Anaplastic Transformation of Metastatic Papillary Thyroid Carcinoma in a Cervical Lymph Node: a Timeline and Short Review

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ABSTRACT

Anaplastic thyroid cancer (ATC) is accepted as the transformation of a pre-existing glandular papillary thyroid carcinoma (PTC). Anaplastic transformation of a neck PTC metastasis in a lymph node is extraordinary. We present a patient with an exceptional timeline of an untreated neck PTC recurrence in a lymph node and its rare anaplastic transformation.

A 68-year-old patient with PTC and neck metastasis, (stage III/II 7th/8th American Joint Committee on Cancer [AJCC], respectively) underwent thyroidectomy and neck dissection in July 2010, followed with radioiodine treatment (150 mCi) (August 2010). He received an additional 150 mCi in June 2012, because an iodine scan suggested right neck recurrence.

In October 2013, an ultrasound revealed a 2.3 cm, suspicious right neck lymph node (level II–III). Yet only in 2017, after growing to 2.7 cm, the patient consented for a fine needle aspiration. PTC was verified, yet intervention was declined. In June 2018, he presented with a rapid growing neck mass occupying right levels II, III, carotid artery encasement and jugular vein involvement. A large bore needle biopsy revealed a highly malignant tumor, surrounded by necrosis, positive for cytokeratin (CK MNF 116), thyroid lineage marker (PAX8), negative for TTF-1 and thyroglobulin, i.e., ATC. The patient deceased in November 2018. This unique "natural history" of an untreated patient with PTC neck recurrence in a lymph node demonstrated a rare, yet a possible long-term consequence of anaplastic transformation.

This case study, in addition to the sparsity of reported information, may advocate treating PTC neck recurrence.

Keywords: Thyroid carcinoma, papillary; Thyroid carcinoma, anaplastic; Neoplastic cell transformation

INTRODUCTION

Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland (up to 75%) and has a relatively favorable prognosis. On the other hand, anaplastic thyroid cancer (ATC) is rare (1% to 2% of all thyroid malignancies) and is the most aggressive form of thyroid cancer. ATC usually has a poor prognosis with a median survival of 4 to 12 months and a 5-year survival rate of 1.0% to 7.1% (1,2).

Short Communication

Received: Jan 11, 2020 Revised: Mar 14, 2020 Accepted: Mar 18, 2020 Correspondence to Udi Cinamon

Department of Otolaryngology-Head and Neck Surgery, Edith Wolfson Medical Center, Sackler Faculty of Medicine, Tel Aviv University, 5180001 Holon, Israel.

E-mail: [email protected]

Copyright © 2020. Korean Association of Thyroid and Endocrine Surgeons; KATES This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://

creativecommons.org/licenses/by-nc/4.0/).

ORCID iDs Udi Cinamon

https://orcid.org/0000-0002-7195-9636 Yoav Horev

https://orcid.org/0000-0002-0874-5280 Hananya Vaknine

https://orcid.org/0000-0002-4299-9807 Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: Udi Cinamon, Hanan Vaknine; Investigation: Udi Cinamon, Hanan Vaknine; Supervision: Udi Cinamon; Writing - original draft: Udi Cinamon, Hanan Vaknine, Yoav Horev; Writing - review & editing: Udi Cinamon, Hanan Vaknine, Yoav Horev.

Udi Cinamon ¹, Yoav Horev ¹, Hananya Vaknine ²

1 Department of Otolaryngology-Head and Neck Surgery, Edith Wolfson Medical Center, Sackler School of Medicine, Tel Aviv University, Holon, Israel

2 Department of Pathology, Edith Wolfson Medical Center, Sackler School of Medicine, Tel Aviv University, Holon, Israel

Anaplastic Transformation of

Metastatic Papillary Thyroid Carcinoma

in a Cervical Lymph Node: a Timeline

and Short Review

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The pathogenesis of ATC remains unclear. However, anaplastic transformation of pre- existing PTC is considered a well-accepted etiology (2,3).

Most often, anaplastic alterations occur in the primary, thyroid well-differentiated lesion.

Conversely, anaplastic transformation of a PTC metastasis within a lymph node is rare (3,4).

This study offers a well-documented timeline of a metastatic PTC cervical lymph node in a patient that previously had received comprehensive, primary treatment for thyroid PTC with neck metastasis. Yet, a neck recurrence was not treated and transformed into anaplastic carcinoma to which he succumbed.

The following is a short review of anaplastic transformations in cervical and distant metastatic PTC. Some risk factors are suggested.

CASE REPORT

A 68-year-old male underwent total thyroidectomy and bilateral neck dissection due to PTC in July 2010. The pathological diagnosis was classic, conventional PTC with no other remarkable features in the gland or lymph metastasis, (Stage III/Stage II 7th/8th AJCC, respectively (5). A detailed pathological description is presented later on.

Following surgery, the patient received radioiodine treatment (150 mCi, August 2010). A total body iodine scan a year later (2011) showed no residual disease and thryroglobulin blood levels were negative. In 2012, there was a slight thyroglobulin elevation and a follow- up total body iodine scan disclosed a minor absorption in the right neck. An additional radioiodine treatment (150 mCi) was administrated in June 2012. Follow-up with repetitive serum thyroglobulin, thyroglobulin antibodies and ultrasound (US) studies of the neck were negative. In November 2013, an US revealed three suspicious nodes in the right neck (levels II–III) up to 2.3 cm and the serum thyroglobulin level was 3.6 ng/mL. The patient chose not to consent for a diagnostic fine needle aspiration (FNA) or surgery but chose to be monitored by US and thyroglobulin blood levels alone (Fig. 1, October 2014).

Until January 2017, there was only a slight clinical change. Then, US revealed a right neck level III nodular growth to 2.7 cm and the thyroglobulin levels were 5.4 ng/mL. At that time the patient consented and underwent a FNA that verified metastatic PTC. He was offered surgery yet refused. The US from December 2017 demonstrated a slight additional progression in the size of the known metastatic neck lymph node.

In June 2018 the patient attended the clinic with a large mass in his right neck (levels II, III).

He reported that the mass grew significantly over a couple of weeks. US demonstrated a large necrotic mass occupying levels II, III of the right neck. A large bore needle biopsy was diagnostic for ATC. The detailed pathological description is presented later on.

Computed tomography scans of the neck, chest and a positron emission tomography/

computed tomography study were obtained in July 2018. Those were remarkable as they demonstrated an 11 cm heterogenic, partially necrotic mass in the right neck (levels II, III) with a carotid artery encasement, Jugular vein involvement and additional suspicious lymph nodes in levels VI, VII. There were no obvious lung or other distal metastasis (Figs. 2–4).

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At this time surgery was not an option owing to the extent of local spread (especially great vessels involvement), the grave nature of the disease and the patients' general medical condition (ischemic heart disease, hypertension, mild heart failure, mild-moderate renal failure, s/p cerebrovascular accident). He received palliative treatment and carboplatin. The patient passed away in November 2018.

Sublingual nerve Strap muscles

Jugular vein

*

Fig. 1. Axial ultrasound study of the right neck (October 2014). A 2.3×2.3 cm suspicious lymph node (level III) adjacent to the Jugular vein is demonstrated. The right thyroid bed is empty (

*

^).

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Fig. 2. An axial neck computed tomography scan frame (June 2018). An 11 cm mass occupies the right neck, level III (

*

). The mass has central necrosis, encases the carotid artery and involves the Jugular vein.

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The pathological data refers to specimens obtained at three points along the case timeline, the primary specimen, FNA from the neck metastasis and its transformation.

The original pathological specimen of the thyroidectomy and neck dissection (July 2010) revealed a 15 mm focus of PTC in the right lobe with focal necrosis. There were several

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Fig. 3. Coronal computed tomography scan of the neck (June 2018). There is a large mass in the right neck, level III with central necrosis.

Fig. 4. Positron emission tomography/computed tomography imaging (July 2018). The study demonstrates the right massive neck involvement including levels VI, VII. There is no obvious chest involvement.

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additional foci in the left lobe, the largest up to 1.0 cm. There were no other remarkable features. The neck specimen contained numerous metastatic lymph nodes in levels II–VI of both sides. The lymph node ratio (positive nodes/all nodes examined) was 57% (40/70). All specimens (thyroid and nodes) had classic features of the conventional histological variant PTC (Fig. 5A and B).

The FNA from the right neck lymph nodes in January 2017 revealed features of metastatic PTC.

The core needle biopsy from the right neck mass, performed 8 years after primary surgery (June 2018) revealed a highly malignant tumor with an "epithelial" appearance, surrounded by a large quantity of necrotic material (Fig. 5C). It was positive for cytokeratin (CK MNF 116, Fig. 5D), and for the thyroid lineage marker PAX8 (Fig. 5E). TTF-1 and thyroglobulin immunostainings were negative. The diagnosis of ATC was established (6-10).

A B

C

E

D

Fig. 5. Pathological timeline. Histological characteristics: (A) Metastatic PTC in a cervical lymph node (July 2010). The pinkish papillary fronds (thick arrows) can readily be appreciated, embedded within bluish lymphoid tissue containing several reactive germinal centers (thin arrows; H&E stain ×40). (B) On higher magnification, the cytological features of PTC, such as overlapping of nuclei, nuclear inclusions (thick arrows) and clearance (thin arrows), are evident (H&E stain ×100). (C) Anaplastic transformation. The core biopsy from the cervical mass demonstrates a high-grade epithelial tumor surrounded by necrosis (2018). Note the different appearance from the “original” lymph node metastasis (B) (H&E stain ×200). (D) The anaplastic tumor is positive for cytokeratin (CK MNF 116-IHC ×100). (E) PAX 8 demonstrates positive nuclear staining in about 50%–60% of the cells (PAX 8-IHC ×100).

PTC = papillary carcinoma; H&E = haematoxylin and eosin.

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From the histological point of view ATC is not a single entity but a morphologic

“wastebasket” having many morphologic variants. Immunohistochemistry has a paramount role in excluding other “anaplastic” looking tumors, such as melanoma and lymphomas.

DISCUSSION

This study offers a rare, well documented timeline of a metastatic PTC cervical lymph node from its appearance, progress and till its grave late anaplastic transformation.

Generally, anaplastic transformation takes place in the primary PTC thyroid site. Rarely, anaplastic transformation may arise in a cervical PTC nodal metastasis. This occurrence may be presented as a noticeable, rapidly growing cervical mass, as in our case (1,8,11). However, anaplastic transformation in a neck lymph node may be found incidentally in a neck dissection specimen intended to treat a primary thyroid PTC with neck metastasis (4,12).

Ito et al. (4) described 5 patients with primary thyroid PTC presenting or developing an anaplastic transformation in cervical lymph nodes. The size of the primary thyroid lesion was 0.4 and up to 3.5 cm. In 2 patients the anaplastic metastases were found in the initial, primary surgical procedure. The other three cases had a late presentation after 4, 6, and 20 years from primary surgical procedure. Follow-up showed that the two patients who were treated at the primary procedure for their cervical anaplastic metastases were alive after 0.5 and 7 years.

Patients with a late anaplastic transformation died from carcinoma. It is noteworthy that none of the patients received primary radioiodine treatment (4). This report concurs with our case and emphasizes the gravity of a late anaplastic transformation.

There are very few reports describing anaplastic transformations of distant PTC metastasis.

The transformation of multiple PTC lung metastasis were reported in 2 cases, when both had been treated for PTC a decade earlier (13,14). Kim et al. (10) studied a 61-year-old patient who developed ATC in a right pleural metastasis along with a PTC metastasis in the right lung, 19 years after primary treatment for PTC. Sotome et al. (15) reported a case of anaplastic transformation in a retro peritoneal PTC metastasis, presenting 17 years after total thyroidectomy for the primary thyroid PTC. Takeshita et al. (16) reported anaplastic transformation of PTC in liver metastases. Angeles-Angeles et al. (17) described a patient with PTC and pancreatic anaplastic metastasis and another patient with anaplastic transformation of breast PTC metastasis who presented 20 years after thyroidectomy due to PTC. Kaushal et al. (18) described a patient with a pathological fracture of the humerus due to an anaplastic transformation of metastatic PTC which led to diagnosis of the primary thyroid PTC. The patient was operated and received radioiodine. She was free of disease for 8 years.

Sugitani et al. (19) reported a study that investigated a collective database of 677 patients with ATC. Of those, 95 patients had an anaplastic transformation in the neck and 6 with metastatic transformation at a distant site. The data revealed that patients with an incidental finding of anaplastic transformation within a cervical lymph node discovered during the primary surgical procedure had a better outcome than patients with an anaplastic transformation in the thyroid primary PTC. Moreover, anaplastic transformation at a distant site showed the worst outcome. The authors identified some personal characteristics as risk factors regarding the ATC group as a whole: Age ≥70 years, presence of acute symptoms, leukocytosis, having a

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large thyroid tumor >5 cm, and distant metastasis. There was no specific reference to patients with cervical transformation.

Kim et al. (10) reviewed a small number of reported patients with PTC who developed anaplastic transformation in distant metastases. The patients' age was 52–83 and the time lag between distal anaplastic presentation and the treatment for primary PTC was between 5 and 30 years. This information is compatible with data presented by Sugitani et al. (19). Yet, there was no specific data regarding patients with cervical anaplastic transformation.

At this time, there are no recognized patient risk factors regarding anaplastic transformation of cervical metastatic PTC. However, it appears that the patients may share similar

characteristics with those developing distal metastases transformation. Most patient are 60 years or older. The size of primary thyroid PTC in the reported cases was between a micro- carcinoma (less than 1 cm) and up to a T4a. Our patient was 68 years old and had a 15 mm focus of PTC in the right lobe with focal necrosis and several, up to 1.0 cm foci in the left lobe.

Excluding incidental anaplastic transformation found in the neck specimen of initial surgical procedure, there is a long-time lag (years) following primary comprehensive treatment and anaplastic transformation, cervical as well as distal. The presented patient was 68 years old and 10 years were required for his metastatic cervical PTC to transform.

A greater primary cervical lymph node involvement with PTC is associated with increased recurrence and may be related to a more aggressive disease. The lymph node ratio (the proportion of metastatic lymph nodes to all lymph nodes dissected) may have a greater prognostic value, taking into consideration both the extent of primary surgery and cervical metastatic burden (20). In the case presented, the lymph node ratio (positive nodes/all nodes examined) was 57% (40/70). Yet, there is not enough data to designate cervical metastatic load as a prediction for a worse prognosis or to predict anaplastic transformation. Noteworthy is that Ito et al. (4) reported a small number of metastatic cervical PTC nodes in the initial surgery of patients with cervical transformation.

Some authors have suggested an association between radioiodine treatment and an increased probability of anaplastic transformation associated with p53 gene mutation (16,21,22). Indeed, it has been well documented that p53 mutations are common in undifferentiated thyroid tumors (50%–80% in ATCs). Moreover, alterations in the p53 sequence may also play a role in the early stages of thyroid carcinogenesis (23,24). Exposure of individuals to radioiodine released from nuclear reactor accidents has dramatically increased the incidence of PTC (25). Yet, a large number of patients with PTC receive radioiodine treatment and the probability of cause and effect (anaplastic transformation) is quite remote. The association between receiving radioiodine and anaplastic transformation has been tested in a few animal and cell line studies (26,27).

The history of the presented patient may give rise to several risk factors: Male gender, focal necrosis within the main thyroid tumor focus, multifocal and bilateral thyroid lesions and a high cervical lymph node ratio. In addition, the patient received radioiodine treatment (X2) without a long-term impact.

In conclusion, untreated PTC nodular recurrence following comprehensive treatment including radioiodine may have long-term consequences, such as anaplastic transformation.

Although this is a single case study, it advocates the surgical treatment in PTC neck recurrence.

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