|Year : 2019 | Volume
| Issue : 2 | Page : 173-175
Medullary and papillary thyroid carcinomas in a patient with a C634Y mutation in the RET proto-oncogene: A case report
Yan Ding1, Jun Feng2, Xun-hua Xu3, Jun Yao2, Rong-Biao Ying2
1 Department of Radiotherapy, Taizhou Central Hospital, Taizhou, Zhejiang Province, China
2 Department of Surgical Oncology, Taizhou Cancer Hospital, Taizhou Branch of Zhejiang Cancer Hospital, Taizhou, Zhejiang Province, China
3 Department of Pathology, Taizhou Cancer Hospital, Taizhou Branch of Zhejiang Cancer Hospital, Taizhou, Zhejiang Province, China
|Date of Web Publication||2-May-2019|
Department of Surgical Oncology, Taizhou Cancer Hospital, Taizhou Branch of Zhejiang Cancer Hospital, Taizhou, Zhejiang Province
Source of Support: None, Conflict of Interest: None
A 41 year old man presented with a familial history of multiple endocrine neoplasia type 2A (MEN2A) and severe hypertension. Rearranged during transfection (RET) gene sequencing confirmed a Cys634Tyr mutation of TGC to TAC. Total thyroidectomy and bilateral neck dissection were performed and the pathological assessment revealed a medullary thyroid carcinoma (MTC), 0.6 cm in size on the right side (number of lymph nodes: 0/2, 0/15, 0/12, and 0/8 in areas VI, II, III, and IV, respectively) and a papillary thyroid carcinoma (PTC), 0.2 cm in size on the left side (numbers of lymph nodes: 2/6, 0/3, 0/10, and 0/6 in areas VI, II, III, and IV, respectively). There were no pathological changes in the MTC observed in the thyroid tissues on the left side. We believe that the follow-up of patients with both MTC and PTC should utilize a combination of the respective principles for rational disease reassessment.
Keywords: Medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, mutation, papillary thyroid carcinoma, rearranged during transfection proto-oncogene
|How to cite this article:|
Ding Y, Feng J, Xu Xh, Yao J, Ying RB. Medullary and papillary thyroid carcinomas in a patient with a C634Y mutation in the RET proto-oncogene: A case report. Indian J Cancer 2019;56:173-5
|How to cite this URL:|
Ding Y, Feng J, Xu Xh, Yao J, Ying RB. Medullary and papillary thyroid carcinomas in a patient with a C634Y mutation in the RET proto-oncogene: A case report. Indian J Cancer [serial online] 2019 [cited 2019 Jul 21];56:173-5. Available from: http://www.indianjcancer.com/text.asp?2019/56/2/173/257559
| » Introduction|| |
Medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) are derived from parafollicular thyroid cells (C cells) and follicular epithelial cells, respectively. Because of their different origins, the simultaneous occurrence of MTC and PTC is rare in patients with multiple endocrine neoplasia type 2A (MEN2A). However, there have been a few sporadic reports from China on MTC and PTC occurring together. MEN2 patients with simultaneous MTC and PTC have been shown to carry V804l, V804M, L790F, S891A, and C634R mutations in the rearranged during transfection (RET) gene,, but here we report a case of RET C634Y mutation, a common mutation in MEN2A.
| » Case Report|| |
A 41-year-old man was admitted in our hospital for epigastric pain. Three days prior to admission, the patient experienced intermittent epigastric pain, with numbness in the little and third fingers of the left hand. He also complained of hidrosis, nervousness, and hypertension. He had hypertension for 10 years and a family history of MEN2A. He was on captopril tablets, but the control of blood pressure was poor. A physical examination revealed a tumor (1.0 × 1.0 × 1.0 cm3) in the right lobe of the thyroid gland characterized by medium texture, clear border, and ability to move up and down with swallowing. The left lobe of the thyroid gland was not enlarged, and no palpable lymph nodes were detected in the neck. RET gene sequencing indicated a Cys634Tyr mutation of TGC to TAC. A type B ultrasound detected multiple low echoes of nodules (areas of 0.8 × 0.7 cm2 and 0.4 × 0.4 cm2) in the right thyroid, and enhanced spot echoes and low echoes of nodules (area of 0.7 × 0.6 cm2) in the left thyroid, and an enhanced intense spot echo. Furthermore, there were low-echo spots in the bilateral adrenal glands, both in right (2.5 × 2.1 cm2) and left (4.4 × 4.1 cm2) sides. Computed tomography (CT) revealed the presence of the thyroid gland, bilateral adrenal glands, and many tiny lymph nodes in the bilateral neck. Biochemical tests indicated the following: serum calcitonin, 188.00 ng/L (0–8.40 ng/L); carcinoembryonic antigen (CEA), 6.89 ng/mL (0–5.00 ng/mL); serum adrenaline, 241.78 ng/L (0–280.00 ng/L); noradrenaline, 1595.51 ng/L (0–1700.00 ng/L); dopamine, 165.22 ng/L (0–200.00 ng/L); urinary adrenaline, 72.23 μg/24 h (0–20.00 μg/24 h); urinary noradrenaline, 585.41 μg/24 h (10.00–80.00 μg/24 h); and dopamine, 705.84 μg/24 h (53.00–493.00 μg/24 h). Thyroid functions and parathormone levels were normal with no metastasis to the lung, liver, or bones. Bilateral pheochromocytoma was operated on and a pathological evaluation revealed an adrenal pheochromocytoma. Total thyroidectomy and bilateral neck dissection were performed subsequently and the pathological assessment revealed a medullary thyroid carcinoma (MTC), 0.6 cm in size on the right side (number of lymph nodes: 0/2, 0/15, 0/12, and 0/8 in areas VI, II, III, and IV, respectively) and a papillary thyroid carcinoma (PTC), 0.2 cm in size on the left side (numbers of lymph nodes: 2/6, 0/3, 0/10, and 0/6 in areas VI, II, III, and IV, respectively). There were no pathological changes in the MTC observed in the thyroid tissues on the left side [Figure 1]. Immunohistochemistry revealed calcitonin (+), TG (+), CK19 (+), HBME1 (−), and galectin-3 (−) cells in the right thyroid gland tissue, and calcitonin (−), TG (+), CK19 (+), HBME1 (+), and galectin-3 (+) cells in the left thyroid lobe.
|Figure 1: (a) Medullary carcinoma of right thyroid gland (HE ×200); (b) Papillary carcinoma of left thyroid gland (HE ×200); (c) Left lymph node metastasis from papillary carcinoma (HE ×200). HE=Hematoxylin and eosin stain|
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Furthermore, Euthyrox was administered after the operation, and the patient was followed-up for 14 months. It was indicated by B-ultrasound that the bilateral thyroid glands were removed without abnormal lymph nodes in the neck or any lumps in the bilateral adrenal glands. Additionally, the serum calcitonin levels were <2.00 ng/L and CEA levels were 2.37 ng/mL.
| » Discussion|| |
The pathogenesis of inherited MTC and simultaneous PTC is still unclear, and a RET gene mutation causes nearly all cases of the former. Currently, there are two hypotheses: (1) they both arise from the same stem cells, and (2) they originate from different stem cells under multiple internal and external factors, which may interact during the process of tumorigenesis. PTC arises from follicular epithelial cells, whereas MTC originates from parafollicular cells, suggesting that the second hypothesis is more reasonable. Kim et al. have suggested that the merging of MTC with PTC is only incidental, leading to the occurrence of PTC. There are several reports on the concurrence of MTC and PTC in MEN2A; in some series, they were seen in about 30% of the patients. The MTC–PTC association usually occurs in patients with mutations harbored in exons 13 or 14, though in this case, the mutation was in exon 11.
The abnormal expression of the RET gene is not limited to the MTC cases and is also seen in about 20%–40% of the PTC cases. Some studies have suggested that a RET gene mutation not only causes MTC but might also induce PTC. Brauckhoff et al. reported RET gene mutations in eight PTC patients, of whom seven had them in exons 13 and 14. Meanwhile, the imbalance in the levels of RET tyrosine protein kinase can also induce the expression of fusion proteins, such as RET/PTC. Rearrangement of RET/PTC is a common genetic change in PTC, occurring at a rate of 10%-40%. These findings suggest that a RET gene mutation can promote the incidence of simultaneously occurring MTC and PTC.
Shifrin et al. reported 40% incidence of simultaneous MTC and PTC when investigating 15 members of a family with the RET V804M proto-oncogene mutation, and classified this as a new syndrome, MEN2C. However, the ATA, 2015 version guidelines for MTC treatment, does not refer to the correlation between this biological behavior and the ATA-A V804M mutation.
Some researchers have considered herniated simultaneous MTC and PTC to be caused by a BRAF (v-raf murine sarcoma viral oncogene homolog B, BRAF) gene mutation, and not a RET pro-oncogene mutation. A BRAF gene mutation is considered to activate MAPK (Mitogen-activated protein kinase, MAPK) signaling, potentially resulting in the malignant transformation of thyrocytes. Based on its role in tumor growth and thereby the development of PTC, BRAF is not considered to be a promoter of PTC. Instead, it is believed to maintain cell proliferation and differentiation of PTC.
Although BRAF gene mutation and rearrangement of RET/PTC are common in PTC, the two do not overlap. Studies have shown that while the RET gene rearrangement is associated with a V600E mutation of the BRAF gene and the occurrence and development of PTC, a mutation in the RET gene is associated with the occurrence of MTC. However, the significance of the BRAF gene mutations in MTC is controversial.,
The role of environmental factors in the development of PTC and MTC should not be ignored. The incidence of PTC in patients with MTC is related to the intake of iodine. High intake of iodine is associated with a high risk of inducing BRAF gene mutations in patients with PTC. Fiore et al. reported inhibition in the RET/PTC3 expression and an increase in the expression of NIS and thyroid-stimulating hormone receptor (TSHr) in C-cells with RET/PTC3 following treatment with a massive dose of iodine. Thus, recombinant RET/PTC-induced expression of NIS could be a mechanism underlying the development of thyroid carcinoma. The patient in this study lived in the southeastern coastal area with a great abundance of marine products, which are an important source of iodine and could have triggered the development of the PTC.
MEN2A patients with PTC are given the same treatment as patients with herniated MTC. In this case, based on the absence of metastases involving the lymph nodes and calcitonin levels <400 ng/L, we performed a total thyroidectomy and bilateral neck dissection. Had there been metastases to the lymph nodes or calcitonin levels >400 ng/L, we would have continued to examine the lungs, neck, and liver using CT, enhanced CT, or magnetic resonance imaging. If we had detected tiny or no remote metastases, we would have performed a bilateral pheochromocytoma plus neck dissection in the bilateral VI area and the metastatic side. Had the patient presented with severe remote metastases, palliative neck operation or other therapies would have been given to alleviate pain. Serum calcitonin levels need to be checked every year after the operation and levels >150 ng/L would be indicative of postoperative recurrence and metastasis.
Low levels of TSH have important implications in the prognosis of PTC. The NCCN guidelines have established TSH control levels associated with different recurrence risks and have recommended that patients with PTC should continue with thyroid hormone therapy after surgery and after 131I treatment. We believe that the follow-up of patients with both MTC and PTC should utilize a combination of the respective principles for rational disease reassessment.
This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Ethics Committee of Taizhou Cancer Hospital. Written informed consent was obtained from participant.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Machens A, Dralle H. Simultaneous medullary and papillary thyroid cancer: A novel entity? Ann Surg Oncol 2012;19:37-44.
Shifrin AL, Xenachis C, Fay A, Matulewicz TJ, Kuo YH, Vernick JJ. One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: Is this a new syndrome--MEN 2C? Surgery 2009;146:998-1005.
American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, et al
. Medullary thyroid cancer: Management guidelines of the American Thyroid Association. Thyroid 2009;19:565-612.
Hasney CP, Amedee RG. Mixed medullary-papillary carcinoma of the thyroid: A case report. Laryngoscope 2010;120(Suppl 4):S153.
Kim WG, Gong G, Kim EY, Kim TY, Hong SJ, Kim WB, et al
. Concurrent occurrence of medullary thyroid carcinoma and papillary thyroid carcinoma in the same thyroid should be considered as coincidental. Clin Endocrinol (Oxf) 2010;72:256-63.
Fugazzola L, Cerutti N, Mannavola D, Ghilardi G, Alberti L, Romoli R, et al
. Multigenerational familial medullary thyroid cancer (FMTC): Evidence for FMTC phenocopies and association with papillary thyroid cancer. Clin Endocrinol (Oxf) 2002;56:53-63.
Brauckhoff M, Gimm O, Hinze R, Ukkat J, Brauckhoff K, Dralle H. Papillary thyroid carcinoma in patients with RET proto-oncogene germline mutation. Thyroid 2002;12:557-61.
Griffith C, Zhang S, Mukhopadhyay S. Synchronous metastatic medullary and papillary thyroid carcinomas in a patient with germline RET mutation: Case report, molecular analysis, and implications for pathogenesis. Endocr Pathol 2010;21:115-9.
Tang KT, Lee CH. BRAF mutation in papillary thyroid carcinoma: Pathogenic role and clinical implications. J Chin Med Assoc 2010;73:113-28.
Schulten HJ, Al-Maghrabi J, Al-Ghamdi K, Salama S, Al-Muhayawi S, Chaudhary A, et al
. Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNBI in medullary thyroid carcinoma. Anticancer Res 2011;31:4179-83.
Fiore AP, Fuziwara CS, Kimura ET. High iodine concentration attenuates RET/PTC3 oncogene activation in thyroid follicular cells. Thyroid 2009;19:1249-56.
NCCN Guidelines. Thyroid Carcinoma. 2017; Version 2:MS21-2.