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CASE REPORT  
Year : 2014  |  Volume : 57  |  Issue : 4  |  Page : 598-602
Mixed medullary-papillary carcinoma of the thyroid: Report of two cases and review of the literature


1 Department of Endocrinology and Metabolism, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
2 Department of Pathology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey

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Date of Web Publication11-Oct-2014
 

   Abstract 

Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are two distinct types of thyroid carcinoma with considerable difference in terms of cellular origin, histopathological appearance, clinical course and prevalence. The histogenetic origin and possible molecular mechanisms responsible for the development of mixed medullary-papillary carcinoma of the thyroid are still unclear. The most widely accepted hypotheses considering co-occurrence of MTC and PTC are stem cell theory, collision effect theory and hostage theory. Herein we describe two rare cases of mixed medullary-papillary thyroid carcinoma with co-occurrence of MTC and PTC which developed with concomitant MEN 2A and different sites of lymph node metastasis in the first patient, while with atypical clinical presentation in the second patient. In conclusion, co-expression of thyroglobulin, synaptophysin and chromogranin by the papillary component of mixed tumor seems to support stem cell theory in our first case, whereas positive staining for calcitonin but not for thyroglobulin in the medullary component of the tumor along with separation of these two tumors from each other by a normal thyroid tissue seem to indicates the likelihood of collision effect theory in our second case.

Keywords: Collision effect theory, mixed thyroid carcinoma, multiple endocrine neoplasia 2A, stem cell theory

How to cite this article:
Gurkan E, Gurbuz Y, Tarkun I, Canturk Z, Cetinarslan B. Mixed medullary-papillary carcinoma of the thyroid: Report of two cases and review of the literature . Indian J Pathol Microbiol 2014;57:598-602

How to cite this URL:
Gurkan E, Gurbuz Y, Tarkun I, Canturk Z, Cetinarslan B. Mixed medullary-papillary carcinoma of the thyroid: Report of two cases and review of the literature . Indian J Pathol Microbiol [serial online] 2014 [cited 2020 Aug 8];57:598-602. Available from: http://www.ijpmonline.org/text.asp?2014/57/4/598/142684



   Introduction Top


Papillary thyroid carcinoma (PTC) is the most common (75-80%) histological type of differentiated carcinoma of the thyroid. It is derived from follicular cells of endodermal origin and produces thyroglobulin and thyroid hormones. [1] Medullary thyroid carcinoma (MTC) that accounts for 5-8% of thyroid carcinomas is of different embryological origin consisting of parafollicular cells derived from ultimobranchial body of neural crest. [2] MTC is considered amongst the neuroendocrine tumors and releases calcitonin and other hormonal peptides. [2] It is either genetic in nature or may also occur sporadically. Genetic form is classified as familial MTC (FMTC), while manifestations as a thyroid component of multiple endocrine neoplasia (MEN) type 2 is also possible. [2]

Mixed thyroid carcinoma is a rare form (<0.5%) of thyroid cancers. [3] While the primary tumor and also the metastases display combined characteristics of MTC and follicular cell thyroid carcinoma, these two components may also occur concurrently. Progression and prognosis resembles that of MTC, which is considered as the primary component of the tumor. [3],[4] Follicular components of the tumor and the metastases show characteristic radioactive iodine (RAI) uptake seen in thyroid carcinomas derived from follicular cells. [5] Although systemic RAI therapy has been applied in the treatment of these tumors given their characteristic RAI uptake, effective systemic treatment for MTC is not yet available. [2]

Thyroid carcinomas are frequently associated with genetic alterations. Activation of point mutations in RET proto-oncogene has been demonstrated in familial as well as in MEN type 2A and MEN type 2B forms of MTC. [2] As for cases with PTC, somatic RET rearrangement (RET/PTC) has been shown with at least 15 types of RET/PTC rearrangements defined to date in the literature. [1]

Multiple endocrine neoplasia type 2A is a hereditary syndrome characterized by MTC, parathyroid hyperplasia and pheochromocytoma. C-cell hyperplasia or MTC have been identified in all patients with MEN type 2A, while pheochromocytoma was reported in 50% and hyperparathyroidism in 20-30% of the cases. [6] Concomitant presence of mixed thyroid carcinoma and MEN type 2A is rarely seen.

Given that PTC and MTC are two distinct types of thyroid carcinoma with considerable differences in terms of cellular origin, histopathological appearance, clinical course and prevalence; their concomitant presence in the same patient is a quite rare event. Until date, a total of 20 cases have been described in the published medical literature. [7],[8]

Herein, we present two rare cases of mixed MTC-PTC with concomitant MEN type 2A along with codon 634 mutation in RET proto-oncogene and different sites of lymph node metastasis in the first case; and atypical clinical presentation with lack of RET proto-oncogene and MEN components in the second case. Whether the co-occurrence of MTC and PTC in our two cases is coincidental or from possible activation of the common tumorigenic pathway was discussed in the view of the relevant literature considering the most widely accepted hypotheses about the pathogenesis of mixed thyroid tumors including stem cell, collision effect and hostage theories.


   Case Reports Top


Case 1

A 44-year-old male patient presented to the emergency department with a complaint of hyperglycemia and hospitalized due to detection of severe hyperglycemia and positive family history for MEN type 2A. Physical examination was unremarkable except multinodular goiter. Medical history revealed hypertension attacks characterized by dizziness, sweating and palpitation. Urinalysis revealed very high levels for metanephrine upon the high-performance lipid chromatography (HPLC): 6801 mcg/day; normal range (NR): 74-297 mcg and normetanephrine upon (HPLC): 2160 mcg/day (NR: 105-354). Magnetic resonance imaging revealed a 7.0 cm × 6.5 cm right adrenal mass suggestive of pheochromocytoma, while no abnormality was detected in the left adrenal gland.

Fine-needle aspiration biopsy (FNAB) was performed of the multinodular goiter detected in neck ultrasonography (USG) and revealed that nodules in the right (11 mm) and the left (40 mm × 27 mm) lobes had cytopathological findings consistent with MTC. Upon serum levels of calcitonin >700 pg/mL (NR: <15), calcium: 11.1 mg/dL (NR: 8.5-10.2), phosphorus (P): 3.3 mg/dL (NR: 2.7-4.5), parathormone (PTH): 92 pg/mL (NR: 19-65) and 25-OH-Vitamin D: 10.8 ng/dL (NR: >30), along with a 24-h urinary calcium of 447 mg/day (NR: 100-300), primary hyperparathyroidism was diagnosed. The patient was determined to have all components of MEN type 2A. Right adrenalectomy revealed pathological diagnosis of pheochromocytoma with benign characteristics and Pheochromocytoma of the Adrenal gland Scaled Score of 3. After 2 months, the patient underwent surgery for total thyroidectomy and bilateral neck dissection for his tumors of 3.7 cm and 1.5 cm in diameter located at the right and left lobes of the gland, respectively. Pathological diagnosis was mixed thyroid carcinoma [Figure 1] composed of MTC and PTC components. Of the dissected right cervical lymph nodes, 5 were consistent with metastasis of papillary carcinoma and 1 with metastasis of the mixed type. Metastasis of papillary carcinoma was determined in 3 of the dissected left cervical lymph nodes, while findings were consistent with metastasis of MTC in the remaining 2 lymph nodes [Figure 2]. According to the immunohistochemical analysis, staining was positive for thyroglobulin in the papillary component and papillary metastasis of the tumor, for calcitonin in the medullary component and the medullary metastasis of the tumor, for chromogranin and synaptophysin with patchy distribution in both papillary and medullary components and for carcinoembryonic antigen carsinoembriogenic antigen in the medullary components [Figure 3] and [Figure 4]. Amyloid accumulation was identified in the medullary components of the tumor via Kongo staining. Ablation was applied with 175 mCi of RAI for the papillary component of the tumor, while the patient was already receiving calcitriol (0.25 mcg, 2 × 1/day) and calcium replacement therapy for the hypoparathyroidism developed since the early postoperative period. Calcitonin level was 5.1 pg/mL at the third postoperative month.
Figure 1: Thyroid section showing co-occurrence of medullary and papillary thyroid carcinoma, (H and E, ×100)

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Figure 2: Lymph node metastasis by mixed thyroid carcinoma (H and E, ×100)

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Figure 3: Thyroglobulin expression in the tumor cells and colloid like material (immunohistochemistry, ×200)

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Figure 4: Chromogranin expression in the tumors (immunohistochemistry, ×200)

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At the sixth postoperative month, iodine screening was within NR, while stimulated thyroglobulin level was 3.4 ng/dL. Hence, neck USG was performed, and a number of reactive lymph nodes were detected the largest of which was 6 mm on the right side and 10 mm on the left, while not considered in favor of relapse or metastasis. Thoracic computed tomography (CT) was normal. Metastases are still on investigation. RET analysis was consistent with codon 634 and Ser904 polymorphism was evident in his two children, while genetic follow-up was not required. The patient's diabetes is under control with the eventual reduction in the need for insulin.

Case 2

A 77-year-old male patient presented to the general surgery department with the complaint of a growing swelling in the neck and shortness of breath for the last 6 months. History of chronic obstructive pulmonary disease was present, while family history was negative for thyroid carcinoma and MEN syndrome. Physical examination revealed blood pressure of 130/80 mmHg and a solid and fixated 6 cm-sized mass in the right thyroid lobe. There was no palpable lymph node, and Pemberton's sign was negative. Decreased breath sounds were detected bilaterally in the respiratory system examination. Thyroid USG revealed a 4 cm × 4 cm × 7 cm heterogeneous solid nodule in the right thyroid lobe, increased thickness of left thyroid lobe and isthmus with an isoechogenic 8 mm-sized nodule in the left lobe. Laboratory findings were as follows: Free T3, 3.5 pg/mL (in the NR); free T4, 1.29 ng/dL (in the NR); thyroid stimulating hormone (TSH), 0.56 mIU/L (in the NR); anti-TPO, 74 IU/mL (NR: 0-57); anti-TG, <20 IU/mL (NR: 0-64); calcitonin, >750 pg/mL (NR: 0.68-30.2); calcium, 9.9 mg/dL; P - 3.3 mg/dL; PTH-10.7 pg/mL; 25-OH-Vitamin D, 15 ng/mL; fasting blood glucose, 87 mg/dL; creatinine, 0.81 mg/dL; alanine transaminase, 13 U/L; complete blood count, normal findings. FNAB of the right thyroid nodule revealed findings suggestive of MTC. Blood pressure was maintained within normal levels during follow-up. Based on the normal 24-h urine levels of metanephrine (enzyme-linked immunosorbent assay [EL|SA]): 129 mcg/day (NR: 52-341) and normetanephrine (EL|SA): 98 mcg/day (NR: 88-444), the likelihood of MEN type 2 syndrome was ruled out. Furthermore, the patient had no clinical or laboratory findings suggestive of primary hyperparathyroidism.

Screening for metastases revealed <1 cm in size, round shape hypoechoic lesions without echogenic hilus in the bilateral cervical chain consistent with lymphadenopathy along with a 11.0 cm × 4.0 cm right supraclavicular lymphadenopathy. Thoracic CT revealed presence of nodules in the anterior segment of the upper lobe and the medial segment of the middle lobe of the right lung, which were considered as suspected metastases. Abdominal USG was normal, and no findings of metastasis were determined in bone scintigraphy and direct radiographic evaluations. Peri-operative frozen section evaluation was consistent with MTC. The patient underwent total thyroidectomy plus modified radical neck dissection on the right and functional neck dissection on the left. Pathological diagnosis was mixed thyroid carcinoma composed of MTC, and PTC components [Figure 5]. Tumor in the right lobe was 10 cm in diameter extending beyond the thyroid capsule. Carcinoma metastases were identified in 19 lymph nodes on the right, while 20 benign lymph nodes were found on the left. The medullary component of the tumor was stained positively for chromogranin, synaptophysin and calcitonin, while staining was negative for thyroglobulin. Ki-67 index was 5%. On the other hand, staining for thyroglobulin was positive in the papillary component of the tumor. RAI ablation therapy was applied for the papillary component, whereas no effective systemic treatment for MTC is yet available. [4]
Figure 5: Papillary and spindle shaped medullary components of mixed
thyroid carcinoma (H and E, ×100)


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   Discussion Top


Medullary thyroid carcinoma is a very rare and aggressive type of thyroid carcinoma with several distinct features, which set it apart from PTC along with different methods applied in both follow-up and treatment. MTC has a very low cure rate and high rates of relapse and mortality, while no systemic therapy is yet available. [1],[2]

Concomitant presence of MTC and PTC in the same patient is a rare clinical event. The histogenetic origin and possible molecular mechanisms responsible for the development of mixed medullary-papillary carcinoma of the thyroid are still unclear. The most widely accepted hypotheses considering co-occurrence of MTC and PTC are stem cell, collision effect and hostage theories.

Stem cell theory asserts that these two tumors are originated from the similar stem cell is derived from the ultimobranchial body. Being interlocked with each other, these cells show immunoreactivity for both thyroglobulin and calcitonin. This hypothesis was further supported by the demonstration of thyroglobulin and calcitonin co-expression in tumor cells which show a similar pattern of X chromosomal inactivation and molecular alterations such as loss of heterozygosis and mutational situation. [3],[9],[10],[11] The term "composite thyroid carcinoma" has been proposed to designate these neoplasms by the authors who support this theory. [9]

Collision effect theory considers the tumor to be composed of two different and separate components. In a past study concerning retrospective evaluation of 65 cases of mixed medullary follicular cell carcinoma, co-occurrence of follicular cell thyroid carcinoma and MTC in the primary tumor was confirmed pathologically only in 11 of the cases. [12] Owing to the separation of follicular cell thyroid carcinoma and MTC via normal thyroid tissue in most of the published case reports, a coincidental or synchronous co-occurrence has been considered likely. In addition, Rossi et al. recommended the description of "coincidental occurrence" since RET and BRAF mutations were demonstrated by them to develop separately in medullary and follicular components of mixed thyroid carcinomas, respectively. [13] These findings support the presence of different genetic and thereby embryologic origin. The term "collision tumor" has been proposed to designate these neoplasms by the authors who support this theory. [13]

As illustrated in [Figure 6], hostage theory assumes that nonneoplastic follicular cells entrapped by MTC cells are stimulated by trophic factors leading to hyperplastic follicular foci. [11] Acquired genetic defects in follicular cells during proliferation may lead to neoplastic transformation. [11]
Figure 6: Diagram illustrating the "hostage theory" of the evolution of mixed medullary-follicular thyroid carcinomas[11]

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In our first case, co-expression of thyroglobulin, synaptophysin and chromogranin by the papillary component of the mixed tumor seems to support stem cell theory. In our second case, however, calcitonin, but not thyroglobulin was positive in the medullary component along with the separation of these two tumors from each other by a normal thyroid tissue which indicated the likelihood of collision effect theory.

Although the exact pathogenetic mechanisms are not clear, hypotheses about common genetic behavior underlying thyroid malignancies have been suggested. Several genetic and environmental factors have been indicated to act in thyroid oncogenesis either as an inducer or a regulator. While the tumor genesis is initiated by the primary effect, tumor growth is increased by stimulating TSH secretion by the secondary effect. [14]

RET proto-oncogene has been indicated in recent studies to contribute to oncogenesis in MTC and PTC by leading tyrosine kinase activation via point mutation or rearrangement. Germ-line point mutations of RET have been described in patients afflicted by MEN type 2 syndrome or FMTC, strongly suggesting an involvement of RET in the pathogenesis of these diseases. Similarly, in PTC, four oncogenically activated forms of the RET proto-oncogene have been identified. [14]

Inclusion of MEN type 2A components, identification of codon 634 mutation in RET proto-oncogene, characteristics consistent with mixed thyroid carcinoma and presence of different tumor metastases at different lymph nodes were remarkable features in our first case. In our second case RET proto-oncogene was negative as was MEN components, while detected lymph node metastases were consistent with MTC metastasis.


   Conclusion Top


Our findings revealed that in our first case of mixed MTC-PTC, co-occurrence of MTC and PTC was developed with concomitant MEN type 2A along with codon 634 mutation in RET proto-oncogene and different sites of lymph node metastasis. Co-expression of thyroglobulin, synaptophysin and chromogranin by the papillary component of the mixed tumor seems to support stem cell theory in this patient. In our second case with atypical clinical presentation of mixed MTC-PTC, RET proto-oncogene was negative as was MEN components, while detected lymph node metastases were consistent with MTC. Positive staining for calcitonin, but not for thyroglobulin in the medullary component of the tumor along with separation of these two tumors from each other by a normal thyroid tissue seem to indicate the likelihood of collision effect theory in this patient. For the clarification of the exact pathogenesis of this rare form of the tumor, more detailed and comprehensive investigations based on a larger number of cases are needed.

 
   References Top

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Papotti M, Negro F, Carney JA, Bussolati G, Lloyd RV. Mixed medullary-follicular carcinoma of the thyroid. A morphological, immunohistochemical and in situ hybridization analysis of 11 cases. Virchows Arch 1997;430:397-405.  Back to cited text no. 3
    
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DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and Genetics: Tumours of the Endocrine Organs. World Health Organization Classification of Tumours Series. Vol. 8. Lyon, France: IARC Press; 2004.  Back to cited text no. 4
    
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Hales M, Rosenau W, Okerlund MD, Galante M. Carcinoma of the thyroid with a mixed medullary and follicular pattern: Morphologic, immunohistochemical, and clinical laboratory studies. Cancer 1982;50:1352-9.  Back to cited text no. 5
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Cohen MS, Phay JE, Albinson C, DeBenedetti MK, Skinner MA, Lairmore TC, et al. Gastrointestinal manifestations of multiple endocrine neoplasia type 2. Ann Surg 2002;235:648-54.  Back to cited text no. 6
    
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Merchant FH, Hirschowitz SL, Cohan P, Van Herle AJ, Natarajan S. Simultaneous occurrence of medullary and papillary carcinoma of the thyroid gland identified by fine needle aspiration. A case report. Acta Cytol 2002;46:762-6.  Back to cited text no. 7
    
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Mazziotti G, Rotondi M, Manganella G, Franco R, Capone PFRS, Colantuoni V, et al. Medullary thyroid cancer, papillary thyroid microcarcinoma and Graves' disease: An unusual clinical coexistence. J Endocrinol Invest 2001;24:892-6.  Back to cited text no. 8
    
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Apel RL, Alpert LC, Rizzo A, LiVolsi VA, Asa SL. A metastasizing composite carcinoma of the thyroid with distinct medullary and papillary components. Arch Pathol Lab Med 1994;118:1143-7.  Back to cited text no. 9
    
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Ljungberg O, Ericsson UB, Bondeson L, Thorell J. A compound follicular-parafollicular cell carcinoma of the thyroid: A new tumor entity? Cancer 1983;52:1053-61.  Back to cited text no. 10
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Volante M, Papotti M, Roth J, Saremaslani P, Speel EJ, Lloyd RV, et al. Mixed medullary-follicular thyroid carcinoma. Molecular evidence for a dual origin of tumor components. Am J Pathol 1999;155:1499-509.  Back to cited text no. 11
    
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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.  Back to cited text no. 12
    
13.
Rossi S, Fugazzola L, De Pasquale L, Braidotti P, Cirello V, Beck-Peccoz P, et al. Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumour: Report of three cases with molecular analysis and review of the literature. Endocr Relat Cancer 2005;12:281-9.  Back to cited text no. 13
    
14.
Bounacer A, Wicker R, Caillou B, Cailleux AF, Sarasin A, Schlumberger M, et al. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene 1997;15:1263-73.  Back to cited text no. 14
    

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Correspondence Address:
Eren Gurkan
Clinic of Endocrinology and Metabolism, Antakya State Hospital, Hatay
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.142684

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

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