Case Report Thyroid Neuroendocrine Cancer Accompanied with Multiple Papillary Thyroid Carcinomas: a Case Report

Int J Clin Exp Pathol 2016;9(2):2396-2401 www.ijcep.com /ISSN:1936-2625/IJCEP0018900

Case Report Thyroid neuroendocrine cancer accompanied with multiple papillary thyroid carcinomas: a case report

Zengguang Liu1, Meishan Jin2, Chang Su1, Jiang Ren1, Fang Wan1, Qiang Guan3, Zhongying Miao1, Guang Chen1, Guimin Wang1

Departments of 1Thyroid Surgery, 2Pathology, The First Hospital of Jilin University, Changchun, Jilin, China; 3De- partment of General Surgery, The Central Hospital of Changchun City, Changchun, Jilin, China Received October 31, 2015; Accepted December 26, 2015; Epub February 1, 2016; Published February 15, 2016

Abstract: Neuroendocrine tumors (NETs) are neoplasms that arise from the cells of endocrine and nervous systems. Most of them are found in the gastrointestinal tract; however, some cases of NETs have been detected in the thyroid gland, especially the malignant NETs. In this paper, we have reported a case of NET in the thyroid gland; the tumor was accompanied with multiple papillary thyroid cancers. The patient had also developed cervical lymphatic metastasis. Before performing the operation, the lesions were detected by ultrasound examination. However, the pathological results of this case were unexpected. The patient was subjected to FNA examination. Thereafter, we performed total thyroidectomy and cervical lymph node dissection. The diagnosis was confirmed by pathological examinations. PET-CT was also performed after the operation to rule out the occurrence of secondary endocrine cancers.

Keywords: Neuroendocrine cancers, thyroid, papillary thyroid carcinomas

Introduction we have reported a case of NET; the tumor was detected in the thyroid gland, and it was Thyroid cancer is very commonly encountered accompanied by multiple papillary thyroid in clinical practice. In general, papillary thyroid carcinomas. cancer is detected in most cases [1], account- ing for about 75-85% of thyroid malignancies. Case report Although the incidence of papillary thyroid is A 54-year-old woman was admitted to our hos- very high, the prognosis of patients is not very pital as she had developed a slowly growing poor [2]. Lymphatic and distant metastasis are mass in her neck. About a month ago, she had usually detected in patients with multiple accidentally found the cervical mass but she lesions, or in patients diagnosed with other did not experience any pain. There was no malignant tumors; many young children also hoarseness in her voice; she also did not expe- develop lymphatic and distant metastasis [3]. A rience any difficulties in breathing or swallow- high frequency ultrasound is generally used for ing. She did not show any signs of hyper- differentiating malignant nodules from benign metabolism or temperature change. Physical ones in the thyroid gland [4]. examinations revealed a mass in the right upper neck. The mass was located under the Neuroendocrine tumors (NETs) are neoplasms jaw, next to the mastoid process; it was 5.0 cm that arise from the endocrine and nervous sys- × 3.0 cm × 3.0 cm in size. As this mass was oval tems. Most NETs are benign, while some are and smooth, we thought it was a swollen lymph malignant. They are most commonly encoun- node. Therefore, we performed an ultrasound tered in the intestine, where they are often scan to examine the swollen mass. We did not known as carcinoid tumors, but they can also detect any swelling in the thyroid gland through occur in the pancreas, lungs, and the remaining the ultrasound scan; physical examination also organs of the human body [5, 6]. In this paper, did not reveal any masses in the thyroid gland. A rare case of neuroendocrine carcinoma in thyroid gland

Figure 3. The swollen lymph node in level II of the right neck, measuring 4.9 cm × 2.3 cm.

Figure 1. The ultrasonic image of the nodule in the middle of the right lobe. It was further diagnosed as papillary cancer by FNA. Figure 4. The pathological image of neuroendocrine cancer (HE stained, 200 ×).

A cervical ultrasound was also performed on the same day. In this scan, we detected two small hypoechoic nodules in the upper part of the left lobe and the middle part of the right lobe. In the upper part of the left lobe, the nodule was 0.24 cm × 0.34 cm in size. In the middle part of the right lobe, the nodule was 0.63 × 0.71 cm in size (Figure 1). Both these nodules were blurry in appearance as they did not have a clear capsule. The shape of the nodules was irregular; their length was greater than their width. Another solid hypoechoic nodule, measuring 1.0 cm × 0.9 cm in size, was detected in the upper pole of the right lobe (see Figure 2). Figure 2. An ultrasonic image of the nodule located However, it had a clear boundary and was regu- in the upper pole of the right lobe. It was confirmed lar in shape. Furthermore, we also detected as neuroendocrine cancer. several swollen lymph nodes in level II of the right neck. The biggest lymph node was 4.9 cm × 2.3 cm in size (see Figure 3). The lymph nodes were heterogeneous and solid; these lymph nodes had clear boundaries. An enhanced cervical CT examination was also performed. Thus, we detected several low-den- sity areas of nodules; the biggest nodule was 1.4 cm × 0.7 cm in size; it was located in the upper pole of the right lobe. Several heterogeneous soft tissues of nodules were enhanced in the oropharynx, which was located in the right parapharyngeal space; the biggest nodule was 4.3 cm × 2.7 cm × 2.3 cm. No positive results were detected while performing chest radiography or laryngoscope examination. The results of the laboratory tests and the refer- ence ranges were listed as follows: TSH: 3.46 uIU/ml (0.27-4.2), FT3: 4.44 pmol/L (3.1-6.8),

2397 Int J Clin Exp Pathol 2016;9(2):2396-2401 A rare case of neuroendocrine carcinoma in thyroid gland

Figure 5. A-F: The immunohistochemical results of the nodule: Tg (-), CgA (+), MaxVison Syn (+), MaxVisonTTF-1 (+), MaxVisonCalcition (-), MaxVisonKi-67: 40%+.

FT4: 16.24 pmol/L (12.0-22.0), TG-Ab: 73.36 nodes were considered to be metastatic in IU/ml (< 115.0), TPO-Ab: 27.09 IU/ml (< 35.0). nature. Subsequently, we also performed total The levels of parathyroid hormone, carcino- thyroidectomy and cervical lymph node dissec- embryonic antigen, and calcitonin were tion. During the operation, we excised several normal. lymph nodes surrounding the right jugular vein; the biggest lymph node was 5.0 cm × 3.0 cm in Fine needle aspiration (FNA) biopsy was per- size. Frost pathological examination of the formed on the nodule located in the middle of lymph nodes indicated that the carcinoma was the right lobe; thyroid papillary cancer was poorly differentiated. A similar nodule was detected in the biopsy, so the swollen lymph found in the upper pole of the right lobe of the

2398 Int J Clin Exp Pathol 2016;9(2):2396-2401 A rare case of neuroendocrine carcinoma in thyroid gland thyroid. It had many necrotic cells, and signs of (NEC), are divided into three types according to fission were detected in the pathological imag- the extent of their differentiation. The well dif- es (see Figure 4). The immunohistochemical ferentiated NECs are also called carcinoids, results of the nodule were as follows: Tg (-), CgA while the moderately differentiated NECs are (+), Syn (+), Calcition (-), Ki-67 (+, 40%), TTF (+), called atypical carcinoids. Furthermore, the HBME-1 (+) (see Figure 5). Thus, we confirmed poorly differentiated NECs are called small cell that the patient had developed neuroendocrine carcinomas. cancer in the thyroid gland. Another four micro papillary carcinomas were detected in the rest In very rare cases, we have detected NETs in of the thyroid gland; two papillary carcinomas the thyroid glands. The origin of these tumors were found in the right lobe (measuring 0.2 cm has been associated with various kinds of cells, and 0.7 cm in length and width, respectively) including the parafollicular cells, paraganglion and the other two papillary carcinomas were cells, and parathyroid gland [11]. According to found in the left lobe (both measuring 0.2 cm in their origin in the thyroid gland, NETs are divid- length). The immunohistochemical results of ed into six groups: parafollicular tumors, para- the four nodules were as follows: Tg (+), CgA (-), ganglion tumors, complex tumors originating Syn (-), Ki-67 (+, < 5%), HBME-1 (+). from both follicular and parafollicular cells, parathyroid tumors, secondary NETs, and In order to determine whether neuroendocrine NECs. Compared with NETs, NECs are found in carcinoma had developed in other parts of the extremely rare cases. After searching the data- patient’s body, we performed positron emis- base of our hospital, we found that only this sion tomography-computed tomography (PET- case was finally diagnosed with NECs out of a CT) scanning of the patient. The results of the total of 12100 patients, who had undergone scan were negative. So, the final diagnosis of surgical treatment from December, 2009 to this patient was primary neuroendocrine can- April, 2015. cer accompanied with multiple thyroid papillary cancers and cervical lymph node metastasis. Most of the patients with NETs were older than The patient was prescribed an oral tablet of 65 years [8]. In the early phase, the hormone sinistral thyroxine to inhibit the function of the produced by the tumor was very low. As a result, thyroid gland, and I131 radiotherapy treatment very few of these patients showed symptoms was provided to the patient. Six months after related to NETs. In this case, the patient was the operation, no positive findings were detect- admitted at our hospital because she had ed during the follow-up. developed a slowly growing mass in the neck. Using various diagnostic techniques, we con- Discussion firmed that swollen mass actually consisted of several swollen lymph nodes. NETs arise from neuroendocrine cells, which are widely distributed in many tissues of the The diagnosis of thyroid NECs includes the fol- body. The functions of neuroendocrine cells are lowing two aspects: 1) The tumor arises from similar to those of neurological and endocrinal the thyroid gland; 2) The tumor fulfills the crite- cells. So, NETs can also develop in many other ria of diagnosing NECs. Before performing the organs of the human body [7]. The incidence of operation, it is very difficult to make a correct NETs is quite low; according to the reports of diagnosis of thyroid NCEs. Most of the cases Jan Maarten, about 25 cases of NETs are are diagnosed on the basis of immunohisto- detected in a population of 1000,000 [8]. Most chemical examinations. NECs are found to be of the NETs (about 76%) are found in the gastro- positive in NSE, CgA, and Syn. The expression intestinal tract, lung, and bronchus [2, 9]. of Ki-67 is associated with the differentiation of Although there are many kinds of NETs, they NECs. In this case, the NECs were poorly differ- are treated as a group of tissues, because the entiated, because the expression of Ki-67 was cells of these neoplasms share common fea- higher than 40%; however, in papillary thyroid tures, such as similar appearance and special cancer tissues, the expression of Ki-67 was secretory granules. Moreover, they often pro- lower than 5%. In pathological images, poorly duce biogenic amines and polypeptide hor- differentiated NECs have small cells; these mones [10]. Malignant neuroendocrine tumors, cells have a deeply stained, round nucleus. For also known as neuroendocrine carcinomas example, consider the case of “small blue cell

2399 Int J Clin Exp Pathol 2016;9(2):2396-2401 A rare case of neuroendocrine carcinoma in thyroid gland tumors”; these tumors contain uniform cells, patient had developed a poorly differentiated which have a round to oval shaped nucleus and tumor. Both the metastatic lymph nodes and a scanty cytoplasm consisting of pink granules. the poorly differentiated tumor are insensitive There can be anaplasia, mitotic activity, and to chemoradiotherapy. necrosis in these tumor cells. High power examination exhibits bland cytopathology. Electron Disclosure of conflict of interest microscopy can identify secretory granules, which are vital to make a correct diagnosis of None. the case. In this case, the patient underwent PET-CT examination after the surgery. No other Address correspondence to: Dr. Guimin Wang, De- tumors were detected in this scan. Although partment of Thyroid Surgery, The First Hospital of the tumor tested negative in Tg, it was positive Jilin University, 71 Xinmin Avenue, Chaoyang Dis- in TTF-1, CgA, and Syn. So, it was finally con- trict, Changchun 130021, China. Tel: (+86) 431- firmed that the patient had developed NECs in 81875286; E-mail: [email protected] the thyroid gland. Two similar cases were reported by Eusebi V in 1992 [12]. References

Medullary thyroid cancer (MTC) is a form of thy- [1] Dinets A, Hulchiy M, Sofiadis A, Ghaderi M, roid carcinoma that originates in the parafollic- Höög A, Larsson C, Zedenius J. Clinical, genet- ic, and immunohistochemical characterization ular cells (C cells), which produce the hormone of 70 Ukrainian adult cases with post-Chor- calcitonin. Medullary tumors are the most com- nobyl papillary thyroid carcinoma. Eur J Endo- monly seen thyroid NETs; they are the third crinol 2012; 166: 1049-60. most common type of thyroid cancers. They [2] Quaedvlieg PF, Visser O, Lamers CB, Janssen- make up about 3% of all thyroid cancer cases Heijen ML, Taal BG. Epidemiology and survival [13]. We have also come across cases in which in patients with carcinoid disease in The Neth- MTCs tested negative for calcitonin [14]; how- erlands. An epidemiological study with 2391 ever, most of these cases have a family history patients. Ann Oncol 2001; 12: 1295-300. of hyperplasia in the parafollicular cells. In this [3] Vermeer-Mens JC, Goemaere NN, Kuenen- case, the tumor tested negative for calcitonin; Boumeester V, de Muinck Keizer-Schrama SM, but we also did not detect a hyperplasia of Zwaan CM, Devos AS, de Krijger RR. Childhood parafollicular cells. papillary thyroid carcinoma with miliary pulmo- nary metastases. J Clin Oncol 2006; 24: 5788- Secondary thyroid NECs originates from the tis- 9. [4] Grani G, Fumarola A. Thyroglobulin in lymph sues of thyroid gland. We performed a thorough node fine-needle aspiration washout: a sys- literature search to determine the incidence of tematic review and meta-analysis of diagnostic secondary thyroid NECs; only 9 cases were accuracy. J Clin Endocrinol Metab 2014; 99: reported until February, 2012 [15-23]. Most 1970-82. cases of secondary thyroid NEC originated from [5] Gustafsson BI, Kidd M, Chan A, Malfertheiner the larynx and long tissue [23]. Cytologically MV, Modlin IM. Bronchopulmonary neuroendo- and pathologically, secondary NETs are similar crine tumors. Cancer 2008; 113: 5-21. to those of MTCs [16, 20, 21]. However, sec- [6] Oberg K, Jelic S. Neuroendocrine bronchial ondary NETs are negative in calcitonin and and thymic tumors: ESMO clinical recommen- CEA, while MTCs are positive. In this case, dation for diagnosis, treatment and follow-up. when the patient underwent PET-CT examina- Ann Oncol 2008; 19 Suppl 2: ii102-3. tion after the surgery, no other NETs were [7] Jacobs C. Neuroendocrine tumors a rare find- ing: part I. Clin J Oncol Nurs 2009; 13: 21-3. found. So, we propose that the patient had [8] van der Zwan JM, Trama A, Otter R, Larrañaga developed primary NEC in the thyroid gland. N, Tavilla A, Marcos-Gragera R, Dei Tos AP, Baudin E, Poston G, Links T; RARECARE WG. Surgery is the conventional treatment in cases Rare neuroendocrine tumours: results of the diagnosed with poorly differentiated thyroid surveillance of rare cancers in Europe project. NECs. The invasiveness of such NECs is very Eur J Cancer 2013; 49: 2565-78. strong, especially tumors that test negative for [9] Biering H, Pirlich M, Bauditz J, Sandrock D, calcitonin [24]. In our case, the prognosis of the Lochs H, Gerl H. PET scan in occult ectopic patient was unfavorable, as there was metasta- ACTH syndrome: a useful tool. Clin Endocrinol sis of the cervical lymph nodes. Moreover, the (Oxf) 2003; 59: 404-5.

2400 Int J Clin Exp Pathol 2016;9(2):2396-2401 A rare case of neuroendocrine carcinoma in thyroid gland

[10] Ramage JK, Davies AH, Ardill J, Bax N, Caplin [17] Mattavelli F, Collini P, Pizzi N, Gervasoni C, Pen- M, Grossman A, Hawkins R, McNicol AM, Reed nacchioli E, Mazzaferro V. Thyroid as a target of N, Sutton R, Thakker R, Aylwin S, Breen D, Brit- metastases. A case of foregut neuroendocrine ton K, Buchanan K, Corrie P, Gillams A, Lewing- carcinoma with multiple abdominal metasta- ton V, McCance D, Meeran K, Watkinson A; ses and a thyroid localization after 21 years. UKNETwork for Neuroendocrine Tumours. Tumori 2008; 94: 110-3. Guidelines for the management of gastroen- [18] Bhalla R, Popp A, Nassar A. Case report: meta- teropancreatic neuroendocrine (including car- static renal carcinoid to the thyroid diagnosed cinoid) tumours. Gut 2005; 54 Suppl 4: iv1-16. by fine needle aspiration biopsy. Diagn Cytopa- [11] Baloch ZW, LiVolsi VA. Unusual tumors of the thol 2007; 35: 597-600. thyroid gland. Endocrinol Metab Clin North Am [19] Yamada H, Hasegawa Y, Mitsudomi T, Nakashi- 2008; 37: 297-310, vii. ma T, Yatabe Y. Neuroendocrine tumor metas- [12] Eusebi V, Damiani S, Riva C, Lloyd RV, Capella tasis to the thyroid gland. Int J Clin Oncol 2007; C. Calcitonin free oat-cell carcinoma of the thy- 12: 63-7. roid gland. Virchows Arch A Pathol Anat Histo- [20] Maly A, Meir K, Maly B. Isolated carcinoid tu- pathol 1992; 417: 267-71. mor metastatic to the thyroid gland: report of a [13] DeLellis RA, Rule AH, Spiler I, Nathanson L, case initially diagnosed by fine needle aspira- Tashjian AH Jr, Wolfe HJ. Calcitonin and carci- tion cytology. Acta Cytol 2006; 50: 84-7. noembryonic antigen as tumor markers in [21] Papi G, Corrado S, Carani C, Asa SL. Metasta- medullary thyroid carcinoma. Am J Clin Pathol sis of a caecal neuroendocrine carcinoma to 1978; 70: 587-94. the thyroid gland. J Clin Pathol 2005; 58: [14] Modigliani E, Cohen R, Campos JM, Conte-De- 1342-3. volx B, Maes B, Boneu A, Schlumberger M, Big- [22] Sivrikoz E, Ozbey NC, Kaya B, Erbil Y, Kaya S, orgne JC, Dumontier P, Leclerc L, Corcuff B, Yilmazbayhan D, Firat P, Kapran Y. Neuroendo- Guilhem I. Prognostic factors for survival and crine tumors presenting with thyroid gland me- for biochemical cure in medullary thyroid carci- tastasis: a case series. J Med Case Rep 2012; noma: results in 899 patients. The GETC Study 6: 73. Group. Groupe d’etude des tumeurs a calcito- [23] Matias-Guiu X, LaGuette J, Puras-Gil AM, Rosai nine. Clin Endocrinol (Oxf) 1998; 48: 265-73. J. Metastatic neuroendocrine tumors to the [15] Massani M, Caratozzolo E, Bridda A, Ruffolo C, thyroid gland mimicking medullary carcinoma: di Pinto FC, Bonariol L, Rossi S, Bassi N. Iso- a pathologic and immunohistochemical study lated thyroidal metastasis as primary manifes- of six cases. Am J Surg Pathol 1997; 21: 754- tation of pancreatic neuroendocrine carcino- 62. ma. Pancreas 2010; 39: 1113-4. [24] Eusebi V, Damiani S, Riva C, Lloyd RV, Capella [16] La Rosa S, Imperatori A, Giovanella L, Garan- C. Calcitonin free oat-cell carcinoma of the thy- cini S, Capella C. Thyroid metastases from typi- roid gland. Virchows Arch A Pathol Anat Histo- cal carcinoid of the lung differentiating be- pathol 1990; 417: 267-71. tween medullary thyroid carcinoma and neuroendocrine tumor metastasis to the thyroid. Thyroid 2009; 19: 521-6.

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