that time, Tg was 1384 ng/mL with TSH of 89.4 mIU/L and negative pretherapy DxWBS. His posttherapy DxWBS was also negative. Between May 2008 and May 2009, serum Tg while on l-thyroxine ranged between 49.0 and 56.7 ng/mL, but CT scans of the chest revealed further progression of the lung metastases. The patient remained stable but he was complaining of dry mouth and eyes, probably related to previous ¹³¹I therapies.

In November 2009, CT/PET whole-body scan revealed further progression of the lung metastases and a new lesion in the unicinate process of the pancreas (Fig. 1). An MRI of the pancreas confirmed the presence of a 1.7-cm pancreatic lesion (Fig. 1). An EUS-guided biopsy confirmed the diagnosis of pancreatic metastasis from PTC (Fig. 2). Part of the specimen was used for extraction of DNA for BRAF mutation testing. Using previously published primers and PCR conditions, exon 15 of the BRAF gene was amplified and directly sequenced (14). The result revealed the presence of BRAF ^V600E mutation (Fig. 2). The same mutation was also confirmed in the original tumor obtained from the total thyroidectomy sample that was performed in February 2002. Due to the progression of the disease, the patient was referred to an oncologist for sorafenib therapy. He was started on sorafenib 400 mg orally twice daily in August 2009. He tolerated the drug well. Although chest CT scan performed 2 months after initiation of sorafenib showed mild improvement in the size of the lung metastases, serum Tg while on l-thyroxine increased from 74.7 ng/mL before starting sorafenib to 149 ng/mL after 4 months of therapy. Using the modified response evaluation criteria for solid tumors (RECIST), comparison of two MRI studies obtained 3 and 6 months after initiation of sorafenib showed significant progression of the lung (42%) and pancreatic (34%) lesions and development of liver metastases. Sorafenib was discontinued in January 2010 after 6 months of therapy. This was followed by further rapid progression of the disease with development of widespread bone metastases and significant elevation in serum Tg while on l-thyroxine from 783.5 ng/mL in May 2010 to 3686 ng/mL in December 2010 to >5000 ng/mL in March 2011. In March 2011, the patient complained of bone pain in the pelvic region related to bone metastases. MRI of the spine and bone scan showed widespread bone metastases involving skull and several vertebrae in the dorsal, lumbar, and sacral regions. In July 2011, he was admitted with severe constipation, fever, dysuria, and anorexia. He was found to have anemia with hematocrit of 0.24. CT scan of the abdomen showed progression of liver and pancreatic metastases with omental nodules consistent with omental metastases, ascites, and small and large bowel thickening. He also had urosepesis. He received intravenous antibiotics and blood transfusion but his condition deteriorated over the next few days and he died after about 9 years and 8 months of his initial diagnosis with PTC and 20 months after discovery of the pancreatic metastasis.

FIG. 1.

Sagittal (A) and axial (B) views of computed tomography/positron emission tomography (CT/PET) scan showing an 18F-fluorodeoxyglucose focus of uptake in the unicinate process of the pancreas (arrows). An axial view (C) of magnetic resonance imaging of the abdomen shows a well-circumscribed lesion corresponding to the focus seen on CT/PET (arrowhead). An endoscopic-ultrasound-guided biopsy confirmed the diagnosis of pancreatic metastasis from papillary thyroid cancer (see Fig. 2).

FIG. 2.

Histopathological and molecular studies of the pancreatic biopsy specimen, including (A) cell block showing epithelial cells with optically clear nuclei (hematoxylin and eosin 40×), (B) cluster of epithelial cells with high nuclear:cytoplasmic ratio (Papanicolaou [PAP] stain 40×), (C) cells showing irregular nuclear membrane and grooving (PAP stain 100×), (D) immunohistochemical stain for thyroglobulin showing focal positive staining, (E) immunohistochemical stain for thyroid transcription factor 1 (TTF-1) showing strong nuclear staining, (F) part of BRAF exon 15 sequencing showing a heterozygous T1799A nucleotide change of the BRAF ^V600E mutation (arrow).

Discussion

In this report, we have described a middle-aged man with classic type of PTC who underwent total thyroidectomy and neck dissection and received RAI ablation. His disease continued to progress despite three more surgeries and three doses of RAI therapy (cumulative dose 496 mCi). He subsequently developed distant metastases to the lungs that showed no evidence of RAI uptake. The patient eventually developed a pancreatic mass that was discovered on CT/PET scan and confirmed on MRI of the pancreas. The nature of this lesion was confirmed to be metastatic PTC on histopathological examination of an EUS-guided biopsy. Molecular study showed the BRAF ^V600E mutation that is known to be associated with more aggressive forms of the disease (15).

Differentiated thyroid cancer (DTC) has been reported to present initially with distant metastases in about 4% of cases (16). During follow-up, distant metastases develop in 2%–34% of cases (7). The risk of distant metastases is related to the risk group of patients (4,5,17). Elderly patients are more likely to develop distant metastases and die from their disease when it is distantly metastatic (4,5,18). Distant metastases are strongly associated with increased risk of death from DTC (4,5). In patients with distant metastasis, the overall survival is 42% at 10 years, 33% at 15 years, and 29% at 20 years (4,5). The disease-specific survival rates are 40% at 5 years, 27% at 10 years, and 24% at 15 years (4,5). The most common sites for distant metastases in DTC are the lungs and, less commonly, the bones (4,5,19). Other sites are very infrequently involved. Metastases to the abdominal organs are quite rare. The most common site for abdominal metastases is the liver (7). However, metastases from DTC to the liver represent only 0.5% of all distant metastases from DTC and are frequently part of widespread distant metastases to other organs, although isolated liver metastases have been rarely described (7). Pancreatic metastases from DTC are extremely rare. To our knowledge, only seven patients have been identified in the literature (summarized in Table 1). Two of these patients had the tall cell variant of PTC (8 –13). Similar to our patient, most previously reported patients had known advanced DTC with metastases to other organs when they were found to have pancreatic metastases (8 –13). However, Angeles-Angeles et al. described a 72-year-old man whose initial presentation was abdominal pain due to a pancreatic mass that was thought to be a primary pancreatic tumor (8). The patient underwent pancreatectomy, and the histopathological examination showed features consistent with PTC. His investigations revealed PTC in an asymptomatic intrathoracic goiter with metastases to the vertebrae, brain, and pancreas (8).

Table 1.

Summary of the Clinical, Pathological Data and Management and Outcome of the Current Case and the Previously Described Seven Cases of Pancreatic Metastases from Differentiated Thyroid Cancer

References	Age/sex	Tumor type	Other sites of metastases	Dx of pancreatic metastases	Management of pancreatic metastases	Time till Dx of pancreatic metastasis	Follow-up and outcome after Dx of pancreatic metastasis
(8)	72/M	PTC	Vertebrae, brain, mediastinum	CT scan, pancreatic surgery	Distal pancreatectomy, RAI	At presentation	Alive with progression at 8 months
(10)	53/M	TC-PTC	Lungs, vertebrae	CT-guided FNA	Pancreatecoduodenectomy, chemotherapy	14 months	Died ∼2 months later
(12)	62/M	TC-PTC	Lungs, CLN, mediastinum	CT/PET, EUS-FNA	Pancreatecoduodenectomy, RAI	82 months	Alive and stable at 24 months
(9)	34/F	FV-PTC	CLN	PET, pancreatic surgery	Pancreatic tumor enucleation	∼120 months	Alive with progression at 9 months
(9)	46/M	PTC	CLN, lungs, bone	PET, pancreatic surgery	Partial pancreatectomy, RAI	180 months	Died at ∼36 months
(11)	62/M	PTC	CLN, lungs, adrenal, liver, bone	CT scan and endoscopy	Partial pancreatecoduodenectomy	∼72 months	Died at 54 months
(13)	39/F	PTC	Unclear	CT scan, US, pancreatic surgery	Pancreatic surgery (type unclear)	84 months	Unclear
Current case	56/M	PTC	Lungs, mediastinum	CT/PET, EUS-biopsy	Sorafenib	84 months	Died at 20 months

PTC, papillary thyroid cancer; TC-PTC, tall cell variant-papillary thyroid cancer; FV-PTC, follicular variant-papillary thyroid cancer; CLNs, cervical lymph nodes; PET, positron emission tomography; RAI, radioactive iodine therapy; EUS-FNA, endoscopic-ultrasound-guided fine-needle aspiration biopsy; Dx, diagnosis; CT, computed tomography; US, ultrasound.

In most patients, pancreatic metastases and other metastatic foci lose their ability to take up RAI (5,7). Six of the eight patients who have been described in the literature and summarized in this report had non-RAI avid pancreatic metastases (8 –12). In the other two cases, no information on RAI uptake was available. Four cases were discovered on FDG PET or CT/PET scan done for evaluation of elevated Tg (9,12) while the other four cases were diagnosed by abdominal CT scans done for investigation of abdominal complaints (8,10,11,13). Their RAI nonavidity and FDG uptake suggest that these tumors were of a high grade (20). In our patient, this was further supported by the finding of a BRAF ^V600E mutation that had been found to correlate with poor prognosis in most studies (21). Of all the previously reported cases, only two were investigated for the presence of the BRAF ^V600E. Similar to our case, the BRAF ^V600E mutation was found in one case. However, testing for BRAF ^V600E was negative in the other case, and RET/PTC1 rearrangements were not detected in either case (9).

Once found on conventional imaging, pancreatic metastases are best confirmed by obtaining tissue for cytological or histopathological examination. EUS with EUS-guided biopsy is a very useful and easy technique if performed by an experienced endoscopist. This technique is especially sensitive for small pancreatic lesions (<2 cm) that may not be seen on CT scans (22,23). The sensitivity of EUS-guided biopsy ranges between 75% and 90% and is superior to CT-guided FNA (24,25). In our case, it yielded an adequate amount of tissue for cytopatholgical examination and DNA preparation for BRAF ^V600E mutation screening. Our patient is the second of the previously described cases of pancreatic metastases from DTC in which EUS-guided biopsy was used for the diagnosis (Table 1).

Due to the rare occurrence of pancreatic metastases from DTC, the best management for this condition is not clear (7). Since most cases are associated with metastases in other sites, surgical excision, with its attendant risks and limited efficacy, is not a practical solution. However, in cases where metastases are associated with significant compression of the adjacent structures and are causing obstructive jaundice or gastric outlet obstruction, palliative endoscopic or surgical procedures may be necessary. Interestingly, the surgical option was used in most previously described patients, in two patients primarily as a diagnostic procedure and in the other five patients as a therapeutic intervention (Table 1). Each of the previously reported patients had one reason or another to perform surgery. In one patient, the patient presented with abdominal pain and was found to have a pancreatic mass suspected to be a primary pancreatic neoplasm as he was not known to have thyroid cancer (8). In another patient, a pancreatic metastasis from thyroid cancer was considered a low possibility (9). It is unclear why biopsy was not performed in these two patients and pancreatic surgery was chosen as a diagnostic/therapeutic procedure. In another patient, the patient had severe bleeding from a pancreatic metastasis that invaded the duodenal wall and pancreatecoduodenectomy was performed to control bleeding (11). In two patients, surgery was performed due to abdominal pain (10,13). In two other patients, surgery was performed in an attempt to control the disease (9,12). With the exception of one patient who was reported to remain stable at 24 months after surgery (12), the disease progressed in all of these patients and pancreatic surgery did not seem to have had a long-term impact on the course of the disease (Table 1). Fortunately, none of those patients were reported to have suffered operative complications.

Tyrosine kinase inhibitors have been recently introduced for therapy of DTC (26,27). Sorafenib is a small multikinase inhibitor of the BRAF gene product, of platelet-derived growth factor receptor, rearranged in transformation (RET), kit kinase, and vascular endothelial growth factor receptor-2 (28). It was approved by the Food and Drug Administration for the treatment of renal cell and hepatocellular carcinoma. Previously reported phase II trials demonstrated therapeutic efficacy of sorafenib (29,30). Gupta-Abramson et al. reported 68% stability of disease and 32% partial response and progression-free survival of 21 months in patients with metastatsic progressive DTC (29). Kloos et al. reported 61% stable disease, 15% partial response, and 15 months of progression-free survival in patients treated with sorafenib for progressive PTC (30). In a recent trial combining sorafenib as an inhibitor of the mitogen-activated protein kinase (MAPK) pathway and tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other proteins, partial response rate was 4.5%, and stable disease for at least 6 months was 36% (31). In our patient, despite seemingly initial stabilization of the disease in the first 2 months of therapy, clear progression of the disease occurred while he was receiving sorafenib although the pattern of progression seemed to have become more rapid after discontinuation of the drug.

In summary, our patient and the previously described patients showed that pancreatic metastases from DTC can be readily and safely diagnosed with EUS-guided biopsy. Pancreatic surgery is generally ineffective approach for their management although it may have a palliative role but does not affect long-term survival. They are also not RAI responsive and are frequently associated with widespread metastases and poor outcome. This patient did not respond well to sorafenib but further experience is needed to determine the overall response rate to sorafenib in DTC with pancreatic metastases.

Footnotes

Disclosure Statement

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

References

Jemal

, Siegel

, Xu

, Ward

. 2010. Cancer statistics. CA Cancer J Clin, 60:277–300.

Mazzaferri

, Jhiang

. 1994. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med, 97:418–428.

Schlumberger

. 1998. Papillary and follicular thyroid carcinoma. N Engl J Med, 338:297–306.

Dinneen

, Valimaki

, Bergstralh

, Goellner

, Gorman

, Hay

. 1995. Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades. J Clin Endocrinol Metab, 80:2041–2045.

Durante

, Haddy

, Baudin

, Leboulleux

, Hartl

, Travagli

, Caillou

, Ricard

, Lumbroso

, De Vathaire

, Schlumberger

. 2006. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab, 91:2892–2899.

Samaan

, Schultz

, Hickey

, Goepfert

, Haynie

, Johnston

, Ordonez

. 1992. The results of various modalities of treatment of well differentiated thyroid carcinomas: a retrospective review of 1599 patients. J Clin Endocrinol Metab, 75:714–720.

Klubo-Gwiezdzinska

, Morowitz

, Van Nostrand

, Burman

, Vasko

, Soberman

, Wartofsky

. 2010. Metastases of well-differentiated thyroid cancer to the gastrointestinal system. Thyroid, 20:381–387.

Angeles-Angeles

, Chable-Montero

, Martinez-Benitez

, Albores-Saavedra

. 2009. Unusual metastases of papillary thyroid carcinoma: report of 2 cases. Ann Diagn Pathol, 13:189–196.

Borschitz

, Eichhorn

, Fottner

, Hansen

, Schad

, Schadmand-Fischer

, Weber

, Schreckenberger

, Lang

, Musholt

. 2010. Diagnosis and treatment of pancreatic metastases of a papillary thyroid carcinoma. Thyroid, 20:93–98.

10.

Jobran

, Baloch

, Aviles

, Rosato

, Schwartz

, LiVolsi

. 2000. Tall cell papillary carcinoma of the thyroid: metastatic to the pancreas. Thyroid, 10:185–187.

11.

Meyer

, Behrend

. 2006. Is pancreatic resection justified for metastasis of papillary thyroid cancer? Anticancer Res, 26:2269–2273.

12.

Siddiqui

, Olansky

, Sawh

, Tierney

. 2006. Pancreatic metastasis of tall cell variant of papillary thyroid carcinoma: diagnosis by endoscopic ultrasound-guided fine needle aspiration. JOP, 7:417–422.

13.

Sugimura

, Tamura

, Kodama

, Kakitsubata

, Asada

, Watanabe

. 1991. Metastatic pancreas cancer from the thyroid; clinical imaging mimicking non functioning islet cell tumor. Radiat Med, 9:167–169.

14.

Xing

, Tufano

, Tufaro

, Basaria

, Ewertz

, Rosenbaum

, Byrne

, Wang

, Sidransky

, Ladenson

. 2004. Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer. J Clin Endocrinol Metab, 89:2867–2872.

15.

Xing

, Westra

, Tufano

, Cohen

, Rosenbaum

, Rhoden

, Carson

, Vasko

, Larin

, Tallini

, Tolaney

, Holt

, Hui

, Umbricht

, Basaria

, Ewertz

, Tufaro

, Califano

, Ringel

, Zeiger

, Sidransky

, Ladenson

. 2005. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab, 90:6373–6379.

16.

Shaha

, Ferlito

, Rinaldo

. 2001. Distant metastases from thyroid and parathyroid cancer. ORL J Otorhinolaryngol Relat Spec, 63:243–249.

17.

Lundgren

, Hall

, Dickman

, Zedenius

. 2006. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study. Cancer, 106:524–531.

18.

Ruegemer

, Hay

, Bergstralh

, Ryan

, Offord

, Gorman

. 1988. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab, 67:501–508.

19.

Hoie

, Stenwig

, Kullmann

, Lindegaard

. 1988. Distant metastases in papillary thyroid cancer. A review of 91 patients. Cancer, 61:1–6.

20.

Pryma

, Schoder

, Gonen

, Robbins

, Larson

, Yeung

. 2006. Diagnostic accuracy and prognostic value of 18F-FDG PET in Hurthle cell thyroid cancer patients. J Nucl Med, 47:1260–1266.

21.

Xing

. 2005. BRAF mutation in thyroid cancer. Endocr Relat Cancer, 12:245–262.

22.

Nakaizumi

, Uehara

, Iishi

, Tatsuta

, Kitamura

, Kuroda

, Ohigashi

, Ishikawa

, Okuda

. 1995. Endoscopic ultrasonography in diagnosis and staging of pancreatic cancer. Dig Dis Sci, 40:696–700.

23.

Yasuda

, Mukai

, Fujimoto

, Nakajima

, Kawai

. 1988. The diagnosis of pancreatic cancer by endoscopic ultrasonography. Gastrointest Endosc, 34:1–8.

24.

Bhutani

, Hawes

, Baron

, Sanders-Cliette

, van Velse

, Osborne

, Hoffman

. 1997. Endoscopic ultrasound guided fine needle aspiration of malignant pancreatic lesions. Endoscopy, 29:854–858.

25.

Gress

, Gottlieb

, Sherman

, Lehman

. 2001. Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med, 134:459–464.

26.

Sherman

. 2009. Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J Clin Endocrinol Metab, 94:1493–1499.

27.

Cabanillas

, Waguespack

, Bronstein

, Williams

, Feng

, Hernandez

, Lopez

, Sherman

, Busaidy

. 2010. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience. J Clin Endocrinol Metab, 95:2588–2595.

28.

Wilhelm

, Carter

, Tang

, Wilkie

, McNabola

, Rong

, Chen

, Zhang

, Vincent

, McHugh

, Cao

, Shujath

, Gawlak

, Eveleigh

, Rowley

, Liu

, Adnane

, Lynch

, Auclair

, Taylor

, Gedrich

, Voznesensky

, Riedl

, Post

, Bollag

, Trail

. 2004. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res, 64:7099–7109.

29.

Gupta-Abramson

, Troxel

, Nellore

, Puttaswamy

, Redlinger

, Ransone

, Mandel

, Flaherty

, Loevner

, O'Dwyer

, Brose

. 2008. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol, 26:4714–4719.

30.

Kloos

, Ringel

, Knopp

, Hall

, King

, Stevens

, Liang

, Wakely

Jr. , Vasko

, Saji

, Rittenberry

, Wei

, Arbogast

, Collamore

, Wright

, Grever

, Shah

. 2009. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol, 27:1675–1684.

31.

Hong

, Cabanillas

, Wheler

, Naing

, Tsimberidou

, Ye

, Waguespack

, Hernandez

, El Naggar

, Bidyasar

, Wright

, Sherman

, Kurzrock

. 2010. Inhibition of the Ras/Raf/MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies. J Clin Endocrinol Metab, 96:997–1005.